Signaling pathway of TNF-α-induced AQP3 expression in human gingiva: Implications in the pathogenesis of periodontitis

Inflammation Research -     

Three cases of lymphocytic thrombophilic arteritis presenting with an annular eruption

We describe three patients who presented with a striking erythematous non‐blanching annular eruption and features of lymphocytic thrombophilic arteritis (LTA), with a prominent lymphocytic vasculitis involving deep dermal vessels. Lymphocytic inflammation was also evident in the superficial vessels and one patient had small superficial ulcers over the ankle area resembling livedoid vasculopathy (LV). Multiple biopsies demonstrated a persistent absence of neutrophils in the infiltrate consistent with a lymphocytic process. In addition to highlighting the annular morphology as a novel presentation of LTA, these cases suggest a possible relationship between LV and LTA and support the notion that they are distinct from neutrophilic vasculitides such as cutaneous polyarteritis nodosa.     

Beyond neurological disease: new targets for edaravone (Review)

Free radicals play major roles in the pathogenesis of tissue damage in many diseases and clinical conditions, and the removal of free radicals may offer a treatment option. Several modulators of free radical scavenger pathways have been developed and some have progressed to clinical trials. One such agent, edaravone, was approved in 2001 in Japan for the treatment of cerebral infarction. It has since been shown that edaravone can diffuse into many organs and, in addition to its effects on hydroxyl radical removal, edaravone modulates inflammatory processes, matrix metalloproteinase levels, nitric oxide production, apoptotic cell death, and necrotic cell death. Edaravone also exerts protective effects in a number of animal models of disease and tissue damage, including models of myocardial, lung, intestinal, liver, pancreatic and renal injury. Together with the proven safety of edaravone following 9 years of use as a modulator of free radical scavenging pathways in neurological disease, these additional effects of edaravone suggest that it may offer a novel treatment for several non-neurological diseases and clinical conditions in humans.     

Induction of high mobility group box 1 release from serotonin-stimulated human umbilical vein endothelial cells

High mobility group box 1 (HMGB1) is a non-histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis. The HMGB1 functions as a potent proinflammatory cytokine in the extracellular spaces. Recently, HMGB1 has been implicated in the progression of atherosclerosis. However, the association between HMGB1 and the development of atherosclerosis is poorly understood. Therefore, we examined whether serotonin (5-HT), a key factor involved in the development of atherosclerosis, induced HMGB1 release in human umbilical vein endothelial cells (HUVECs). We found that 5-HT induced the release of HMGB1 but not of ERK1/2 and JNK from HUVECs via the 5-HT receptor (5-HT1B)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. The p38MAPK inhibitor SB203580 and the 5-HT1B antagonist GR55526 markedly inhibited HMGB1 release from 5-HT-stimulated HUVECs. The vascular endothelial growth factor (VEGF) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis. We found that HMGB1 induced VEGF production in macrophage-like RAW264.7 cells. HMGB1 induced the activation of p38MAPK, ERK1/2 and Akt. The PI3-kinase inhibitor LY294002 significantly inhibited VEGF production in HMGB1-stimulated macrophages, while other kinase inhibitors did not. These results suggest that HMGB1 release may contribute as a risk factor in the development and progression of atherosclerosis.     

Combined renin angiotensin blockade in childhood steroid‐resistant nephrotic syndrome

Background: Reduced proteinuria results in delayed deterioration of renal function and remission of proteinuria predicts a good long‐term prognosis in steroid‐resistant nephrotic syndrome (SRNS). The aim of this study was to analyze the effects of the combined angiotensin‐converting enzyme inhibitor and angiotensin II receptor blocker in reducing proteinuria in SRNS. Methods: A prospective study of eight patients with SRNS was conducted at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University from September 2003 to December 2007. Enalapril was given at 0.1 mg/kg/day and was increased by 0.1 mg/kg/day every 4 weeks up to 0.6 mg/kg/day (maximum 40 mg/day) and 1 mg/kg/day of losartan was added for 4 weeks and stepped up to 2 mg/kg/day (maximum 100 mg/day) for another 4 weeks. Results: There were five boys (62.5%) and three girls (37.5%). The mean age at diagnosis was 8.3 ± 4.1 years (range 2.05–13 years) and age at enrollment was 11.7 ± 3.8 years (range 6–16 years). Renal histology revealed seven focal segmental glomerulosclerosis and one immunoglobulin M nephropathy. The results showed significant reduction on mean spot urine protein : creatinine ratio from 9.6 ± 2.3 to 3.6 ± 1.6 (P < 0.05) and 24‐h urine protein from 182.8 ± 59.6 to 28.7 ± 8.2 mg/m²/h (P < 0.05). Urine protein reduction ratio at the end of the study was 50% (P= 0.08). Serum cholesterol, albumin, potassium, blood pressure and renal function had no significant change. No clinical and laboratory side‐effects were reported. Conclusion: Combined high‐dose angiotensin II receptor blocker to high‐dose angiotensin‐converting enzyme inhibitor therapy is safe and effective in reducing proteinuria in childhood SRNS. However a large‐scale study should be conducted to validate this result.     

Tumor necrosis factor-alpha stimulates gingival epithelial cells to release high mobility-group box 1

Background and Objective: High‐mobility‐group box 1 functions as a late‐phase inflammatory mediator. It can be released extracellularly by macrophages and necrotic cells through lipopolysaccharide and tumor necrosis factor‐α. The objective of this study was to clarify the source of high‐mobility‐group box 1 in chronic periodontitis tissues and tumor necrosis factor‐α‐stimulated gingival epithelial cells, and subsequently elucidate its inducible inflammatory pathway. Material and Methods: Chronic periodontitis and healthy gingival sections were stained for high‐mobility‐group box 1 by immunohistochemistry and immunofluorescence. The amounts of high‐mobility‐group box 1 released into the gingival crevicular fluid and supernatants from gingival epithelial cells stimulated by tumor necrosis factor‐α were examined by western blot. The phosphorylation of mitogen‐activated protein kinases (MAPKs) in gingival epithelial cells was also examined. Results: High‐mobility‐group box 1 was detected in the cytoplasm and nucleus of gingival epithelial cells with periodontitis. Western blotting revealed a significant increase in high‐mobility‐group box 1 expression in the gingival crevicular fluid from periodontitis patients. High‐mobility‐group box 1 production in gingival epithelial cells was increased following stimulation with tumor necrosis factor‐α. The molecular dialogue between tumor necrosis factor‐α and gingival epithelial cells involved modulation of the activities of p38MAPK, Jun N‐terminal kinase and p44/42. Interestingly, only phosphorylation of p38MAPK contributed to more than half of the signaling initiated by tumor necrosis factor‐α‐elicited high‐mobility‐group box 1 release. Conclusion: High‐mobility‐group box 1 is continuously released from the gingival epithelial cells modulated by tumor necrosis factor‐α. These findings imply that high‐mobility‐group box 1 expression and possibly p38MAPK constitute important features in periodontitis.