Thrombospondin-1 (TSP-1) is upregulated in several inflammatory diseases. Recent data have shown that macrophages from TSP-1-deficient mice have a reduced inflammatory phenotype, suggesting that TSP-1 plays a part in macrophage activation. DNA microarray approach revealed that Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) may induce the enhanced TSP-1 expression in human monocytes, suggesting a role of TSP-1-mediated pathogenesis in periodontitis. Until recently, the function of TSP-1 has been a matter of debate. In this study, we explored the role of TSP-1 in inflammatory cytokine secretions and its putative mechanism in pathogenesis of periodontitis. We demonstrated that TSP-1 expression was significantly upregulated in gingival tissues with periodontitis and in P. gingivalis LPS-stimulated THP-1 cells. Deficiency of TSP-1 by transfecting siRNAs decreased IL-6, IL-1β, and TNF-α secretions in THP-1 cells, whereas overexpression of TSP-1 resulted in an upregulation of IL-6, IL-1β, and TNF-α productions. Additional experiments showed that Pyrrolidine dithiocarbamate (PDTC) inhibited IL-6, IL-1β, and TNF-α expression induced by overexpression of TSP-1, accompanying with downregulation of phosphorylated p65 and IκBα protein levels in response to P. gingivalis LPS. These results indicated that TSP-1 played a significant role in P. gingivalis LPS-initiated inflammatory cytokines (IL-6, IL-1β, and TNF-α) secretions of THP-1 cells, and the NF-κB signaling is involved in its induction of expression. Thus, TSP-1 effectively elevated P. gingivalis LPS-induced inflammation mediated by the NF-κB pathway and may be critical for pathology of periodontitis.
The relationship between osteoblasts and angiogenesis is vital for bone regeneration, especially mandibular and maxillary bones. Transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VeGF) are closely related to angiogenesis; however, the regulatory mechanism between them remains unknown. The present study aimed to reveal this mechanism to provide novel insight for development of potential therapeutic opportunities. Western blotting and reverse transcription-quantitative Pcr was used to assess the protein and mrna expression levels in Mc3T3-e1 preosteoblast cells and HuVecs, eliSas were used to detect the expression levels of secreted VeGF, MTT assays were used to assess the viability of the cells, migratory ability was assessed using Transwell assays, angiogenesis assays were used to analyze the formation of blood vessels, and TGF-β1 regulation was confirmed using a dual-luciferase reporter assay. The overexpression of specificity protein 1 (SP1) or TGF-β1 increased VeGF expression levels and secretion, and promoted angiogenesis of co-cultured HuVecs. SP1 also promoted SMad2 phosphorylation. These effects of SP1 were all reversed by the TGF-β1 inhibitor. The VeGF inhibitor bevacizumab also reduced the SP1/TGF-β1/SMad2 pathway-induced angiogenesis of preosteoblasts. in conclusion, it was demonstrated that SP1 promoted TGF-β1 expression, activated the SMad2 pathway and induced VeGF secretion, which may enhance angiogenic processes in preosteoblasts.
BackgroundDiabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established.MethodsWild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed.ResultsCompared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice.ConclusionOur study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.
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