About: A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner

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About: A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner
Creator	Lee, Kwong-Man Leung, Kwok-Sui Li, Zi-Rong Qin, Ling Sheng, Hui Wang, Xin-Luan Wang, Yi-Xiang Xie, Xin-Hui Yao, Xin-Sheng Zhang, Ge Griffith, James Yeung, David, Ka-Wai
Source	Elsevier; Medline; PMC
abstract	BACKGROUND: Intravascular-thrombosis and extravascular-lipid-deposition are the two key pathogenic events considered to interrupt intraosseous blood supply during steroid-associated osteonecrosis (ON) development. However, there are no reported candidate agents capable of simultaneously targeting these two key pathogenic events. The authors' published experimental studies have shown that Epimedium-derived flavonoids possess an anti-ON effect. Further, the authors have recently identified a small molecule Icaritin as an intestinal metabolite of Epimedium-derived flavonoids. OBJECTIVE: The present study was to evaluate the prevention effect of the available semisynthesized small molecule Icaritin on steroid-associated ON development in a rabbit model. METHODS: After receiving an established inductive protocol for inducing steroid-associated ON, eighty-four male 28-week-old New-Zealand white rabbits were divided into the following three daily oral administration groups, including low dose Icaritin group (L-ICT; n = 28; 5 mg·kg(− 1)·day(− 1)), high dose Icaritin group (H-ICT; n = 28; 10 mg·kg(− 1)·day(− 1)), and control vehicle group (CON; n = 28). Before and after induction, dynamic contrast-enhanced MRI was performed on proximal femur for intra-osseous perfusion function index. Meanwhile, blood samples were examined for coagulation, fibrinolysis, lipid-transportation, endothelium injury, oxidative stress, and hepatocyte injury index, while marrow samples were quantified for adipogenic potential index of mesenchymal stem cell by in vitro culture and proliferator-activated receptor-gamma (PPARgamma) protein expression by western blot. At baseline, week 1 and 2 post-induction, 4, 8 and 16 rabbits in each group were sacrificed, respectively. After sacrifice, femora were dissected for micro-CT-based micro-angiography, followed by histological examination of ON lesion, intravascular thrombosis, extravascular fat-cell and vascular endothelial growth factor (VEGF) localized expression. RESULTS: The ON incidence in the L-ICT and H-ICT groups was both significantly lower than that in the CON group (p < 0.05 for both). The ON incidence in the H-ICT group was significantly lower than that in the L-ICT group (p < 0.05). A significant decrease in the vascularization index and a significant increase in the permeability index seen in the CON group was attenuated in the L-ICT group and almost prevented in the H-ICT group at week 1 post-induction. Reduced perfusion to vessel-like structural units was more rarely found in the H-ICT group than in the L-ICT group. Regarding intravascular thrombosis, a significant increase in the thrombotic vessel count, endothelium injury index, coagulation index, and a significant decrease in both the fibrinolysis and oxidative stress index in the CON group were attenuated in the L-ICT group and prevented in the H-ICT group. For extravascular lipid-deposition, a significant increase in the fat cell area fraction, adipogenic potential index, PPARgamma expression and lipid-transportation index in the CON group was attenuated in the L-ICT group and prevented in the H-ICT group. Increased immunoreactivity of VEGF in the CON group was attenuated in the L-ICT group and prevented in the H-ICT group. Regarding safety, the hepatocyte injury index did not show significant change from baseline in any group. CONCLUSION: Icaritin, a novel semisynthesized small molecule with osteoprotective potential, exerts dose-dependent effect on reducing incidence of steroid-associated ON with inhibition of both intravascular thrombosis and extravascular lipid-deposition. Suppression of the up-regulated PPARgamma expression for extravascular adipogenesis of mesenchymal stem cells and protection from activated oxidative stress for intravascular endothelium injury were found to be involved in the underlying mechanisms.
has issue date	2008-10-22(xsd:dateTime)
bibo:doi	10.1016/j.bone.2008.10.035
bibo:pmid	19015051
has license	no-cc
sha1sum (hex)	d3d78ab5f29fe81e31d6ca71183d8ae136885deb
schema:url	https://doi.org/10.1016/j.bone.2008.10.035
resource representing a document's title	A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner
has PubMed Central identifier	PMC7185883
has PubMed identifier	19015051
schema:publication	Bone
resource representing a document's body	covid:d3d78ab5f29fe81e31d6ca71183d8ae136885deb#body_text
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