Liquiritigenin alleviates doxorubicin-induced chronic heart failure via promoting ARHGAP18 and suppressing RhoA/ROCK1 pathway.

Chronic heart failure (CHF) is one of the most common chronic diseases with increasing incidence and mortality. Liquiritigenin (LQG) is shown to protect mice from cardiotoxicity. However, its underlying mechanism remains unclear. Our study aimed to reveal the role of ARHGAP18 in LQG-mediated cardioprotective effects in CHF. In the current study, CHF cell model and rat model were established by the application of doxorubicin (DOX). The reactive oxygen species (ROS) level and cell apoptosis were determined by flow cytometry. The cardiac function of rats was evaluated by measuring left ventricular systolic pressure, left ventricular end diastolic pressure, and serum level of lactate dehydrogenase and brain natriuretic peptide. The expression of active RhoA was elevated and that of ARHGAP18 was decreased in DOX-induced CHF cell model. ARHGAP18 could reduce DOX-induced RhoA activation, ROS elevation, and cell apoptosis. Meanwhile, the knockdown of ARHGAP18 could promote the activation of RhoA, the level of ROS, and the rate of cell apoptosis, which could be reversed by the application of RhoA inhibitor. LQG promoted the expression of ARHGAP18 and exerted similar effects of ARHGAP18 in CHF cell model. The application of LQG could also reverse the effects mediated by ARHGAP18 knockdown. Moreover, LQG significantly improved cardiac function and ameliorated DOX-induced cardiotoxicity of CHF rats. In conclusion, LQG could alleviate DOX-induced CHF via promoting ARHGAP18 and suppressing RhoA/ROCK1 pathway. LQG was a potential agent for CHF treatment.

Quantitative proteomic analysis reveals that the Rap1/MAPK/ERK pathway is inhibited through selenomethionine strengthening antioxidant activity.

To investigate the influence on the proteome of chicken skeletal muscles of Selenomethionine (SeMet) use, 36 chicks were fed with SeMet feeding for 35 days. A total of 72 1-day old broiler chicks were randomly allocated into two groups (n = 36/group): the control group (C group), the SeMet supplemented group (SeMet group). The Selenium (Se) concentrations of skeletal muscles from the chicks with basal diet (negative control group) and SeMet feeding were found to be 0.01 mg/kg and 0.40 mg/kg, respectively. The skeletal muscles from the two groups were investigated using isobaric Tags for Relative and Absolute Quantitation (iTRAQ), coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. This proteomic analysis identified proteins that were differentially expressed between the two groups. A total of 3564 proteins from the SeMet and the control (C) groups at 35 days were analyzed. 86 proteins were found by iTRAQ to be differentially expressed in the SeMet group, including 38 up-regulated proteins and 48 down-regulated proteins. These differential proteins were later identified as being mainly involved in antioxidant and enzyme-regulating activities. Fluorescent quantitative PCR(qPCR) and Western blot analyse proved to be consistent with the results of iTRAQ identification. The differentially expressed proteins (DEPs) identified in our work could be specific biomarkers related to SeMet intake in chicks. SeMet intake may strengthen antioxidant activity through Rap1/mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) signal pathways.

YY1-Induced Upregulation of Long Noncoding RNA ARAP1-AS1 Promotes Cell Migration and Invasion in Colorectal Cancer Through the Wnt/ß-Catenin Signaling Pathway.

Introduction: It has been reported that long noncoding RNAs (lncRNAs) are crucial regulators in progression of human cancers, including colorectal cancer (CRC). However, the function of lncRNA ARAP1 antisense RNA 1 (ARAP1-AS1) in CRC remains unclear. Aim: The aim of this study was to investigate the function and molecular mechanism of lncRNA ARAP1-AS1 in CRC. Results: ARAP1-AS1 was highly expressed in CRC tissues and cell lines. ARAP1-AS1 knockdown suppressed cell migration, invasion, and epithelial-mesenchymal transition (EMT). YY1 transcription factor (YY1) enhanced the transcription activity of ARAP1-AS1. The YY1/ARAP1-AS1 axis promoted CRC cell migration and invasion. YY1/ARAP1-AS1 could regulate the Wnt/ß-catenin signaling pathway. Conclusions: This study revealed that YY1-induced upregulation of ARAP1-AS1 promoted cell migration, invasion, and EMT process in CRC through the Wnt/ß-catenin signaling pathway.

Cancer growth regulation by 4-hydroxynonenal.

While reactive oxygen species (ROS) gain their carcinogenic effects by DNA mutations, if generated in the vicinity of genome, lipid peroxidation products, notably 4-hydroxynonenal (HNE), have much more complex modes of activities. Namely, while ROS are short living and have short efficiency distance range (in nm or µm) HNE has strong binding affinity for proteins, thus forming relatively stable adducts. Hence, HNE can diffuse from the site or origin changing structure and function of respective proteins. Consequently HNE can influence proliferation, differentiation and apoptosis of cancer cells on one hand, while on the other it can affect genome functionality, too. Although HNE is considered to be important factor of carcinogenesis due to its ability to covalently bind to DNA, it might also be cytotoxic for cancer cells, as well as it can modulate their growth. In addition to direct cytotoxicity, HNE is also involved in activity mechanisms by which several cytostatic drugs and radiotherapy exhibit their anticancer effects. Complementary to that, the metabolic pathway for HNE detoxification through RLIP76, which is enhanced in cancer, may be a target for anti-cancer treatments. In addition, some cancer cells can undergo apoptosis or necrosis, if exposed to supraphysiological HNE levels in the cancer microenvironment, especially if challenged additionally by pro-oxidative cytostatics and/or inflammation. These findings could explain previously observed disappearance of HNE from invading cancer cells, which is associated with the increase of HNE in non-malignant cells close to invading cancer utilizing cardiolipin as the source of cancer-inhibiting HNE.

Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome.

On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.

Upregulation of miR-124 by physcion 8-O-ß-glucopyranoside inhibits proliferation and invasion of malignant melanoma cells via repressing RLIP76.

Melanoma is the most malignant type of skin cancer. In recent years, mounting studies have evidenced the involvement of miRNAs in melanoma. One of these miRNAs, miR-124 has been found aberrantly downregulated in a variety of human malignancies. In this study, our results showed that the expression of miR-124 was significantly lower in malignant melanoma tissues and cell lines and miR-124 functioned as a tumor suppressor in melanoma. Moreover, our findings showed that miR-124 exerted anti-tumor effect by directly targeting RLIP76, a stress-inducible non-ABC transporter that plays a crucial role in the development of melanoma. Furthermore, our study also showed that physcion 8-O-ß-glucopyranoside, a natural compound from medicinal plant, could inhibit the proliferation and invasion of melanoma cells by targeting miR-124/RLIP76 signaling.

Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression.

The prognosis of glioblastoma remains poor, even treatment with surgery, radiation, or chemotherapy. Therefore, it is still important to develop a new strategy for treatment of glioblastoma. Previous reports demonstrated that rRNA is produced at abnormally high levels in tumor cells. Nuclear export of all non-coding RNAs are known to depend on RanGTPase system. Hydrolyzation of RanGTP-RNA complex by RanGTPase activating protein 1 (RanGAP1) releases RNA from nucleus to cytoplasm. Therefore, inhibition of RNA transportation would be a useful strategy to affect cancer cell fate. In this study, 5-30 µM of oridonin, a natural diterpenoid compound isolated from the traditional Chinese medicine, Rabdosia rubescens, induced U87MG glioma cell apoptosis and RNA accumulation in nucleus at 12h-time point. Before U87MG cell apoptosis, the RanGAP1 protein amount decreased and RanGTP accumulated in nucleus as respectively determined by immunoprecipitation and immunofluorescence, suggesting that decrease of RanGAP1 may result in nuclear entrapment of RanGTP and RNA, and then induce U87MG cell death. In contrast, over-expression of the RanGAP1 protein reversed oridonin-induced U87MG cell apoptosis. Hence, we demonstrated that downregulation of the RanGAP1 protein level by oridonin may result in RNA accumulation in nucleus via nuclear entrapment of RanGTP which eventually led to the apoptosis of glioma cells.