MARCH9 Suppresses Lung Adenocarcinoma Progression by Downregulating ICAM-1.

BACKGROUND/AIMS: To investigate the clinical significance and functional mechanisms of membrane-associated RING-CH protein 9 (MARCH9) in lung adenocarcinoma (LAC). METHODS: Immunohistochemistry staining was performed to explore the expression of MARCH9 in LAC tissues and adjacent normal lung tissues. Patients' prognosis was evaluated using overall survival. The prognostic role of MARCH9 was tested with univariate and multivariate analyses. To confirm the effect of MARCH9 in cell proliferation and invasion, overexpression of MARCH9 was induced in two LAC cell lines. Cell cycle, apoptosis, migration, invasion, and immunoprecipitation experiments were performed to further explore the signaling pathways involved. RESULTS: Analysis of a series of 143 clinical samples revealed that MARCH9 was down-regulated in tumor tissues compared with normal lung tissues, and this was closely associated with lymph node metastasis (P = 0.004). Univariate and multivariate analyses indicated that MARCH9 was an independent prognostic biomarker for LAC; low MARCH9 expression indicated poor overall survival. Cellular studies with A549 and H1299 cells demonstrated that MARCH9 can attenuate tumor migration and invasion but had little effect on cell cycle or apoptosis. Moreover, an interaction between MARCH9 and ICAM-1 protein was identified, and overexpression of MARCH9 was found to attenuate the oncogenic effect of ICAM-1, suggesting that MARCH9 may inhibit tumor progression by downregulating ICAM-1 signaling. CONCLUSION: MARCH9 downregulation in LAC tissues correlated with poor clinical outcomes. MARCH9 may serve as a novel biomarker and potential therapeutic target for LAC.

[Effects of xinfuli granule on cardiomyocyte apoptosis in rats with dilated heart failure induced by adriamycin].

OBJECTIVE: To investigate the effects of Xinfuli Granule (XG) on cardiomyocyte apoptosis in rats with adriamycin-induced dilated cardiomyopathy (DCM). METHODS: Seventy-two male SD rats were randomly divided into 6 groups, i.e., the normal control group, the model group, the irbesartan group, the low dose XG group, the medium dose XG group, and the high dose XG group. The DCM heart failure rat model was established using peritoneal injection of ADR. Equal volume of normal saline was injected to those in the normal control group, once per week for 6 consecutive weeks. The medication was started from the 5th week by gastrogavage. XG was dispensed into 0.5 g/mL suspension with distilled water. The XG was administered at the daily dose of 0.675 g/kg, 1.350 g/kg, and 2.700 g/kg to those in the low dose XG group, the medium dose XG group, and the high dose XG group, respectively. Irbesartan was administered to rats in the irbesartan group at the daily dose of 50 mg/kg. Equal volume of normal saline was administered to those in the normal control group and the model group by gastrogavage, once in the morning for 4 consecutive weeks. Myocardial apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the expressions of the Bcl-2 and Bax protein of cardiomyocytes were measured by immunohistochemical assay. RESULTS: Compared with the normal control group, the cardiomyocyte apoptosis rate and Bax expression level obviously increased, but the expression of Bcl-2 and the Bcl-2/Bax ratio decreased significantly in the model group (P < 0.05). Compared with the model group, the expression of Bax and the Bcl-2/Bax ratio increased significantly in the high dose XG group and the irbesartan group (P < 0.01). The Bax expression level obviously decreased in all groups except the normal control group (P < 0.01). CONCLUSIONS: XG could obviously attenuate cardiomyocyte apoptosis in the adriamycin-induced DCM rats, and reverse the occurrence and development of heart reconstruction. The underlying mechanism might be related to regulating and controlling the expressions of Bax and Bcl-2.

Xinfuli improves cardiac function, histopathological changes and attenuate cardiomyocyte apoptosis in rats with doxorubicin-induced cardiotoxicity.

BACKGROUND: Xinfuli Granule (XG), a compound Chinese herbal medicine, has been effectively used in China for the treatment of heart failure for more than fifty years. This study aimed to investigate the effects and the underlying mechanisms of Xinfuli in rats with doxorubicin-induced cardiotoxicity. METHODS: Sprague-Dawley rats were treated with intraperitoneal injection of Doxorubicin (DOX, 2.5 mg/kg per week) for six weeks, and then randomly divided into four groups which received intragastrically administration of normal saline (control group) or different dosage of XG (0.675 g/kg per day, 1.35 g/kg per day, and 2.7g/kg per day, respectively) for six weeks. Transthoracic echocardiography was performed to evaluate the left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) before and after the XG treatment and histopathologic changes were also examined. Myocardial cell apoptosis was detected by TUNEL staining. The expression of related genes and proteins were analyzed using immunohistochemical staining. RESULTS: Compared to those in the control group, rats in XG treated groups showed significantly improved cardiac function and milder cardiac histopathological changes, lower cardiomyocyte apoptosis index, higher expression of Bcl-2 and lower expression of Bax. CONCLUSIONS: Administration of XG improves cardiac function and histopathological changes in rats with doxorubicin-induced cardiotoxicity. These effects are associated with inhibition of cardiomyocyte apoptosis, perhaps via regulation of Bcl-2 and Bax protein expression.