Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.
Aortic Valve Stenosis , Calcinosis , Hyperlipidemias , Animals , Aortic Valve/metabolism , Calcinosis/genetics , Cells, Cultured , Endothelial Cells/metabolism , Humans , Hyperlipidemias/genetics , Hyperlipidemias/metabolism , Immunomodulation , Inflammation/genetics , Inflammation/metabolism , Lipoproteins, LDL/metabolism , Mice , PPAR gamma/genetics , PPAR gamma/metabolism , Pioglitazone/pharmacology , Transcriptome
The antimetastatic properties of soybean saponin were investigated by evaluating matrix metalloproteinase (MMP-2 and MMP-9) production in HT-1080 cells. The mRNA expression levels of MMP-2 and MMP-9 were determined by RT-PCR analysis. The levels of secreted MMP-2, MMP-9 and tissue inhibitor of metalloproteinase-2 (TIMP-2) were determined by gelatin zymography and/or ELISA. The invasion of a Matrigel-coated membrane by human fibrosarcoma HT-1080 and HT-29 colon cancer cells was quantitatively assessed by counting the migrated cells. The treatment of HT-1080 cells with soybean saponin inhibited the mRNA expression of and reduced the amounts of secreted MMP-2 and MMP-9, whereas it increased the amount of secreted TIMP-2 dose-dependently. Soybean saponin significantly inhibited the invasion of HT-1080 cells through a Matrigel-coated membrane. The antimetastatic properties by soybean saponin were further confirmed by in vivo mice experiment via the tail vein injection of CT-26 colon cancer cells after feeding the mice the dietary soybean saponin. The incidence of metastatic tumor colonization of lungs of mice moderately decreased 2 weeks after the tail vein injection of CT-26 cells. Our current data support the notion that soybean saponin inhibits tumor cell metastasis by suppressing MMP-2 and MMP-9 productions, and stimulating TIMP-2 secretion, thereby suggesting that soybean saponin has a chemopreventive property against cancer metastasis.
Colonic Neoplasms/enzymology , Fibrosarcoma/enzymology , Glycine max/chemistry , Matrix Metalloproteinases/metabolism , Neoplasm Metastasis/prevention & control , Saponins/pharmacology , Animals , Cell Line, Tumor , Colonic Neoplasms/pathology , Fibrosarcoma/pathology , Gene Expression , Gene Expression Regulation, Neoplastic , HT29 Cells , Humans , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Tissue Inhibitor of Metalloproteinase-2/metabolism
The multifunctional G-protein-coupled metabotropic glutamate receptor (mGluR) family comprises eight subtypes, some of which participate in tumorigenesis. The purpose of this study was to evaluate mGluR5 expression in oral squamous cell carcinoma (SCC) tissues and oral cancer cell lines. We also investigated the prognostic significance of mGluR5 and its functional importance in the migration, invasion, and adhesion of oral cancer cells. We evaluated the expression of mGluR5 in samples from 131 oral SCC patients and in several oral cancer cell lines by immunohistochemistry and RT-PCR. We observed varying levels of mGluR5 in human oral SCC tissues and cancer cell lines. There was a significant association between strong mGluR5 immunoreactivity and overall survival (P=0.0109). The functional significance of the expression of mGluR5 in oral cancer cells was then investigated in HSC3 oral tongue cancer cells. An mGluR5 agonist, DHPG increased tumor cell migration, invasion, and adhesion in HSC3 cells (P<0.05). This was reversed by the mGluR5 antagonist MPEP. Our results strongly suggest that mGluR5 is a new prognostic marker and contributes to tumor cell migration and invasion in oral cancer.
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Receptors, Metabotropic Glutamate/biosynthesis , Cell Adhesion/physiology , Cell Line, Tumor , Cell Movement/physiology , Female , Humans , Immunohistochemistry , KB Cells , Male , Middle Aged , Neoplasm Invasiveness , Prognosis , Receptor, Metabotropic Glutamate 5 , Reverse Transcriptase Polymerase Chain Reaction
