Journal of Receptors and Signal Transduction最新文献

Purpose: The interaction between PD-L1 on tumor cells and the programmed death 1 (PD1) on immune cells helps them to escape the immune system elimination. Therefore, developing therapeutic agents to block this interaction has garnered a lot of attention as a therapeutic approach. In the present study, we have tried to screen for an inhibitory compound to inhibit the interaction between the PD1/PD-L1 molecules.

Methods: In this regard, the structure of PD-L1 and its inhibitor were prepared and employed to generate an e-Pharmacophore model. A library of approved compounds was prepared and toxicity analysis using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictor was performed. The built e-Pharmacophore model was validated and used to screen the prepared compound library. Ligand docking and binding energy calculation were performed on the screened ligands.

Results: A seven-feature e-Pharmacophore model was generated using the PD-L1 complex. All of the compounds within the library passed the ADMET criteria. Performing the virtual screening, only 79 compounds have survived the criteria to fit four pharmacophoric features. The compound with the highest binding energy was the liothyronine (T3).

Conclusion: The ability of T3 in PD1/PD-L1 checkpoint blockade along with its potential in T4 reduction could be a desirable combination in cancer treatment. These abilities of T3 could be used to restore the ability of the immune system to eliminate tumor cells.

To investigate the effects of formononetin on rats with gastric ulcer and further to explore its possible mechanism. Rats were randomly divided into sham operation group (Sham), model group (Model), omeprazole control group (Omeprazole) and formononetin in different dose groups (FOR-L, FOR-M, FOR-H). Rats model with gastric ulcer were established by 100% glacial acetic acid. Hematoxylin-eosin (H&E) staining was used to observe the pathological morphology of gastric mucosa. Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to detect the level of inflammatory and angiogenesis related factors. The expressions of nuclear factor kappa-B (NF-κB) signaling pathway-related proteins were detected by western blot. Formononetin and omeprazole could ameliorate the pathological morphology of gastric mucosa in gastric ulcer rats. Compared with Model group, the levels of tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, IL-6, myeloperoxidase (MPO), human endothelin (ET)-1 and p-P65 protein in formononetin treatment and omeprazole groups were significantly decreased (p < 0.05). Moreover, formononetin could increase the content of vascular endothelial growth factor (VEGF), nitric oxide (NO) and the levels of CD34, tight junction proteins (ZO-1 and occludin) and p-IκBα in a dose-dependent manner. Formononetin can ameliorate gastric ulcer in rats by inhibiting inflammation and promoting gastric mucosal angiogenesis, and its mechanism maybe related to NF-κB signaling pathway.

Objective: To investigate the feasibility and to optimize the parameters of nonlinear blending technique in dual-energy CT on solitary pulmonary nodules (SPN).

Methods: The simulated enhanced SPN were used the mixture of nonionic iodinated contrast agent (Iopromide 370mgI/100 ml) and normal saline and then randomly placed inside an anthropomorphic chest phantom. The phantom was examined on SOMATOM definition flash with dual mode (80/140 kV) and single energy mode (120 kV) (the same CTDIvol). Nonlinear blending images and linear blending images with a weighting factor of 0.3 were generated and the image qualities were analyzed.

Results: For different simulated density SPN, when 0 HU was chosen as the Blending Center (BC) and 0 to 30 HU were chosen as the Blending width (BW), the nonlinear blending images yielded a higher contrast-to-noise (CNR). There were significant differences in the image noise and signal-to-noise (SNR) of different simulated density SPN at non-linear blending images, linear blending images and 120 kV images (p < .05); But the differences of CNR between the three groups were not statistically significant (p > .05). The SNR of different simulated density SPN at non-linear blending images was significantly increased compared with it at linear blending images and 120 kV images (p < .05); And the image noise at non-linear blending was lower than it at linear blending images (p < .05).

Conclusion: Nonlinear blending technique in dual-energy CT can increase the SNR of enhanced SPN, and it is helpful in diagnosis of SPN.

Pleural fibrosis is an irreversible pathological process occurred in the development of several lung diseases. TMEM88 is a member of transmembrane (TMEM) family and has been found to be involved in the regulation of fibrogenesis. However, the role of TMEM88 in pleural fibrosis remains unknown. In this study, we aimed to explore the role of TMEM88 in pleural fibrosis in vitro using transforming growth factor-β1 (TGF-β1)-induced human pleural mesothelial cell line MeT-5A cells. Our results showed that the expression levels of TMEM88 were downregulated in pleural fibrosis tissues and TGF-β1-treated Met-5A cells. Overexpression of TMEM88 inhibited the proliferation of Met-5A cells under TGF-β1 stimulation. In addition, TMEM88 overexpression prevented TGF-β1-induced extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) in Met-5A cells with decreased expression levels of Col I and fibronectin, increased levels of cytokeratin-8 and E-cadherin, as well as decreased levels of vimentin and α-SMA. Furthermore, overexpression of TMEM88 inhibited the expression of TGF-β receptor I (TβRI) and TβRII and suppressed the phosphorylation of Smad2 and Smad3 in Met-5A cells. In conclusion, these results indicated that TMEM88 exhibited an anti-fibrotic activity in pleural fibrosis via inhibiting the activation of TGF-β1/Smad signaling pathway.

Osteosarcoma (OS), a prevalent aggressive malignancy in the bone, has limited therapeutic targets and diagnostic biomarkers. In the current investigation, RT-qPCR showed that CDKN2B-AS1 was enhanced in OS samples and cells. This research was set to examine the modulation of CDKN2B-AS1 in OS. The expression of CDKN2B-AS1 and downstream molecules was analyzed by RT-qPCR method. CCK8, EdU staining along with Transwell assays were applied to evaluate cell proliferation and invasion. Those in vitro investigations specified that silencing of CDKN2B-AS1 with shRNAs obviously impeded the proliferation and invasion of MG63 cells. To authenticate the relationships between CDKN2B-AS1 and microRNA-122-5p (miR-122-5p) or cyclin G1 (CCNG1) and miR-122-5p, we next employed luciferase reporter assay. We displayed that CDKN2B-AS1 repressed miR-122-5p to restore CCNG1 expression. All in all, our findings substantiated the indispensable function of CDKN2B-AS1 in OS progression and the possible molecular mechanism.

Purpose: This study mainly aimed to explore the influences of Calcium Voltage-Gated Channel Subunit Alpha1 B (CACNA1B) on the development of breast cancer and the related mechanism.

Materials and methods: The information of patients with breast cancer from TCGA database was used for analyses of CACNA1B expression and its prognostic value. Loss- and gain- of functions of CACNA1B were conducted in MCF7 and Bcap-37 cells, respectively. CCK-8, colony formation and transwell assays were applied for evaluating the cell viability and motility. Western blot was used for protein expression detection.

Results: We revealed that highly expressed CACNA1B in breast cancer tissues was related to poor prognosis according to the data gained from TCGA database. The outcomes of functional assays showed that depletion of CACNA1B restrained MCF7 cell growth, invasion and migration and high-expression of CACNA1B fortified the growth, invasion and migration in Bcap-37 cells. Finally, we manifested that silencing CACNA1B obviously raised the protein expression level of E-cadherin and reduced the protein levels of Cyclin D1, N-cadherin and Snail in MCF7 cells, whilst, over-expression of CACNA1B reduced the level of E-cadherin and increased the expression of Cyclin D1, N-cadherin and Snail in Bcap-37 cells.

Conclusions: These results identified CACNA1B as a forwarder of the growth, invasion and migration in breast cancer cells.

Background: Sinonasal squamous cell carcinoma (SNSCC) is a main subtype of sinonasal malignancy with unclear pathogenesis. microRNAs (miRNAs) are involved in SNSCC progression. Nevertheless, the role and mechanism of miR-362-3p in SNSCC development are unclear.

Methods: The SNSCC tissues (n = 23) and normal sinonasal samples (n = 13) were harvested. SNSCC cell line RPMI-2650 cells were transfected using Lipofectamine 3000. miR-362-3p and pituitary tumor-transforming gene 1 (PTTG1) were determined by quantitative reverse transcription polymerase chain reaction and western blot. Cell proliferation was analyzed via Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays. Cell migration and invasion was assessed using wound healing assay and transwell assay. Epithelial-mesenchymal transition (EMT)-associated protein (E-cadherin, N-cadherin and Vimentin) levels were measured via western blot. The binding relationship was analyzed via bioinformatic analysis and dual-luciferase reporter assay.

Results: miR-362-3p abundance was decreased in SNSCC samples. miR-362-3p addition constrained cell proliferation, migration, invasion and EMT, but miR-362-3p knockdown played an opposite effect. PTTG1 was targeted and negatively modulated by miR-362-3p. PTTG1 abundance was elevated in SNSCC samples. PTTG1 overexpression mitigated miR-362-3p-modulated suppression of cell proliferation, migration, invasion and EMT in SNSCC cells.

Conclusion: miR-362-3p repressed cell proliferation, migration, invasion and EMT in SNSCC via targeting PTTG1.

Objective: Isoflurane is an extensively used inhalational anesthesia, and its carcinogenic or anti-cancerous effect has been identified recently. However, the specific role of isoflurane in cervical cancer remains unclear.

Aim: This study aimed to investigate the function of isoflurane in cervical cancer as well as the underlying mechanism.

Methods: After isoflurane treatment, HeLa cell viability, percentage of apoptotic cells, expression of active caspase-3/9 were examined by CCK-8 assay, Annexin V-FITC/PI double staining, and Western blot analysis, respectively. ROS generation, ratio of NAD⁺/NADH, and ATP level after isoflurane stimulation were determined using commercial assay kits. Afterwards, activation of AMPK and autophagy was assessed through Western blot analysis and immunofluorescence. Whether AMPK mediated the isoflurane-induced apoptosis and autophagy was explored by adding an AMPK inhibitor (Compound C). The in vivo function of isoflurane was finally investigated on a HeLa cell xenograft model.

Results: Isoflurane inhibited cell viability and induced apoptosis evidenced by upregulation of active caspase-3/9 in HeLa cells. Oxidative stress was triggered by isoflurane, as isoflurane elevated ROS level, and lowered ratio of NAD⁺/NADH and ATP level. Further results showed isoflurane activated the AMPK/mTOR pathway and induced autophagy. In addition, inhibition of AMPK led to ameliorated effects of isoflurane on apoptosis and autophagy. In vivo experiments proved isoflurane could repress tumorigenesis, activate AMPK, and induce autophagy in Xenograft mouse.

Conclusions: Isoflurane activated AMPK to inhibit proliferation and promote apoptosis and autophagy both in vitro and in vivo.

Objectives: Ovarian cancer is the second commonly seen cancer in the US, patients with ovarian cancer are commonly diagnosed in the advanced stage. Pazopanib is an inhibitor of multiple tyrosine kinases and has been approved in treatment for carcinoma by FDA. N-myc downstream-regulated gene 2 (NDRG2) has been regarded as a cancer suppressor gene and presented an inhibition effect in cancer proliferation, invasion, and migration.

Design: NDRG2 was overexpressed or inhibited in SKOV-3 cells, then experiments were performed to detect the apoptosis of cells. The expression or secretion of pro-cancer molecules was detected. And the expression of apoptosis-related proteins and the ASK1/JNK1 signaling pathway was detected.

Methods: The NDRG2 overexpression and inhibition model was firstly constructed in SKOV-3 cells, the apoptotic cells were detected using flow cytometry. The expression of cellular metastasis genes was detected using the qPCR method. The angiogenesis factors was detected using the ELISA method. Expression of each target protein was detected using western blotting analysis.

Results: NDRG2 overexpression and inhibition model were constructed in the SKOV-3 cell line, overexpression of NDRG2 enhanced the effect of pazopanib on inhibition of the expression of metastasis-related molecules and angiogenesis-related factors. The apoptosis process of cells was also enhanced after overexpression of NDRG2, and these effects were regulated by the activation of the ASK1/JNK1 signaling pathway.

Limitations: The effect of NDRG2 in animal models and more cell lines needs to be explored in further study.

Conclusions: NDRG2 might be a therapeutic target in treatment for ovarian cancer.

Objective: To investigate the regulatory effect of long non-coding RNA (lncRNA) SUMO1P3 on invasion, migration and cell cycle of gastric cancer (GC) cells through Wnt/β-catenin signaling pathway.

Methods: Tumor tissues and adjacent normal tissues from the GC patients were collected, and human normal gastric epithelial cells GES1 and GC cells SGC-7901, MKN45, HGC-27 and AGS were selected for study. The expression of SUMO1P3 in GC tissues and cells were detected by RT-qPCR. The effects of SUMO1P3 on the proliferation, invasion and migration of SGC-7901 and MKN45 cells were detected by CCK-8, transwell and wound healing assay respectively, and the effects of SUMO1P3 on apoptosis and cycle progression of SGC-7901 and MKN45 cells were detected by flow cytometry. The expressions of Wnt/β-catenin pathway-related and cell cycle-related proteins were detected by Western blot.

Results: The expression of SUMO1P3 was significantly upregulated in GC tissues and cell lines. Downregulation of SUMO1P3 significantly inhibited the SGC-7901 and MKN45 cell proliferation, invasion, migration, and cycle progression and promoted the cell apoptosis, while overexpression of SUMO1P3 showed the opposite effect. Further study showed that downregulation of SUMO1P3 significantly reduced the expressions of Wnt1, β-catenin, c-myc, and Cyclin D1 in SGC-7901 and MKN45 cells.

Conclusion: SUMO1P3 may promote invasion, migration, and cycle progression of SGC-7901 and MKN45 cells by enhancing the Wnt/β-catenin pathway.