ABSTRACT
p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.
ABSTRACT
Till the 21st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters.However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators.Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.
ABSTRACT
Neuroinflammation is an immune response within the central nervous system against various proinflammatory stimuli. Abnormal activation of this response contributes to neurodegenerative diseases such as Parkinson disease, Alzheimer’s disease, and Huntington disease. Therefore, pharmacologic modulation of abnormal neuroinflammation is thought to be a promising approach to amelioration of neurodegenerative diseases. In this study, we evaluated the synthetic flavone derivative 3′,4′-dihydroxyflavone, investigating its anti-neuroinflammatory activity in BV2 microglial cells and in a mouse model. In BV2 microglial cells, 3′,4′-dihydroxyflavone successfully inhibited production of chemokines such as nitric oxide and prostaglandin E2 and proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 in BV2 microglia. It also inhibited phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation. This indicates that the anti-inflammatory activities of 3′,4′-dihydroxyflavone might be related to suppression of the proinflammatory MAPK and NF-κB signaling pathways. Similar anti-neuroinflammatory activities of the compound were observed in the mouse model. These findings suggest that 3′,4′-dihydroxyflavone is a potential drug candidate for the treatment of microglia-related neuroinflammatory diseases.
Subject(s)
Animals , Mice , Central Nervous System , Chemokines , Cytokines , Dinoprostone , Huntington Disease , Interleukin-1beta , Interleukin-6 , Microglia , Neurodegenerative Diseases , Nitric Oxide , Parkinson Disease , Phosphorylation , Protein Kinases , Tumor Necrosis Factor-alphaABSTRACT
OBJECTIVES: This study evaluated the ototoxicity by mixed organic solvents on workers'hearing using the upper limit of hearing(ULH). METHODS: Seven hundred ninety-seven male workers in the ship building industry who were evaluated by interview with an upper limit of hearing from August 2000 to July 2002 were enrolled in the study. The subjects were divided into 3 groups according to exposure profile and job: officers, field supporters, and painters. To assess the ototoxicity of mixed organic solvent exposure on hearing, with regard to confounders, the general liner model was used. RESULTS: After controlling for the possible confounders, such as age, career, noise exposure level, tinnitus, alcohol intake, and smoking, the estimated mean for ULH of the painter group was higher than that of the officer and the field supporter groups. These differences of mean ULH were at the borderline of statistically significance(p=0.069). CONCLUSIONS: The results of this study suggest that a relatively lower level of mixed organic solvent chronically affected the hearing organ or auditory pathway. ULH seems to be a useful method for early detection of the ototoxicity of organic solvents.
Subject(s)
Humans , Male , Auditory Pathways , Construction Industry , Hearing , Noise , Ships , Smoke , Smoking , Solvents , TinnitusABSTRACT
We studied the success rate of bilateral 7mm medical rectus recession for 24 patients with large angle congenital esotropia through long-term follow-up. The success rate was 100%(24/24) at immediate postoperative period, 83.3%(20/24) at postoperative 6 months, 79.1%(19/24) at postoperative 1 year, 64.1%(9/14) at postoperative 18 months and 54.5% (6/11) at postoperative 2 years. Residual esotropia rate was 0%(0/24) at immediate postoperative period, 16.6%(4/24) at postoperative 6 months, 16..6%(4/24) at postoperative 1 year, 14.2%(2/14) at postoperative 18 months and 18.1%(2/11) at postoperative 2 years. Consecutive exotropia rate was 0%(0/24) at immediate postoperative period, 0%(0/24) at postoperative 6 months, 4.1 %(1/24) at postoperative 1 year, 21.4%(3/14) at postoperative 18 months and 27.2%(3/11) at postoperative 2 years. Residual esotropia may develop before 6 months and consecutive exotropia after 1 year postoperatively.
Subject(s)
Humans , Esotropia , Exotropia , Follow-Up Studies , Muscles , Postoperative PeriodABSTRACT
In third nerve palsy, the functions in the four of the six extraocular muscles are compromised and its treatment is the most difficult problem in the paralytic strabismus. In surgical method, large recession and resection of horizontal rectus muscles, lateral rectus muscle transposition to medial rectus muscle and superior oblique muscle transposition are used for strabismus surgery on oculomotor nerve palsied eye. We compared the results of two methods of surgical correction. In three eyes, lateral muscle transpositions to medial rectus muscle were performed. On the last follow up examination (men; 6.7 months), two eyes resulted in severe hypertropia and unacceptable ocular alignment and no improvement of limited adduction. In six eyes of whom superior oblique muscle transpositions were performed, all resulted in acceptable ocular alignment, no hypertropia, and the limitations of adduction were improved markedly. Therefore, in the treatment of third nerve palsy, sperior oblique muscle transposition is more effective than lareral rectus muscle transposition to medial rectus muscle.
Subject(s)
Exotropia , Follow-Up Studies , Muscles , Oculomotor Nerve Diseases , Oculomotor Nerve , StrabismusABSTRACT
A cilioretinal artery occlusion associated with a central retinal vein occlusion is a rare condition and has been reported to have a good visual prognosis. We report a young patient with this condition who also demonstrated prolonged filling of the branch retinal arteries with fluorescein angiography. Her initial visual acuity was 0.03 in the affected eye. Two months later, normal central retinal artery inflow resumed. Her visual acuity has improved to 0.5 over the three years' follow-up.
Subject(s)
Humans , Arteries , Fluorescein Angiography , Follow-Up Studies , Prognosis , Retinal Artery , Retinal Vein , Visual AcuityABSTRACT
The preoperative diagnosis of the masked bilateral superior oblique palsy (SOP) is very diffcult, so the clinical manifestation is very important. We studied to determine diagonostic criteria of the masked bilateral SOP. Among 24 patients. who were diagnosed as unilateral SOP preoperatively, 5 patients developed postoperative masked bilateral SOP. 2 patients had been diagnosed masked bilateral SOP preoperatively. We compared 17 cases of unilateral SOP with seven cases of masked bilateral SOP about V-shift, head tilt test and the degree of excyclotorsion. The mean V-shift of the masked SOP patients was 5.3PD and that of the unilateral SOP patients was 1.5PD(p=0.09). The mean excyclotosion difference between the primary position and downgaze was 9.7 degree in masked cases and 2.6 degree in unilateral ones respectively (p=0.35). The mean difference of hyperdeviation the right versus the left tilted head position was 22PD in masked cases and 18.1PD in unilateral ones (p=0.35). The cases of excyclotorsion difference over 5 degrees between primary and downgaze were five(71%) in masked cases but none in unilateral cases(p=0.0001). So above finding may be strongly suggested as diagnosing the masked bilteral SOP.