ABSTRACT
BACKGROUND: RNA binding motif protein 15 (RBM15), a writer of N6-methyladenosine (m6A) methylation, contributes significantly to the development of various tumors. However, the function of RBM15 in cervical cancer (CC) has not been determined. METHODS: Based on the GSE9750, GSE63514, and m6A datasets, m6A-related differentially expressed genes (DEGs) were screened out. The hub genes were identified by generating a Protein-Protein Interaction (PPI) network. RT-qPCR was conducted to assess the mRNA expression of hub genes. CCK8, scratch wound healing, and transwell assays were utilized to examine the influence of RBM15 on HeLa and SiHa cells. Tumor xenograft models were used to assess the effects of RBM15 on tumorigenesis. A mechanistic analysis of RBM15 in CC tumors was conducted using the GeneCards and Coxpresdb databases, followed by a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the pathway-related genes were subsequently validated using Western blotting. RESULTS: Five DEGs were screened, including WTAP, RBM15, CBLL1, and YTHDC2. Among them, WTAP, RBM15, CBLL1, and YTHDC2 were hub genes and can be used as biomarkers for CC. RBM15 expression was considerably increased, while WTAP, CBLL1, and YTHDC2 were significantly downregulated. Knockdown of RBM15 significantly suppressed the proliferation, invasion, and migration of CC cells and tumorigenesis. Moreover, knockdown of RBM15 significantly reduced the expression levels of proteins related to the JAK-STAT pathway. CONCLUSIONS: Knockdown of RBM15 inhibited the progression of CC cells, which probably by inhibiting the JAK-STAT pathway pathway.
Subject(s)
Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/genetics , Janus Kinases , STAT Transcription Factors , Signal Transduction/genetics , Neoplastic Processes , Cell Transformation, Neoplastic , Carcinogenesis , RNA-Binding Proteins/genetics , Ubiquitin-Protein LigasesABSTRACT
Preterm birth is the leading cause of infant mortality. The mechanisms that instigate preterm birth remain elusive and this makes it difficult to predict or prevent preterm birth. In this study, the authors found that SP-A induced pathological damage to the placenta and promoted preterm birth. Through mechanism, SP-A promoted the expression of STOX1 which further promoted the oxidative stress in the placenta by inhibiting the activities of a series of antioxidant enzymes including SOD, CAT and GSH-Px. SP-A also induced dysregulation of arginine metabolism by inhibiting NOS2 and ARG2. Overexpression of STOX1 aggravated SP-A induced oxidative stress, pathological damage, and preterm birth, whereas knockdown of STOX1 alleviated SP-A induced oxidative stress, pathological damage and preterm birth. The present study uncovers that SP-A induces preterm birth by promoting oxidative stress via upregulating STOX1, which provides new targets for the prediction and prevention of preterm birth.
Subject(s)
Premature Birth , Antioxidants/metabolism , Carrier Proteins/metabolism , Female , Humans , Infant, Newborn , Infant, Premature , Oxidative Stress/physiology , Pregnancy , Surface-Active AgentsABSTRACT
Abstract Preterm birth is the leading cause of infant mortality. The mechanisms that instigate preterm birth remain elusive and this makes it difficult to predict or prevent preterm birth. In this study, the authors found that SP-A induced pathological damage to the placenta and promoted preterm birth. Through mechanism, SP-A promoted the expression of STOX1 which further promoted the oxidative stress in the placenta by inhibiting the activities of a series of antioxidant enzymes including SOD, CAT and GSH-Px. SP-A also induced dysregulation of arginine metabolism by inhibiting NOS2 and ARG2. Overexpression of STOX1 aggravated SP-A induced oxidative stress, pathological damage, and preterm birth, whereas knockdown of STOX1 alleviated SP-A induced oxidative stress, pathological damage and preterm birth. The present study uncovers that SP-A induces preterm birth by promoting oxidative stress via upregulating STOX1, which provides new targets for the prediction and prevention of preterm birth.
ABSTRACT
BACKGROUND: Synuclein-γ has been demonstrated to be highly expressed in various human cancers including cervical cancer, and has been shown to play a critical role in tumor aggressiveness. We aimed to investigate the role of Synuclein-γ in human cervical cancer in vitro and in vivo. METHOD: Reverse transcription-quantitative polymerase chain reaction assay and Western blot assay were used to detect the mRNA and protein expression, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay were performed to measure the viabilities of cancer cells. Flow cytometry assay was used to detect the cell cycle and apoptosis. Moreover, an animal experiment was performed to evaluate the biological behavior of Synuclein-γ in vivo. RESULTS: In the current study, we found that Synuclein-γ was obviously over-expressed in cervical cancer tissues compared to the adjacent non-cancer tissues. Cervical cancer cells transfected with Synuclein-γ siRNA demonstrated significant inhibition of cancer proliferation (P < 0.01), cell cycle arrest at G0/G1 phase, and cell apoptosis (P < 0.05). Moreover, down-regulation of Synuclein-γ significantly inhibited cervical cancer growth in vivo. In addition, protein levels of AKT, c-Myc and Cyclin D1 were much lower in the Synuclein-γ siRNA-treated groups than that in the control group. CONCLUSIONS: Synuclein-γ inhibition reduced cervical cancer tumor growth through the AKT pathway. This effect represented a therapeutic opportunity and provided a novel target for cervical cancer treatment.
Subject(s)
Neoplasm Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Uterine Cervical Neoplasms/metabolism , gamma-Synuclein/metabolism , Apoptosis , Cell Line, Tumor , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , Middle Aged , Uterine Cervical Neoplasms/physiopathologyABSTRACT
Compound SIPI5047 was synthesize by using piperazine as starting material in five reaction steps, and its central none-opioid analgesic activity was studied. Its analgesic activity, pharmacological mechanism, action type and drug dependence were well studied in vivo and in vitro. The results show that SIPI5047 has potent analgesic activities in vivo, which is quite similar to morphine and also much more powerful than paracetamol. SIPI5047 has no efficacy to reduce fever or inflammation, but has an obvious action on central nervous system. SIPI5057 has no apparent affinity with the mu-receptor and it is an antagonist that acts on the polyamine site of the NMDA receptor. SIPI5057 appears no drug dependence. SIPI5047 is a novel central none-opioid analgesic agent and more worthy of further research as a new drug candidate.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Pain Measurement/methods , Piperazines/chemical synthesis , Piperazines/pharmacology , Analgesics/toxicity , Animals , Female , Male , Mice , Motor Activity/drug effects , Piperazines/toxicity , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Substance-Related Disorders/etiologyABSTRACT
To synthesize aralkyl-ketone piperazine derivatives as analgesic agents, the N atom of the one side of piperazine ring is protected by formyl group firstly, then the unprotected N atom is alkylated to prepare aralkyl-ketone piperazine derivatives. Their analgesic biological activities were well studied by mice writhing model, rat hot plate model and rat tail flick model. Sixty four compounds were synthesized and pharmacological tests in vivo revealed these compounds have potent analgesic activities, especially compound I12, I14, I14 I21 and I37. These four compounds are more worthy for further research.
