Cardiovascular & hematological disorders drug targets最新文献

The COVID-19 pandemic has revealed various long-term cardiovascular complications linked to increased inflammatory responses, particularly through Interleukin-6 (IL-6) activity. IL-6 is a major cytokine in the immune system that plays a bimodal role: it supports acute immune defense but contributes to chronic inflammation and tissue damage when dysregulated. High levels of IL-6 during and after COVID-19 are linked with poor outcomes, such as Acute Respiratory Distress Syndrome (ARDS), myocarditis, endothelial dysfunction, and thrombotic events. Chronic IL-6 signaling impairs vascular homeostasis, leading to endothelial dysfunction and increased thrombosis. Viral and cytokine-driven inflammation leads to endothelial damage caused by COVID-19. These include mechanisms that implicate the downregulation of ACE2, oxidative stress, and reduced bioavailability of nitric oxide. All these contribute to arterial stiffness, atherosclerosis, and thrombosis. It is possible to reduce the risk of heart disease by using targeted therapies, such as IL-6 inhibitors, which can help reduce inflammation. Biomarkers of endothelial health and inflammation include EPCs and CECs. Pharmacological strategies, such as RAS inhibitors and statins, may have additive effects on endothelial function, but ACE2 upregulation remains a major question. Rehabilitation and exercise-based approaches are further supportive of vascular recovery. When IL-6 activity stays high after an infection, it causes blood to clot too easily and cause thrombotic problems. This makes patients more likely to experience an ischemic stroke or pulmonary embolism. Anticoagulants and IL-6 inhibitors like tocilizumab reduce these risks. IL-6's long-term effects on the heart need to be studied more, and biomarker screening, lifestyle changes, and personalized therapies must be used to prevent heart disease as much as possible. A holistic management approach that integrates anti-inflammatory and anticoagulation strategies will significantly improve outcomes in survivors of COVID-19.

Introduction: Oroxylin A is primarily sourced from the roots of Scutellaria baicalensis, a medicinal plant commonly used in traditional Chinese medicine. It can also be found in other Scutellaria species. The plant's rich bioactive profile makes it a significant source of various flavonoids, including Oroxylin A.

Aims: The proposed aim of this study is to investigate in-vitro anti-oxidant activity, toxicity studies and in-vitro cardioprotective activity of Oroxylin-A against Doxorubicin mediated myocardial damage on H9c2.

Methods: The total phenolic content was estimated using Folin-Ciocalteu test and in-vitro activity was performed using DPPH assay. Acute toxicity studies were performed according to OECD 423 guidelines. In vitro cardioprotective activity was performed on H9c2 cells and was estimated for the biomarkers.

Results: Oroxylin-A showed good antioxidant activity. No abnormalities were found in animals upon its usage, indicating that Oroxylin-A was safe at 2000 mg/kg. 150ug/ml of Oroxylin-A significantly increased the cell viability up to 99% and also decreased the LDH and ROS generation indicating that Oroxylin-A showed significant cardioprotective activity on H9c2 cells.

Discussion: Oroxylin-A demonstrated potent antioxidant and cardioprotective effects by reducing ROS generation and LDH release while enhancing H9c2 cell viability against doxorubicininduced toxicity. Its safety at higher doses further supports its therapeutic potential. These findings highlight Oroxylin-A as a promising natural cardioprotective agent, warranting further in vivo and mechanistic studies to validate its clinical applicability.

Conclusion: This research underscores the potential of Oroxylin A as a candidate for further investigation as a cardioprotective agent. Also, the present study contributes to the growing body of knowledge aimed at identifying natural compounds that may offer protective effects against myocardial damage, providing hope for future therapeutic interventions in the field of cardiovascular medicine.

Introduction: Metabolism dysfunction associated with fatty liver disease During metabolic hepatic inflammation (MAFLD), is characterized by systemic metabolism deregulation leading to increased hepatic erythrophagocytosis and subsequent iron overload and ferroptosis. Studies in animal models have shown that erythrocyte phosphatidylserine exposure drives erythrophagocytosis. However, the mechanism of erythrophagocytosis in human MAFLD has not been fully elucidated yet. Therefore, in this study, we explored the opsonins recognizing phosphatidylserine. In particular, we measured the levels of erythrocyte calreticulin, lactadherin, mannose-binding lectin, and thrombospondin-1.

Methods: Twenty-four patients (15 men and 9 women) with MAFLD and 9 healthy controls (4 men and 5 women) were enrolled. Erythrocytes were isolated from EDTA-containing blood through multiple centrifugations and isotonic buffer. Protein levels were measured in erythrocyte lysates (triton X-100 0.1% v/v) or plasma with enzyme-linked immunosorbent assays.

Results: Erythrocyte TSP-1 levels were reduced in MAFLD patients. This reduction was not followed by changes in plasma TSP-1 levels or erythrocyte calreticulin, lactadherin, and mannose- binding protein.

Discussion: Our results suggest that erythrophagocytosis in human MALFD, unlike animal models, is not mediated by opsonization of exposed phosphatidylserine.

Conclusion: Our study underlines the need for disease models that could better reflect the molecular pathogenesis of human MAFLD.

Introduction: Acute lymphoblastic leukemia (ALL), a hematopoietic cancer of T or B lymphoblasts, is the most prevalent cancer in children. Ongoing research aims to better understand the factors contributing to ALL and create more successful treatment options. Therefore, the current study presented cytogenetic, genetic, and hematologic features from 318 ALL patients under eighteen years of age who were referred to Ali Asghar Hospital of Tehran, Iran, from 2013 to 2023.

Methods: This study was designed as a retrospective cross-sectional analysis, focusing on 318 children in Tehran, Iran, who had been newly diagnosed with ALL. All data were extracted from the patient case files that included additional information, such as clinical data, and demographic information. The Flow cytometry technique was employed to perform immunophenotyping for various markers. Moreover, the standardized protocol was carried out for conventional cytogenetic analysis.

Results and discussion: Out of 318, 179 (56.3%) and 139 (43.7%) were males and females, respectively. The most common subtype of ALL was Common B Cell ALL, accounting for 182 cases (57.23%), followed by Pre B cell ALL with 74 cases (23.27%) and T cell ALL with 27 cases (8.49%). Out of 222 patients, 17 (7.7%) had genetic abnormalities, with the highest incidence of abnormalities being associated with Runx 1 (four cases). Additionally, out of 228 patients, 143 (62.7%) were identified as having cytogenetic abnormalities, with the most prevalent abnormalities being hyperdiploidy (54 cases) and t (12;21) (28 cases).

Conclusion: Our findings showed that some cytogenetic abnormalities, such as t (9;22) and hyperdiploidy, were consistent with previous studies. These results offer valuable foundational insights that can help direct future research on ALL patients and inform potential treatment strategies.

Background: Casimiroa edulis La Llave (Rutaceae), commonly known as "zapote blanco", is a tree widely distributed in Mexico's tropical and subtropical areas. The decoction of its leaves is traditionally used as a natural remedy to treat hypertension and anxiety.

Objectives: The present study aimed to determine the vasorelaxant and antihypertensive effects of C. edulis extracts and evaluate the acute and sub-acute toxicity of one of the most active extracts.

Methods: The hydro-alcohol and organic (hexane, dichloromethane, and methanol) extracts, obtained from the leaves of C. edulis, were evaluated on isolated aorta rat rings in the presence and absence of endothelium to determine their vasorelaxant effect. Then, most active extracts were studied to evaluate the functional mechanism of their vasorelaxant action and antihypertensive effect on spontaneously hypertensive rats (SHR). The acute and sub-acute toxicity of dichloromethane extract was evaluated following the OECD 423 and 407 protocols.

Results: The hexane (HE) and dichloromethane (DE) extracts from Casimiroa edulis induced significant vasorelaxant action on isolated rat aortic rings with (Emax 104.7 ± 1.4% and Emax 97.3 ± 6.7%, respectively) and without (Emax 94.9 ± 3.5% and Emax 67.4 ± 1.0%, respectively) endothelium, and this effect was partially endothelium-dependent. Their vasorelaxant action was modified by L-NAME (nitric oxide synthase inhibitor) and ODQ (soluble guanylyl cyclase inhibitor); however, indomethacin did not modify the effect. Also, both HE and DE significantly decreased the contraction induced by KCl in a concentration-dependent manner and the maximal effect induced by CaCl2. Moreover, DE showed a significant decrease in systolic and diastolic blood pressure in SHR at 7 hours and 15 days after treatment, respectively. Finally, the toxicity test of DE allowed classifying it in category 5, indicating it to be a non-toxic extract based on OECD guideline 423; the LD50 value was estimated to be greater than 2,000 mg/Kg and smaller than 5,000 mg/Kg in Wistar rats.

Conclusion: The results demonstrated hexane and dichloromethane extracts to exert a vasorelaxant effect through endothelium-dependent NO release and cGMP increase, as well as by calcium channel blockade. Also, dichloromethane extract showed efficacy and security as a potential antihypertensive agent.

Introduction: POEMS syndrome is a rare multisystem disorder associated with plasma cell dyscrasia and abnormal cytokine production, including vascular endothelial growth factor (VEGF). The mandatory criterion for its diagnosis includes polyneuropathy and monoclonal plasma cell disorder, along with other major and minor criteria. This case highlights the diagnostic and therapeutic challenges of POEMS syndrome by depicting the case of a 61-year-old male with progressive sensory-motor polyneuropathy, lymphadenopathy, and splenomegaly.

Case presentation: The patient presented with a year-long history of bilateral limb weakness and sensory disturbances, accompanied by abdominal distention, weight loss, and other systemic symptoms. Clinical examination revealed skin hyperpigmentation, splenomegaly, and a right axillary lymph node enlargement. Neurological evaluation showed distal limb hypotonia, absent reflexes, and sensory deficits. Diagnostic investigations, including nerve conduction studies, imaging, and bone marrow biopsy, confirmed POEMS syndrome based on polyneuropathy, monoclonal IgG lambda plasma cells, Castleman disease, sclerotic bone lesions, elevated VEGF, and minor criteria, such as endocrinopathy and skin changes. The treatment comprised lenalidomide and dexamethasone, resulting in significant improvement at the three-month follow-up, including normalized VEGF levels and resolution of ascites.

Conclusion: This case highlights the necessity of identifying the many presentations of POEMS syndrome for prompt diagnosis and treatment. Despite its rarity and diagnostic complexity, prompt treatment can significantly improve clinical outcomes. POEMS syndrome should be considered in patients with unexplained neuropathy and systemic features, enabling better outcomes through targeted therapies.

Erythrocytes constitute the main cell type of the blood, contain the majority of the iron in the body, and have a high turnover rate. Erythrocyte death and subsequent degradation lead to ferroptosis. In this context, modifications of the erythrocyte plasma membrane lipidome are instrumental to the phenomenon. Thus, phospholipase A2, phospholipase D, lysophospholipase D, sphingomyelinase, ceramidase, and sphingosine kinase acting together orchestrate a major membrane structural rearrangement, leading to phosphatidylserine exposure, reduced deformability, and band 3 clustering. Band 3 clustering may lead to antibody and complement opsonization, CD47 conformational change, and phosphatidylserine exposure. Meanwhile, arginine, glutamine, and adenosine metabolism modulate the anti-oxidant capacity of erythrocytes, thus impacting phosphatidylserine exposure and chemokine release. Metabolism-induced augmented erythrophagocytosis accompanied by insufficient upregulation of heme oxygenase-1 and iron retention due to inflammatory signals lead to iron-dependent lipid peroxidation. Neudesin, interleukin 33, interleukin 18, TNF-α, interleukin 6, prostaglandins, epinephrin, itaconate, and hepcidin influence the capacity of the macrophage to manipulate iron. BACH1, NRF2, and SPIC are the main transcription factors implicated in the regulation of the expression of heme oxygenase-1 and ferroportin. Insufficient adaptation of the metabolism of the cell to neutralize lipid peroxides leads to iron-dependent programmed lytic death, called ferroptosis. As a result of ferroptosis, damage-associated molecular patterns and lipid peroxides are released, activating the neighboring immune cells and triggering inflammation. Erythrophagocytosis-induced ferroptosis has been recognized as a main mechanism eliciting the metabolism dysfunction associated with steatohepatitis, atherosclerosis, uremia, and other pathogenic states. A better understanding of the molecular mechanisms implicated in the process could bring forward potential novel therapeutic targets. In this mini-review, the current literature is summarized with regard to the immunometabolic mechanisms that mediate erythrophagocytosis-induced ferroptosis and inflammation.

Recent cardiovascular outcome trials (CVOTs) have reshaped the therapeutic landscape of type 2 diabetes mellitus (T2DM), revealing that certain glucose-lowering agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), offer substantial cardiovascular benefits beyond glycemic control. Injectable GLP-1RAs, such as semaglutide and liraglutide, have been shown to reduce major adverse cardiovascular events (MACE), but barriers, including cost, access, and the burden of injections, persist. The SOUL trial marks a significant milestone by evaluating oral semaglutide in high-risk patients, demonstrating a 14% reduction in MACE versus placebo and reinforcing GLP-1RAs cardioprotective potential in an oral formulation. This advancement holds promise for patient populations underrepresented in prior trials. However, gastrointestinal side effects and strict dosing requirements challenge long-term adherence. While the findings suggest improved accessibility and real-world applicability, further comparative trials with injectables, extended follow-up, and cost-effectiveness studies are essential. As evidence evolves, oral GLP-1RAs may represent a more patient-centered approach to managing diabetes and cardiovascular risk. This perspective article aims to explore the implications of the SOUL trial, highlight ongoing challenges in adherence and implementation, and discuss the future role of oral GLP-1RAs in cardiovascular and diabetes care.

Background: High blood glucose levels are a hallmark of Diabetes Mellitus (DM), which is classified as a metabolic disease. DM is closely associated with various Cardiovascular Disease (CVD) risk factors, and poor glycemic control is known to elevate the risk of developing CVD. Ranolazine, a novel anti-anginal medication, has demonstrated cardioprotective effects, making it an important agent in the management of heart-related complications in diabetic patients. The mechanism underlying the anti-ischemic effect of ranolazine primarily involves the blockade of the cardiac isoform of voltage-gated Sodium Channels (NaChs), specifically Nav1.5. By inhibiting the late Sodium Current (INa, late), ranolazine helps stabilize cardiac function and reduce ischemic episodes. Recent large Randomized Controlled Trials (RCTs) have shown that ranolazine significantly reduces levels of glycosylated hemoglobin (HbA1c), which is a critical marker for glycemic control. This dual action of ranolazine in improving both cardiac performance and glycemic control positions it as a valuable therapeutic option in the management of patients with DM and cardiovascular risk.

Objectives: This review aims to provide a comprehensive overview of the preclinical and clinical research concerning ranolazine's potential as an antidiabetic agent. By examining existing studies, we explore the drug's mechanisms of action, its impact on glycemic control, and its role in managing DM-related cardiovascular complications. Through the available data, we highlight the emerging evidence supporting ranolazine's use beyond its traditional role as an anti-anginal medication, as well as its promising implications for DM management.

Methods: Using the terms ranolazine, DM, beta-cells, alpha cells, and preclinical and clinical trials, an EMBASE search for English language articles was conducted from 1979 to 2024.

Results: Ranolazine has demonstrated a well-tolerated glucometabolic action and positively regulates glucose levels in individuals with DM. A meta-analysis has revealed that ranolazine effectively improves HbA1c levels without increasing the risk of hypoglycemia, offering significant advantages for patients with type 2 Diabetes Mellitus (T2DM) and stable angina. In addition to its effects on glycemic control, ranolazine has been shown to lower both baseline and postprandial glucagon levels in preclinical trials. This reduction in glucagon is associated with a decrease in hyperglycemia, suggesting that the blockade of Sodium Channels (NaChs) is integral to the glucose-lowering effects of ranolazine. Overall, these findings support the potential of ranolazine as a beneficial treatment option for managing glucose levels in diabetic patients, particularly those with concurrent cardiovascular conditions.

Conclusion: A novel approach for treating T2DM could involve selective Nav1.3 block