Cardiovascular & hematological disorders drug targets最新文献

Recent research has uncovered that secondary metabolites-biologically active compounds produced by plants, microbes, and other organisms-play a significant role in regulating the differentiation and function of macrophages. Macrophages, key components of the innate immune system, are crucial for a wide range of physiological processes, including immune response modulation, tissue homeostasis, and host defense against pathogens. This research delves into the mechanisms by which secondary metabolites influence macrophage differentiation signaling pathways, with a focus on how specific compounds affect macrophage polarization and functional phenotypes. Understanding these effects can open new avenues for developing therapeutic strategies that target macrophage-mediated immune responses. Secondary metabolites, such as nitrogen (N) and sulfur (S) containing compounds, terpenoids, and phenolic compounds from plants and microbes, can modulate macrophage differentiation by influencing cytokine production and activity. The activation of signaling pathways in macrophages involves multiple receptors and transcription factors, including IFN-γ receptor activation leading to STAT1 activation, TLR4 triggering IRF5, NFκB, and AP1, IL-4 receptor activation leading to STAT6 and IRF4 activation, PPARγ activation via the fatty acid receptor, TLR4 increasing CREB and C/EBP levels. The complex interplay between transcription factors and cytokines is crucial for maintaining the balance between the M1 and M2 states of macrophages. Despite these insights, further research is needed to unravel the specific molecular mechanisms involved and to identify promising secondary metabolites that could be translated into clinical applications.

Objective: This study aimed to assess the hypoglycemic effects of methanolic extract of Foeniculum vulgare in male Wistar rats that were diabetic due to streptozotocin.

Methods: Experimental diabetes was initially induced in male Wistar rats by intravenous injection of streptozotocin (55 mg/kg). Subsequently, the rats received daily oral administration of the methanolic extract of Foeniculum vulgare (250 mg/kg) and the standard drug metformin (300 mg/kg) for 28 days. Furthermore, a tolerance test was carried out.

Results: The study findings suggest that the diabetic rats in the untreated control group showed hyperglycemia and significant weight loss, as well as polydipsia, polyphagia, and polyuria. However, rats treated with methanolic extract of Foeniculum vulgare for 28 days showed a significant reduction in blood glucose levels and a marked improvement in body weight. Additionally, there was a notable decrease in the daily rate of food consumption and water intake and a significant reduction in serum glucose level, triglycerides, total cholesterol, creatinine, urea, AST, and ALT levels compared to the untreated diabetic control group. Histopathological examination revealed that after 28 days of treatment with 250 mg/kg of methanolic extract of the Foeniculum vulgare, the size of the islets of Langerhans in the pancreas tissue was decreased. Moreover, liver tissue demonstrated normalization with a normal central lobular structure, and kidney tissue showed normalization with a normal Bowman's capsule.

Conclusion: These findings suggest that the methanolic extract of Foeniculum vulgare can potentially treat diabetes and should be evaluated further for drug development.

Background: Drug repurposing involves investigating new indications or uses for drugs that have already been approved for clinical use. Empagliflozin is a C-glycosyl compound characterized by the presence of a beta-glucosyl residue. It functions as a sodium-glucose co-transporter 2 inhibitor and is utilized to enhance glycemic control in adults diagnosed with type 2 diabetes mellitus. Additionally, it is indicated for the reduction of cardiovascular mortality risk in adult patients who have both type 2 diabetes mellitus and pre-existing cardiovascular disease.

Objective: The study's objective revolves around exploring the repurposing potential of a novel SGLT2 inhibitor acting as an antidiabetic drug named Empagliflozin through computational methods, with a specific focus on its interaction with cardioprotective key target proteins.

Methods: The study was performed by docking the empagliflozin with different target proteins (NHE1- CHP1, BIRC5, GLUT1, and XIAP) by using Autodock, and different values were recorded. The docked files were analysed by the BIOVIA Discovery Studio Visualizer. The in silico analysis conducted in this study examines the binding free energy values of Empagliflozin with key target proteins.

Results: Results revealed that NHE1-CHP1 exhibits the lowest binding free energy, followed by BIRC5, GLUT1, and XIAP, with the highest value. This descending order of binding energies suggests varying degrees of effectiveness in binding molecules, with lower energies indicative of more potent biological activity. The analysis underscores the importance of intermolecular interactions, particularly hydrogen bond formations facilitated by oxygen, nitrogen, and carbonyl groups in compound structures. Notably, NHE1-CHP1 demonstrates superior binding interactions with Empagliflozin compared to the other target proteins, highlighting its potential as a cardioprotective agent.

Conclusion: These findings offer valuable insights into the therapeutic possibilities of Empagliflozin in cardioprotection, indicating promising avenues for further research and development in this domain.

Background: Premature Ovarian Insufficiency (POI) is associated with infertility. Little is known about the potential circulating biomarkers that could be used to predict POI. We have investigated the possible association between white and red blood cells, platelet indices, and eight established single nucleotide polymorphisms (SNPs) associated with POI risk.

Methods: 117 women with premature menopause (PM) and 183 healthy women without a history of menopause before age 40 were recruited for this study. The tetra-primer amplification refractory mutation system-polymerase chain reaction (Tetra ARMS PCR) and allele-specific oligonucleotides- polymerase chain reaction (ASO-PCR) were carried out for genotyping for eight SNPs reported to be associated with POI. Decision tree analysis was applied to test the diagnostic value of hematological parameters to identify the risk of POI.

Results: Women with POI had lower neutrophil (NEUT) and white blood cell (WBC), whereas red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and mean cell hemoglobin (MCH) were higher. Platelet (PLT) count was also lower in affected women. Our data also indicated that HGB and HCT count were significantly associated with rs16991615 and rs244715. Mean Platelet volume (MPV) and platelet distribution width (PDW) were associated with rs244715, rs1046089, rs4806660, and rs2303369. The rs16991615 was also associated with RBC count, and rs451417 was associated with NEUTs. The decision tree (DT) model reveals that women with the NEUT count at a cut-off value of less than 2.8 and HCT equal to or more than 38.7% could be identified as high-risk cases for POI. Overall, we found the DT approach had a sensitivity = 85%, specificity = 72%, and accuracy = 74%.

Conclusion: The genetic variants involved in POI are associated with changes in reproductive hormone levels and with changes in hematological indices.

Background: Kounis syndrome is defined as a combination of acute coronary syndrome and allergic reactions.

Objective: In this review, we aim to describe the etiological, clinical, and diagnostic characteristics of Kounis syndrome.

Methods: A literature search using PubMed was conducted for the past 32 years using keywords, resulting in the selection of 761 scientific papers. From these, 217 articles describing 235 clinical cases were selected. Patients under 18 years of age or without a confirmed diagnosis were excluded.

Results: Among the 235 patients, type I Kounis syndrome was observed in 49.7%, type II in 27.2%, type III in 5.9%, and a combination of types I and II in 1.0%; in 16.2%, it was not possible to classify the type of Kounis syndrome. The median age was 57 years, and 68.5% of the patients were male. The most common causes were antibiotics (32.3%) and non-steroidal anti-inflammatory drugs (24.3%). The clinical features included chest pain (59.1%), hypotension (74.2%), itching (30.6%), and dyspnea (30.6%). Electrocardiographic monitoring revealed ST-segment elevation in 42.9% and was normal in only 5.5% of patients. Coronary angiography was performed in 80.4% of the patients, revealing unchanged coronary arteries in 50.3% of cases. Сonclusion: Allergic myocardial infarction is a serious complication of drug therapy.

The landscape of severe dyslipidemia treatment is undergoing a remarkable transformation with the advent of angiopoietin-like 3 (ANGPTL3) inhibitors. ANGPTL3, a pivotal regulator of lipoprotein lipase and endothelial lipase, orchestrates the catabolism of triglyceride-rich and high-density lipoproteins, thus playing a critical role in lipid homeostasis. This review article examines the therapeutic potential of ANGPTL3 blockade and its implications for patients with severe dyslipidemias, particularly those unresponsive to traditional lipid-lowering regimens. We delve into the molecular mechanisms by which ANGPTL3 influences lipid metabolism and appraise the clinical utility of emerging therapeutics, such as monoclonal antibodies and antisense oligonucleotides. Moreover, we discuss the impact of ANGPTL3 inhibition on cardiovascular risk factors and project its promising role in reducing cardiovascular morbidity and mortality. The narrative synthesizes data from recent clinical trials, including the efficacy and safety profiles of ANGPTL3 inhibitors, and forecasts the potential of these agents to revolutionize the management of dyslipidemic conditions. The advent of ANGPTL3-targeted therapies signifies a potential breakthrough in the therapeutic armamentarium against complex lipid disorders, heralding a new era of precision medicine in cardiovascular risk mitigation.

Background: Cryptogenic stroke, whose underlying pathology is unknown, accounts for 30-40% of all ischemic strokes. Studies have mentioned the association between atrial septal abnormalities and cryptogenic stroke, but there are still disparities in the results among different studies.

Objective: We aimed to clarify the prevalence of atrial septal abnormalities in patients with cryptogenic stroke.

Methods: We conducted a cross-sectional study on 91 patients with cryptogenic stroke/transient ischemic attack from March 2021 to March 2022. We evaluated the demographic data of the patients and also the existence of neurologic attacks. Furthermore, echocardiography was performed to determine the type of atrial septal abnormality.

Results: Out of 91 patients with cryptogenic stroke/transient ischemic attack, 16 patients (17.5%) had patent foramen ovale, 1 man (1.1%) had atrial septal aneurysm, and 1 woman (1.1%) had an atrial septal defect. Patients with patent foramen ovale were significantly younger than those without. The size of patent foramen ovale in patients with cryptogenic stroke was larger than those with transient ischemic attack, but this difference was not significant. Also, the size of the patent foramen ovale (length and width) was not significantly related to any of the demographic variables (p-value = 0.544, 0.604).

Conclusion: Based on our results, the prevalence of atrial septal abnormalities was relatively high. Considering these issues and the importance of preventing neurological accidents in patients, especially young people, it is recommended to always consider atrial septal disorders and, if diagnosed, to carry out the necessary treatment in this field.

Background: Hypertension is a major risk factor for cardiovascular diseases. Peristrophe bivalvis (PB) is used for the treatment of hypertension, painful sprains, skin diseases, tuberculosis, acute bronchitis, anti-inflammatory conditions, hepatitis, and diabetes. Its antihypertensive potential has been investigated and documented. This study investigated the antihypertensive mechanism of aqueous extract of PB leaf (APB) on L-NAME-induced hypertension.

Methods: Thirty male wistar rats (150-170 g) were grouped into five (n=5). Group 1 received 10 mL/kg of distilled water (control), while groups 2-5 were administered 60 mg/kg of L-NAME (L-NAME60) orally for eight weeks to induce hypertension. After eight weeks, groups 2-5 received L-NAME60+distilled water (HNT), distilled water (HRE), L-NAME60+APB (200 mg/kg, [HAPB]), and L-NAME60+ramipril (10 mg/kg, [HRA]), respectively, for five weeks. The BP was measured by the tail-cuff method. The blood sample was obtained under anesthesia, and tissue samples were obtained after euthanasia. Serum renin, ACE, angiotensin-II, endothelin-1, and cyclic guanosine monophosphate (cGMP) levels were measured using ELISA techniques. Malondialdehyde, superoxide dismutase (SOD), and reduced glutathione (GSH) levels were measured by spectrophotometry. Data were analyzed using ANOVA at α0.05.

Results: The BP significantly decreased in HAPB compared to HNT. Renin, ACE, and angiotensin- II levels significantly decreased while cGMP levels increased in the HAPB group compared to HNT. Malondialdehyde levels significantly decreased, and SOD and GSH levels increased compared to HNT.

Conclusion: Peristrophe bivalvis aqueous leaf extract reduced blood pressure in hypertensive rats by modulating the cGMP signalling pathway and the renin-angiotensin system.

Background: Diltiazem hydrochloride is a calcium channel-blocker with a plasma elimination half-life of 4.4 ± 1.3 h and has a narrow absorption window. So, this work aimed to prepare a gastro-retentive floating matrix tablet.

Methods: The direct compression method was used to manufacture tablets. 3² factorial design was applied for optimization, taking Hydroxypropyl Methylcellulose K100M (HPMC K 100M) and the amount of sodium bicarbonate as independent factors and cumulative percentage release at 1 h, at 6 h, and at 12 h and floating lag time as dependent variables.

Results: The high amount of HPMC K100M and sodium bicarbonate shows good results. The optimized preparation was evaluated for differential scanning calorimetry, in-vivo gastric retention in male albino rabbits, kinetic modeling, and stability study. An in vivo study revealed gastric retention of tablets up to 6 h in healthy male Albino rabbits. The stability study indicated no significant change in the buoyancy and release profiles of the drug.

Conclusion: From this study, it can be concluded that the gastro-retentive diltiazem hydrochloride floating matrix tablet was successfully prepared and retained inside the rabbit stomach for up to 6 h and was stable under accelerated stability study.

Systemic amyloidosis is a rare protein misfolding and deposition condition that causes slow organ failure. Each of the more than 15 exclusive sorts of systemic amyloidosis, which encourage amyloid production and tissue deposition, is introduced by a unique precursor protein. Amyloidosis can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin, and soft tissues. It can either be acquired or hereditary. Insidious and doubtful signs often cause a put-off in diagnosis. In the closing decade, noteworthy progressions have been made in the identity, prediction, and handling of amyloidosis. Shotgun proteomics based on mass spectrometry has revolutionized amyloid typing and enabled the identification of novel amyloid forms. It is critical to correctly identify the precursor protein implicated in amyloidosis because the kind of protein influences the proper treatment strategy. Cardiac amyloidosis is a disorder characterized by the systemic accumulation of amyloid protein in the myocardium's extracellular space, which causes a variety of symptoms. The buildup of amyloid aggregates precipitates myocardial thickening and stiffening, culminating in diastolic dysfunction and, in due course, heart failure. We examine every kind of systemic amyloidosis in this text to offer practitioners beneficial equipment for diagnosing and treating those unusual diseases. This review presents a comprehensive analysis of cardiac amyloidosis and consolidates current methods for screening, diagnosis, evaluation, and treatment alternatives.