作者: Rattanapisit, Kaewta ; Kubera, Anchanee ; Phoolcharoen, Waranyoo ; Chaikiawkeaw, Daneeya ; Pavasant, Prasit ; Everts, Vincent ; Nammultriputtar, Ketsaraporn ; Khorattanakulchai, Narach

AbstractBackgroundRecently we have generated recombinant human osteopontin (rhOPN) using a plant platform (Nicotiana benthamiana) and demonstrated, when coated on culture plates, its osteogenic induction capacity of human periodontal ligament (PDL) cells. The aim of this study is to elucidate the molecular mechanism underlying the rhOPN‐induced osteogenic differentiation of human PDL cells.MethodsFull length rhOPN (FL‐OPN) and three constructs of OPN containing integrin binding domain (N142), calcium binding domain (C122) and mutated calcium‐binding domain (C122δ) were generated from N. benthamiana. Human PDL cells were isolated from extracted third molars and cultured on FL‐OPN, N142, C122, or C122δ‐coated surfaces. Real‐time PCR and Western blot analyses were used to determine mRNA and protein expression. In vitro calcification was determined by Alizarin red staining. A chemical inhibitor and RNAi silencing were used to elucidate signaling pathways. In silico analyses were performed to predict the protein‐protein interaction. In vivo analysis was performed using a rat calvaria defect model.ResultsHuman PDL cells seeded on FL‐OPN and C122‐coated surfaces significantly increased both mRNA and protein expression of osterix (OSX) and enhanced in vitro calcification. Soluble FL‐OPN as well as a surface coated with N142 did not affect OSX expression. Inhibition of activin receptor‐like kinase (ALK‐1) abolished the induction of osterix expression. In silico analysis suggested a possible interaction between the calcium binding domain (CaBD) of OPN and ALK‐1 receptor. C122, but not C122δ coated surfaces, induced the expression of p‐Smad‐1 and this induction was inhibited by an ALK‐1 inhibitor and RNAi against ALK‐1. In vivo data showed that 3D porous scaffold containing C‐122 enhanced new bone formation as compared to scaffold alone.ConclusionThe results suggest that next to full length OPN, the CaBD of OPN, if coated to a surface, induces osteogenic differentiation via interaction with ALK‐1 receptor.

2011-11-01·European Journal of Pharmacology3区 · 医学

C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents monocrotaline-induced pulmonary arterial hypertension in rats

3区 · 医学

Article

作者: Zopf, David A. ; Gralinski, Michael R. ; Huang, Jinbao ; Nikula, Kristen J. ; Senese, Peter B. ; das Neves, Liomar A. A.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT(2B) (Ki=5.2 nM, IC(50)=6.9 nM), when administered to rats for three weeks in daily oral 10mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mmHg vs. 28 ± 2 mmHg in MCT-vehicle group, P<0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P<0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P<0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.

1978-01-01·Veterinarno-meditsinski nauki

[Histopathological studies of silworms (Bombyx mori Linn.) spontaneously infected with nuclear polyhedrosis].

Article

作者: Manchev, M ; Ianchev, I

Pathohistological changes in silkworms, spontaneously affected by nuclear polyhedry are investigated. The J-124 X C-122 hybrid after the fourth moulting is tested. After being subjected to a low temperature stress the silkworms were killed and material for pathohistological studies were taken from them. It is established that the most suitable tissues for the replication of the polyhedry virus of the silkworm were the cells of the fat bodies, the tracheal matrix and the hypoderm. Not all polyhedra form simultaneously. The virus as polyhedral bodies is detected in the infected tissues, cells respectively, on the 55th day (at the earliest) by the action of the low temperature stress. The histopathological investigation is recommended as a method for reliable and relatively early diagnoses.

100 项与 C-122 相关的药物交易

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