ABSTRACT
OBJECTIVES: The results of elastic imaging in evaluating the function and histopathological changes of allogeneic renal transplantation are contradictory, one of the important reasons may be that there are differences in human parameters related to kidney transplantation among individuals. The purpose of this study is to explore the related human body parameters on shear-wave elastography (SWE) effects on quantitative stiffness of graft cortex. METHODS: From March 2021 to November 2021, a total of 63 patients with allogeneic kidney transplantation in the Department of Ultrasonography, Third Xiangya Hospital, Central South University, were selected to collect the parameters of two-dimensional, color Doppler and SWE. The subjects were divided into a <20% group and a 20%-30% group according to the variation of cortical hardness measurement. Mann Whitney U test was used to compare the differences in relevant human parameters, and Spearman rank correlation was used to analyze the correlation between relevant human parameters and cortical hardness of transplanted kidney. RESULTS: There was no significant difference between the 2 groups in age, sex, postoperative time, resistance index of interlobar artery, SCr, blood uric acid, ratio of fat layer to muscle layer, and BMI (all P>0.05). Compared with the <20% group, the patients in the 20%-30% group had smaller cortical hardness of the transplanted kidney, greater total distance between the transplanted kidney and the skin surface, and thicker fat layer or muscle layer in front of the transplanted kidney (all P<0.05). The age of patients, the total distance from the transplanted kidney to the skin surface, the thickness of fat layer and muscle layer, the ratio of fat layer to muscle layer, BMI, and the variation of cortical hardness were significantly negatively correlated with the cortical hardness of the transplanted kidney (all P<0.05). CONCLUSIONS: Human parameters relevant to kidney transplantation affect the accuracy of SWE in measuring the cortical hardness of the transplanted kidney. It is very important to obtain the highly stabile elastic measurement value and interpret the elastic measurement results according to different levels of human body related parameters in combination with individual conditions.
Subject(s)
Elasticity Imaging Techniques , Kidney Transplantation , Humans , Elasticity Imaging Techniques/methods , Kidney , Ultrasonography/methods , Transplantation, HomologousABSTRACT
High expression of cyclin D1 has a crucial role in the maintenance of unlimited cell growth in human cancer cells. The present study indicated that cyclin D1 was overexpressed in human nonsmall cell lung cancer (NSCLC) tumor tissues and cell lines. Knockout of cyclin D1 suppressed NSCLC cell growth, colony formation and in vivo tumor growth. Of note, the natural product xanthohumol (Xanth) inhibited NSCLC cells via the downregulation of cyclin D1. A further mechanistic study revealed that Xanth suppressed ERK1/2 signaling and reduced the protein levels of FOSrelated antigen 1 (Fra1), which eventually inhibited the transcriptional activity of activator protein1 and decreased the mRNA level of cyclin D1. Furthermore, suppression of ERK1/2 impaired Fra1 phosphorylation and enhanced Xanthinduced Fra1 ubiquitination and degradation. In addition, the S265D mutation compromised Xanthinduced Fra1 degradation. Finally, the in vivo antitumor effect of Xanth was validated in a xenograft mouse model. In summary, the present results indicated that targeting ERK1/2Fra1cyclin D1 signaling is a promising antitumor strategy for NSCLC treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cyclin D1/genetics , Flavonoids/pharmacology , Propiophenones/pharmacology , Proto-Oncogene Proteins c-fos/genetics , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , MAP Kinase Signaling System/drug effects , Mice , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Aerobic glycolysis is one of the hallmarks of human cancer cells. Overexpression of hexokinase 2 (HK2) plays a crucial role in the maintaining of unlimited tumor cell growth. In the present study, we found that the oral squamous cell carcinoma (OSCC) cells exhibited an aerobic glycolysis phenotype. Moreover, HK2 is highly expressed in OSCC patient derived-tissues and cell lines. Depletion of HK2 inhibited OSCC cell growth in vitro and in vivo. With a natural product screening, we identified Tanshinone IIA (Tan IIA) as a potential anti-tumor compound for OSCC through suppressing HK2-mediated glycolysis. Tan IIA decreased glucose consumption, lactate production, and promoted intrinsic apoptosis in OSCC cells. The mechanism study revealed that Tan IIA inhibited the Akt-c-Myc signaling and promoted E3 ligase FBW7-mediated c-Myc ubiquitination and degradation, which eventually reduced HK2 expression at the transcriptional level. In summary, these results indicate that targeting HK2-mediated aerobic glycolysis is a promising anti-tumor strategy for OSCC treatment.
Subject(s)
Abietanes/pharmacology , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Apoptosis/drug effects , Carcinoma, Squamous Cell/pathology , Cell Proliferation/drug effects , Head and Neck Neoplasms/metabolism , Humans , Mouth Neoplasms/drug therapy , Mouth Neoplasms/genetics , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Xenograft Model Antitumor Assays/methodsABSTRACT
BACKGROUND: The F-box protein S-phase kinase-associated protein 2 (Skp2) is overexpressed and correlated with poor prognosis in human malignancies, including colorectal cancer (CRC). METHODS: A natural product library was used for natural compound screening through glycolysis analysis. The expression of Skp2 in CRCs and the inhibitory effect of dioscin on glycolysis were examined through methods of immunoblot, immunofluorescence, immunohistochemical staining, anchorage-dependent and -independent growth assays, EdU incorporation assay, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment. FINDINGS: We demonstrated that Skp2 was highly expressed in CRC tissues and cell lines. Knockout of Skp2 inhibited HK2 and glycolysis and decreased CRC cell growth in vitro and in vivo. We screened 88 commercially available natural products and found that dioscin, a natural steroid saponin derived from several plants, significantly inhibited glycolysis in CRC cells. Dioscin decreased the protein level of Skp2 by shortening the half-life of Skp2. Further study showed that dioscin attenuated Skp2 phosphorylation on S72 and promoted the interaction between Skp2 and Cdh1, which eventually enhanced Skp2 lysine 48 (K48)-linked polyubiquitination and degradation. Depletion of Cdh1 impaired dioscin-induced Skp2 reduction, rescued HK2 expression, and glycolysis in CRC cells. Finally, dioscin delayed the in vivo tumor growth, promoted Skp2 ubiquitination, and inhibited Skp2 expression in a mouse xenograft model. INTERPRETATION: This study suggests that in addition to pharmacological inactivation of Skp2, enhancement of ubiquitination-dependent Skp2 turnover is a promising approach for cancer treatment.