Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

Abstract: Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Int. J. Mol. Sci. 2013, 14 18900 Therefore, antihypertensive treatments are recommended for the prevention of stroke. Thre

Cleavage of host cytokeratin-6 by lysine-specific gingipain induces gingival inflammation in periodontitis patients

Background/Purpose. Lysine-specific gingipain (Kgp) is a virulence factor secreted from Porphyromonas gingivalis (P. gingivalis), a major etiological bacterium of periodontal disease. Keratin intermediate filaments maintain the structural integrity of gingival epithelial cells, but are targeted by Kgp to produce a novel cytokeratin 6 fragment (K6F). We investigated the release of K6F and its induction of cytokine secretion. Methods. K6F present in the gingival crevicular fluid of periodontal disease patients and in gingipain-treated rat gingival epithelial cell culture supernatants was measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometer-based rapid quantitative peptide analysis using BLOTCHIP. K6F in gingival tissues was immunostained, and cytokeratin 6 protein was analyzed by immunofluorescence staining and flow cytometry. Activation of MAPK in gingival epithelial cells was evaluated by immunoblotting. ELISA was used to measure K6F and the cytokines release induced by K6F. Human gingival fibroblast migration was assessed using a Matrigel invasion chamber assay. Results. We identified K6F, corresponding to the C-terminus region of human cytokeratin 6 (amino acids 359–378), in the gingival crevicular fluid of periodontal disease patients and in the supernatant from gingival epithelial cells cultured with Kgp. K6F antigen was distributed from the basal to the spinous epithelial layers in gingivae from periodontal disease patients. Cytokeratin 6 on gingival epithelial cells was degraded by Kgp, but not by Arg-gingipain, P. gingivalis lipopolysaccharide or Actinobacillus actinomycetemcomitans lipopolysaccharide. K6F, but not a scrambled K6F peptide, induced human gingival fibroblast migration and secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1. These effects of K6F were mediated by activation of p38 MAPK and Jun N-terminal kinase, but not p42/44 MAPK or p-Akt. Conclusion. Kgp degrades gingival epithelial cell cytokeratin 6 to K6F that, on release, induces invasion and cytokine secretion by human gingival fibroblasts. Thus, Kgp may contribute to the development of periodontal disease

Anthocyanins Extracted from Oryza sativa L. Prevent Fluorouracil-Induced Nuclear Factor-κB Activation in Oral Mucositis: In Vitro and In Vivo Studies

This study aims to investigate the immunomodulatory effect of anthocyanins (ANTs) from Oryza sativa L. extracts on 5-fluorouracil (5-FU)-induced oral mucositis, using a rat model and oral keratinocytes. ANTs were detected by high-performance liquid chromatography (HPLC)-electrospray ionization mass spectrometry. Animals were randomly given varying doses of ANT-rich extract treatment (500 mg/kg and 1000 mg/kg) in the absence or presence of 5-FU-induced mucositis. Buccal mucosae were photographed and scored for macroscopic analysis and incisional biopsies of cheek pouches were collected for microscopic examination of oral mucositis. 5-FU caused marked hemorrhage, extensive ulcerations and abscesses compared to non-treated animals with slight erythema. Histologically, a loss of collagen bundles and inflammatory cell infiltrates was observed. After 29 days of ANT treatment, lesions resolved, and abundant collagen fibers were evident in the lamina propria. Buccal mucosa of 5-FU-injected rats showed increased Nuclear factor-kappa B (NF-κB) p50 and p65 in oral keratinocytes. The administration of ANT reduced NF-κB-positive cells in 5-FU rats (p < 0.001) compared to the non-treatment group. In oral keratinocytes, ANT treatment significantly restored 5-FU-induced growth inhibition and impaired the nuclear accumulation of NF-κB p50 and p65. Our study demonstrated that ANT from Oryza sativa L. exhibited effective anti-inflammatory properties against 5-FU-induced oral mucositis by inhibiting NF-κB activation

Overexpression of Receptor for Advanced Glycation End Products and High-Mobility Group Box 1 in Human Dental Pulp Inflammation

High mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE), which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia (P. intermedia) lipopolysaccharide (LPS) on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1). RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF-κB activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection

www.mdpi.com/journal/ijms The Efficacy of Edaravone (Radicut), a Free Radical Scavenger, for Cardiovascular Disease

Abstract: Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of edaravone for treatment of cardiovascular disease, and covers clinical and experimenta