Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe^-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.
Animals ; Atherosclerosis/prevention & control* ; Mice ; Receptor, Fibroblast Growth Factor, Type 1/metabolism* ; Signal Transduction/drug effects* ; Anthraquinones/pharmacology* ; Humans ; Integrin beta1/metabolism* ; Epithelial-Mesenchymal Transition/drug effects* ; Male ; Transforming Growth Factor beta/metabolism* ; Disease Models, Animal ; Mice, Inbred C57BL ; Human Umbilical Vein Endothelial Cells/drug effects*

OBJECTIVE： To conduct sulfated modification of polysaccharide from Dictamnus dasycarpus （DDP-Ⅲ）， and to compare structure characteristics and anti-psoriasis activity of DDP-Ⅲ before and after sulfated modification. METHODS： DDP-Ⅲ was separated and purified with DEAE-52 anion exchange cellulose column and Sephadex G-100 column. After derived with 1-phenyl-3-methyl-5-pyrazolone， HPLC was used to determine the composition of its monosaccharide. SDDP-Ⅲ was synthesized using esterification reagent （anhydrous pyridine+chlorosulfonic acid） to modify DDP-Ⅲ. The degree of sulfate substitution was determined by barium chloride-gelatin turbidimetric method. The structures were compared by IR， Raman spectrum and SEM before and after modification. The male ICR mice were randomly divided into normal group， model group， positive group （tripterygium glycosides， 20 mg/kg） and DDP-Ⅲ/SDDP-Ⅲ low-dose， medium-dose and high-dose groups （56， 112， 224 mg/kg）. Except that normal group was given vaseline for external use， and other groups were given Imiquimod cream for external use to induce psoriasis model. At the same time， administration groups were given relevant medicine intragastrically 0.4 mL， and both normal group and model group were given constant volume of water intragastrically， once a day， for consecutive 14 d. Two hours after last medication， the serum contents of IL-17 and IL-23 were determined by ELISA. The skin scales near the tail were observed by HE staining， and the number of scales with granular layer was recorded. RESULTS： DDP-Ⅲ was composed of mannose， rhamnose， glucuronic acid， galacturonic acid and glucose. The degree of sulfate substitution was 0.65 for SDDP-Ⅲ. IR and Raman spectrum showed that the characteristic absorption peaks of sulfate radical group appeared near 1 255 cm－1 and 823 cm－1， 1 240 cm－1 and 815 cm－1 for SDDP-Ⅲ， except for same characteristic absorption peak as DDP-Ⅲ. SEM analysis showed that DDP-Ⅲ was flaky， smooth and tightly arranged； SDDP-Ⅲ was massive or granular with porous structure and loose arrangement. Animal experiment showed that compared with normal group， the epidermis of skin lesion was significantly thickened and the granular layer was significantly reduced； serum contents of IL-17 and IL-23 were increased significantly， while the number of scales with granular layer was decreased significantly （P＜0.05 or P＜0.01）. Compared with model group， above symptoms of administration groups were improved to different extent， and serum contents of IL-17 and IL-23 in positive group， DDP-Ⅲ high-dose groups， SDDP-Ⅲ medium-dose and high-dose groups were decreased significantly； the number of scales with granular layer was increased significantly， and above indexes of SDDP-Ⅲ medium-dose and high-dose groups were significantly better than corresponding DDP-Ⅲ group （P＜0.05 or P＜0.01）. CONCLUSIONS： DDP-Ⅲ contains five monosaccharide components such as mannose， etc. Both DDP-Ⅲ and SDDP-Ⅲ possess anti- psoriasis effects， and SDDP-Ⅲ exhibits stronger anti-psoriasis effect than DDP-Ⅲ. Its mechanism may be associated with inhibiting IL-23/IL-17 signaling pathway.

Objective To investigate the sonographic diagnosis and genetic counseling of fetal cardiac rhabdomyoma.Methods Four cases of fetal cardiac rhabdomyoma diagnosed at Peking Union Medical College Hospital from August 2016 to January 2017 were enrolled in this retrospective study.The results of ultrasound,other image modalities,genetic testing,and pregnancy outcomes were analyzed.Results In all fetuses echogenic solid masses were observed in the ventricles,which were single in 2 cases and multiple in the other two cases.In two fetuses no extracardiac anomalies were identified,and in another two tuberous sclerosis was diagnosed based on the clinical features including renal cyst in one case and intracranial tubers on ultrasound and MRI in another case.There was negative family history for genetic diseases in all cases except one.After counseling,all parents opted for pregnancy termination.Autopsy was performed in 3 cases,in whom characteristic cardiac rhabdomyomas were found in left ventricle.Microscopic examination of one case showed cysts arising from tubules in both kidneys.In another case mutilple tubers were observed on the trunk.Conclusions Cardiac rhabdomyomas are characteristic on prenatal ultrasound.Targeted screening based on ultrasound and family history are helpful for the early diagnosis of tuberous sclerosis.Genetic testing should be considered in suspected cases.