Journal of Receptors and Signal Transduction最新文献

Purpose: Curcumin has shown anti-tumor activity in multiple malignancies. The aim of our study was to explore the molecular mechanism behind the anti-tumor activity of curcumin in hepatocellular carcinoma (HCC).

Methods: The proliferation, migration, invasion, and apoptosis were analyzed by 5-ethynyl-2'-deoxyuridine (EDU) assay, transwell migration assay, transwell invasion assay, and flow cytometry. Western blot assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted to analyze protein and RNA expression. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the interaction between microRNA-378b (miR-378b) and circular RNA_0078710 (circ_0078710) or DNA primase, polypeptide 2 (PRIM2). Tumor xenograft assay was conducted to assess the roles of curcumin and circ_0078710 in vivo.

Results: Curcumin stimulation restrained the proliferation, migration, and invasion, and triggered the apoptosis of HCC cells. Curcumin down-regulated the expression of circ_0078710 in HCC cells in a dose-dependent manner. Circ_0078710 knockdown aggravated curcumin-mediated anti-tumor effects in HCC cells. Circ_0078710 acted as a molecular sponge for miR-378b. Circ_0078710 interference-induced effects in curcumin-stimulated HCC cells were partly abolished by the silence of miR-378b. MiR-378b bound to the 3' untranslated region (3'UTR) of PRIM2. PRIM2 overexpression partly reversed circ_0078710 interference-mediated influences in curcumin-treated HCC cells. Circ_0078710 silencing aggravated curcumin-mediated suppressive effect in tumor growth in vivo.

Conclusions: Circ_0078710 silencing aggravated curcumin-mediated anti-tumor effects through mediating the miR-378b/PRIM2 signaling in HCC cells.

Several intracellular pathological processes have been reported to be regulated by the FAM19A5/S1PR1 signaling pathway. However, the role of FAM19A5/S1PR1 signaling pathway in the viability and proliferation of mantle cell lymphoma is not been completely understood. The task of this study is to explore the influence of FAM19A5/S1PR1 signaling pathway in affecting the survival and growth of mantle cell lymphoma. shRNAs against FAM19A5 or S1PR1 were transfected into mantle cell lymphom. Cell viability and proliferation were measured through MTT assay and CCK8 assay, respectively. Our results demonstrated that loss of FAM19A5 significantly reduced the viability of mantle cell lymphom, an effect that was followed by a drop in cell proliferation capacity. Besides, inhibition of S1PR1 also impairs cell survival and interrupt mantle cell lymphom proliferation in vitro. Taken together, our results illustrate that FAM19A5/S1PR1 signaling pathway is associated with the regulation of mantle cell lymphom viability and proliferation. This finding will provide a potential target for the treatment of malignant lymphoma in the clinical practice.

Nonalcoholic steatohepatitis (NASH) is considered as a common liver disease. SIRT1, a pivotal sensor, controls activation of metabolic, inflammatory and apoptotic pathways. Rosmarinic acid (RA) has positive effects on the liver injuries; nevertheless, its mechanisms are not completely studied. The aim of this study was to explore the role of rosmarinic acid on the pathways involved by SIRT1 for amelioration of a mouse model of NASH. To do this, C57/BL6 mice were divided into four equal groups (6 in each group). Animals received saline and rosmarinic acid as the control groups. NASH was induced by methionine-choline-deficient (MCD) diet. In the NASH + RA group, Rosmarinic acid was injected daily in mice fed on an MCD diet. Rosmarinic acid decreased plasma triglyceride, cholesterol, liver Steatosis and oxidative stress. Rosmarinic acid administration also increased SIRT1, Nrf2 and PPARα and decreased SREBP1c, FAS, NFκB and caspase3 expressions. Moreover, TNFα, IL6, P53, Bax/Bcl2 ratio and caspase3 expressions decreased. Our study demonstrated that remarkable effects of rosmarinic acid on the mice with NASH might be due to activation of SIRT1/Nrf2, SIRT1/NFκB and SIRT1/PPARα pathways, which alleviate hepatic steatosis, oxidative stress, inflammation and apoptosis.

Emodin has been shown to exert a renoprotective effect in diabetic nephropathy (DN). In this paper, we investigated whether circular RNAs (circRNAs) might be involved in the renoprotective mechanism of emodin in DN. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured using the corresponding assay kits. The expression levels of circ_0000064, microRNA (miR)-30c-5p, large multifunctional protease 7 (Lmp7), fibronectin (FN), and collagen type I (Col.1) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Subcellular localization assay was used to assess the cellular localization of circ_0000064. Targeted relationships among circ_0000064, miR-30c-5p and Lmp7 were confirmed by dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation (RIP) assays. Our data showed the alleviative effect of emodin on HG-induced oxidative stress, inflammation and extracellular matrix (ECM) accumulation in SV-MES13 cells. Circ_0000064 was an importantly downstream effector of emodin function in HG-induced SV40-MES13 cells. Moreover, circ_0000064 directly targeted miR-30c-5p, and circ_0000064 modulated Lmp7 expression through miR-30c-5p. Circ_0000064 silencing alleviated HG-induced cell oxidative stress, inflammation and ECM accumulation via up-regulating miR-30c-5p. The enforced expression of miR-30c-5p attenuated HG-induced oxidative stress, inflammation and ECM accumulation in SV40-MES13 cells by targeting Lmp7. Our findings identified that emodin alleviated HG-induced oxidative stress, inflammation and ECM accumulation in SV40-MES13 cells at least partially by the regulation of the circ_0000064/miR-30c-5p/Lmp7 axis.

Hyperuricemia may be a risk factor for cardiovascular diseases such as hypertension and atherosclerosis, but the mechanisms underlying uric acid-induced pathological conditions remain unknown. In this study, we investigated the effect of short time and long-term administration of increasing uric acid concentrations on cell viability, proliferative and apoptotic pathways in vascular smooth muscle cells (VSMCs). Cell viability/proliferation was determined with WST-1 assay. Expression levels of mitogen-activated protein kinases (MAPKs) (phosphorylated (p)-p38 and p-p44/42 MAPK), extrinsic (caspase 3, caspase 8), and intrinsic (B-cell lymphoma-extra-large (Bcl-xL)) apoptotic pathway proteins were measured by Western blotting. In order to assess the proliferative effects of uric acid incubations on VSMCs, we monitored the proliferative/apoptosis signaling pathways for up to 24 h. Our results indicated that uric acid increases cell viability at time and dose-dependently in VSMCs. Immunoblotting results showed that uric acid treatment elevated the expression level of p-p38 MAPK but did markedly reduce the protein levels of p-p44/42, compared with all the uric acid doses-treated VSMCs, especially at 1 h. Uric acid stimulation increased caspase-3 protein levels and decreased Bcl-xL, but did not alter caspase-8 protein expression at the same dose and time. Furthermore, low uric acid incubations (0-7.5 mg/dL) did not affect any signaling pathways for long time points (6-24 h). In conclusion, our study demonstrates for the first time that VSMCs induced with uric acid can affect cell viability, proliferative, and apoptosis pathways at the widest time and dose range. These findings provide a better understanding of the uric acid effects related to vascular impairments.

Baicalin plays important roles in different types of cancer. A previous report showed that baicalin attenuates cisplatin resistance in lung cancer. However, its mechanism remains unclear. In this study, we investigated the effect and mechanism of baicalin on DNA repair and sensitivity of lung cancer cells to cisplatin. A549 and A549/DPP cells were treated with baicalin and cisplatin. A549/DPP cells were transfected with XRCC1 and siXRCC1. Cell viability and DNA damage were detected by MTT and comet assay. Apoptosis rate and cell cycle were detected by flow cytometry assay. The expressions of Bax, Bcl-2, and Cyclin D1 were detected by western blot. XRCC1 expression was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Baicalin and cisplatin decreased cell viability in A549 and A549/DPP cells in dose-dependent manner. Baicalin enhanced the effect of cisplatin on promoting apoptosis, arresting cell on S stage and triggering DNA damage accompanied with the upregulation of Bcl-2-associated X protein (Bax) and downregulation of B-cell lymphoma 2 (Bcl-2) and Cyclin D1 in A549/DPP cells. Moreover, baicalin promoted the inhibitory effect of cisplatin on XRCC1 expression in A549 and A549/DPP cells. However, the synthetic effects of baicalin and cisplatin on A549/DPP cells were partially inhibited by XRCC1 overexpression and promoted by XRCC1 knockdown. This study demonstrates that baicalin interferes with XRCC1-mediated cellar DNA repair to sensitize lung cancer cells to cisplatin.

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy with high mortality. Recent findings suggest that the succinate dehydrogenase complex subunit A (SDHA) is lowly expressed in many types of cancers and involved in tumorigenesis. However, the potential regulatory roles and molecular mechanisms by which SDHA affects the development and progression of ccRCC remain largely unknown. In this study, our results showed that there was significant downregulation of SDHA in ccRCC tissue relative to corresponding non-cancerous tissue, and low expression of SDHA was associated with Fuhrman pathological grade, tumor size, TNM stage, metastasis, and poor prognosis in ccRCC patients. Moreover, overexpression of SDHA inhibited the proliferation, invasion, and migration capacities of ccRCC cells. Mechanistically, SDHA impeded the proliferation and metastasis of ccRCC cells by inactivation of the Wnt/β-catenin pathway. In vivo experiments, SDHA suppressed ccRCC growth in a nude mouse model. In conclusion, our study results indicated that SDHA may act as a new molecular marker for judging the occurrence and development of ccRCC and serve as a therapeutic target for the treatment of human ccRCC.

Purpose: Breast cancer (BCa) is one of the most common gynecological malignancies. Ubiquitin-coupled enzyme E2T (UBE2T) has been demonstrated to play crucial roles in various tumors.

Methods: UBE2T levels were detected using quantitative real time PCR and western blot. CCK-8 and colony formation assays were used to evaluate cell proliferation. A xenograft model was used to evaluate the effects of UBE2T on tumor growth in mice, and immunohistochemistry (IHC) assay was performed to detect the expression of UBE2T and Ki-67. Transwell assay was performed to determine cell migration and invasion. The ATP level, glucose consumption and lactate production were measured using the corresponding commercial kits. Western blot assay was used to detect the levels of epithelial-mesenchymal transformation (EMT), glycolytic and the PI3K/AKT pathway related proteins regulated by UBE2T.

Results: Upregulation of UBE2T expression in human BCa tissues was found in human clinical BCa tissues and The Cancer Genome Atlas (TCGA) dataset. The expression of UBE2T was confirmed to be up-regulated in BCa cells compared to normal breast epithelial cell line (MCF-10A). Overexpression of UBE2T promoted proliferation, migration, invasion and glycolysis in BCa cells, while UBE2T knockdown showed the opposite results. Moreover, UBE2T knockdown suppressed tumor growth in mice. Further mechanism analysis shows that UBE2T participated in the regulation of BCa progression through affecting the PI3K/AKT signaling pathway.

Conclusion: UBE2T promoted proliferation, invasion and glycolysis through modulating PI3K/AKT signaling pathway in BCa, implying that UBE2T may provide a promising therapeutic target for the therapy of BCa.

The activation of glial cells and its possible mechanism play an extremely important role in understanding the pathophysiological process of some clinical diseases, and catestatin (CST) is involved in regulating this activation. In this project, we found that CST could enhance the activation of satellite glial cells (SGCs) and microglial cells and that the expression of P2X₄ was increased; the co-expression of the P2X₄ receptor with glial fibrillary acidic protein (GFAP) and the P2X₄ receptor with CD11b was also increased significantly in glial cells of the ATP + CST group, and TNF-α and IL-1β also showed a rising trend; the expression of phosphorylated ERK1/2 was also increased in the ATP + CST group. In summary, we conclude that CST could enhance ATP-induced activation of SGCs and microglial cells mediated by the P2X₄ receptor and that the ERK1/2 signaling pathway may be involved in this activation process.