ABSTRACT
P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokinesTNF-α, 1L-6, and 1L-1ß in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 nM, 17.6 µM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC50 values of 0.29 µM and 0.61 µM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Drug Design , Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , THP-1 Cells , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Several prognostic factors are known to be related to the recovery of sudden sensorineural hearing loss (SSNHL). Recent studies have suggested that cardiovascular risk factors (CVRFs) are associated with the occurrence of SSNHL. However, the value of CVRFs as a predictor of recovery in patients with SSNHL has been rarely evaluated. We aim to evaluate the prognostic value of CVRFs in relation to hearing recovery of SSNHL. SUBJECTS AND METHOD: A total of 278 patients who were diagnosed and treated for SSNHL and who underwent blood sampling and follow-ups for more than 3 months were reviewed retrospectively. We reviewed CVRFs such as age, body mass index, blood pressure, cholesterol, smoking history, the presence of diabetes mellitus and other related underlying diseases. Patients were divided into three groups (low, medium, and high CVRF groups) according to the CVRF grades. Hearing thresholds were repeatedly measured on the initial visit, 1 week, 1 month and 3 months after treatment. Treatment outcome was analyzed by comparing hearing recovery rate and post-treatment audiometric changes among the three CVRF groups. RESULTS: Seventy (25.2%), 129 (46.4%) and 79 (28.4%) patients were included into the low, medium and high CVRF groups, respectively. The hearing threshold was significantly reduced at 3 months after treatment in all three groups (p<0.001). The hearing recovery rate of the low CVRF group was significantly higher than that of the medium and high CVRF group (p=0.011). On the last visit, the high CVRF group significantly showed more poor hearing improvement than the low CVRF group did (p=0.045). CONCLUSION: Our findings suggest that the presence of CVRFs may be a poor prognostic sign for hearing recovery in patients with SSNHL.
Subject(s)
Humans , Blood Pressure , Body Mass Index , Cholesterol , Diabetes Mellitus , Follow-Up Studies , Hearing Loss, Sensorineural , Hearing , Methods , Retrospective Studies , Risk Factors , Smoke , Smoking , Treatment OutcomeABSTRACT
Intravascular papillary endothelial hyperplasia (IPEH) is a rare benign reactive vascular lesion, characterized by thrombus formation and subsequent intravascular endothelial proliferation. IPEH should be differentially diagnosed from angiosarcoma because of their microscopic similarity. The clinical manifestation of IPEH varies according to involved site. We report a rare case of IPEH in the maxillary sinus of 35-year-old male presenting with epistaxis, which is completely removed without complications.
Subject(s)
Adult , Humans , Male , Endothelium , Epistaxis , Hemangiosarcoma , Hyperplasia , Maxillary Diseases , Maxillary Sinus , ThrombosisABSTRACT
Diagnosis of traumatic arteriovenous fistula (AVF) is usually delayed because it takes time to be enlarged enough to emerge radiologically or because symptoms occur a few months after the trauma. A 56-year-old woman presented with a newly developed tinnitus immediately after a head trauma. Pulsatile high-frequency tinnitus was heard also by examiner and recorded using a transcanal microphone. Angiography revealed an intracranial dural AVF fed by the middle meningeal artery, draining the superior sagittal sinus on the affected side. After percutaneous transarterial embolization, tinnitus successfully disappeared. The clinical presentation, radiologic and angiographic features, and management are discussed. To our knowledge, this is the first reported case of pulsatile tinnitus caused by AVF developed immediately after a trauma. We emphasize that precise physical examination, laboratory tests, and appropriate radiographic imaging are essential for accurate diagnosis and treatment when a patient presents with pulsatile tinnitus, especially after a head trauma.
