scholarly journals Protective Effects of L-Theanine on IPEC-J2 Cells Growth Inhibition Induced by Dextran Sulfate Sodium Via p53 Signaling Pathway

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7002
Author(s):  
Longlin Zhang ◽  
Mengmeng Ma ◽  
Zhengyi Li ◽  
Haihan Zhang ◽  
Xi He ◽  
...  
Keyword(s):  
Amino Acid ◽  
Signaling Pathway ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Nucleotide Metabolism ◽  
Normal Operation ◽  
Protective Effects ◽  
P53 Signaling ◽  
P53 Signaling Pathway

L-theanine is a nonprotein amino acid found in tea leaves and has been widely used as a safe food additive in beverages or foods because of its varied bioactivities. The aim of this study was to reveal the in vitro gastrointestinal protective effects of L-theanine in DSS-induced intestinal porcine enterocyte (IPEC-J2) cell models using molecular and metabolic methods. Results showed that 2.5% dextran sulfate sodium (DSS) treatment inhibited the cell proliferation of IPEC-J2 and blocked the normal operation of the cell cycle, while L-theanine pretreatment significantly preserved these trends to exert protective effects. L-theanine pre-treatment also up-regulated the EGF, CDC2, FGF2, Rb genes and down-regulated p53, p21 proliferation-related mRNA expression in DSS-treated cells, in accompany with p53 signaling pathway inhibition. Meanwhile, metabolomics analysis revealed that L-theanine and DSS treated IPEC-J2 cells have different metabolomic profiles, with significant changes in the key metabolites involved in pyrimidine metabolism and amino acid metabolism, which play an important role in nucleotide metabolism. In summary, L-theanine has a beneficial protection in DSS-induced IPEC-J2 cells via promoting proliferation and regulating metabolism disorders.

scholarly journals N-α-Acetyltransferase 10 protein inhibits invasion and metastasis of oral squamous cell carcinoma via regulating Pirh2-p53 signaling pathway

2020 ◽  
Author(s):  
Fazhan Wang ◽  
Jun Zheng ◽  
Yongyong Yang ◽  
Jie Yang ◽  
Ting Luo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Nude Mice ◽  
Invasion And Metastasis ◽  
P53 Signaling ◽  
P53 Signaling Pathway

Abstract Background Naa10p (N-α-Acetyltransferase 10 protein) was reported to be involved in tumor invasion and metastasis in several of tumors. However, the role and mechanism of Naa10p mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Methods The functional role of Naa10p in OSCC cells were determined using Transwell assay in vitro and xenograft tumorigenesis in nude mice. Immunoprecipitation, GST-pull down assays and immunofluorescence were performed to confirm the interaction between Naa10p and RelA/p65 in OSCC cells. Lastly, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and western blot were used to evalute the effect of Naa10p expression on the Pirh2-p53 signaling pathway. Results Naa10p inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, there is a physical interaction between Naa10p and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, MMP-2 and MMP-9. Conclusion Naa10p function as a tumor metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis, and might be a prognostic marker as well as a therapeutic target for OSCC.

Application of minimal mathematical models for the dynamics of the signaling pathway of the p53 - miRNA to the analysis of laboratory data

2021 ◽  
pp. 4-49
Author(s):  
Софья Дмитриевна Сенотрусова ◽  
Ольга Фалалеевна Воропаева ◽  
Юрий Иванович Шокин
Keyword(s):  
Mathematical Models ◽  
Signaling Pathway ◽  
Numerical Solutions ◽  
Laboratory Data ◽  
Minimal Models ◽  
Basic Model ◽  
P53 Signaling ◽  
Wide Range ◽  
P53 Signaling Pathway

Работа посвящена практическому использованию минимальных математических моделей динамики сигнального пути p53 для описания достаточно широкого круга лабораторных экспериментов, в которых взаимодействие p53 и белковингибиторов p53 опосредуется микроРНК, образующими с p53 петлю положительной обратной связи. Представлены базовая модель, разработанные на ее основе новые минимальные модели, алгоритм численного решения прямых и обратных коэффициентных задач и результаты сопоставления полученных численных решений с экспериментальными данными о динамике уровней белков p53, p21, Bax, белков-ингибиторов Mdm2, Wip1, Sirt1 и различных микроРНК (miR-16, miR-34a, miR-192, miR-194, miR-215) в условиях стрессовых воздействий. С привлечением полученных математических моделей исследованы базовые механизмы функционирования сигнального пути p53 в условиях, приближенных к условиям конкретных лабораторных экспериментов in vitro и in vivo. Продемонстрированы синергический эффект гиперактивации сигнального пути p53, в котором задействованы микроРНК, и механизмы бимодального переключения. Показана ключевая роль p53-зависимых микроРНК в реализации некоторых гипотетических терапевтических стратегий, связанных с управлением механизмом активации апоптоза клеток. В рамках принятой базовой модели даны оценки вероятности рассогласования в диагностике дегенеративных заболеваний, основанной на анализе уровня p53зависимых микроРНК и p53, при слабой и умеренной дерегуляции микроРНК. This study addresses the practical use of minimal mathematical models of the dynamics of a hypothetical system of the p53 signaling pathway to describe a fairly wide range of laboratory experiments. In such system, the interaction of p53 and p53 inhibitor proteins is mediated by microRNAs that form a positive feedback loop with p53. A basic model, new minimal models developed on its basis, an algorithm for the numerical solution of direct and inverse coefficient problems, and the results of comparing the obtained numerical solutions with experimental data on the dynamics of the levels of p53, p21, Bax proteins, inhibitor proteins Mdm2, Wip1, Sirt1, and various microRNAs (miR-16, miR-34a, miR-192, miR-194, miR-215) under stress conditions are presented. In numerical experiments, the main mechanisms of the p53 signaling pathway were investigated. A synergistic effect of hyperactivation of the p53 signaling pathway and bimodal switching mechanisms has been demonstrated. We show the key role of p53-dependent microRNAs in the implementation of some hypothetical therapeutic strategies associated with the control mechanism for activation of cells apoptosis. Within the framework of the accepted basic model, we estimated the probability of mismatch in the diagnosis of the patient’s status. The status is based on the analysis of the level of p53-dependent microRNAs and p53, with weak and moderate deregulation of microRNAs.

SASS6 promotes proliferation of esophageal squamous carcinoma cells by inhibiting the p53 signaling pathway

2020 ◽  
Author(s):  
Yuanji Xu ◽  
Kunshou Zhu ◽  
Junqiang Chen ◽  
Liyan Lin ◽  
Zhengrong Huang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Squamous Carcinoma ◽  
Tumor Formation ◽  
Squamous Carcinoma Cells ◽  
P53 Signaling ◽  
P53 Signaling Pathway

Abstract SASS6 encodes for the Homo sapiens SAS-6 centriolar assembly protein and is important for proper centrosome formation. Although centrosomes are amplified in a wide variety of tumor types, abnormally high SASS6 expression had previously only been identified in colon cancer. Moreover, the role of SASS6 in esophageal squamous cell carcinoma (ESCC) pathogenesis has not yet been elucidated. The aim of this study was to investigate the role and mechanisms of SASS6 in ESCC. In this study, we found that the mRNA and protein levels of SASS6 were increased in human ESCC samples. In addition, SASS6 protein expression was associated with the esophageal cancer stage and negatively affected survival of patients with ESCC. Furthermore, silencing of SASS6 inhibited cell growth and promoted apoptosis of ESCC cells in vitro and inhibited xenograft tumor formation in vivo. A genetic cluster and pathway analysis showed that SASS6 regulated the p53 signaling pathway. Western blot demonstrated that CCND2, GADD45A and EIF4EBP1 protein expression decreased and that TP53 protein expression increased after the knockdown of SASS6 in ESCC cells. Therefore, SASS6 promoted the proliferation of esophageal cancer by inhibiting the p53 signaling pathway. SASS6 has potential as a novel tumor marker and a therapeutic target for ESCC.

scholarly journals Cinacalcet Targets the Neurokinin-1 Receptor and Inhibits PKCδ/ERK/P65 Signaling to Alleviate Dextran Sulfate Sodium-Induced Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuehong Chen ◽  
Huan Liu ◽  
Qiuping Zhang ◽  
Yubin Luo ◽  
Liang Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Structural Integrity ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Therapeutic Effects ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

Objective: Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This study was performed to assess the therapeutic effects of cinacalcet on dextran sulfate sodium (DSS)-induced colitis.Methods: Primary macrophages obtained from bone marrow and the macrophage cell line RAW264.7 were used to examine the inhibitory effect of cinacalcet on cytokine production, the PKCδ/ERK/P65 signaling pathway, and NF-κB P65 translocation. Colitis was induced using DSS to assess the treatment effect of cinacalcet. Bioinformatics approaches were adopted to predict potential targets of cinacalcet, and a drug affinity responsive target stability (DARTs) assay was performed to confirm binding between cinacalcet and potential target.Results:In vivo analysis showed that cinacalcet reduced the disease activity score, prevented shortening of the colon, diminished inflammatory cell infiltration, and protected the structural integrity of the intestinal wall. Cinacalcet also reduced production of the inflammatory cytokines TNFα, IL-1β, and IL-6 in the colon and sera of mice with DSS-induced colitis. In vitro studies revealed that cinacalcet suppressed the translocation of P65 and inhibited production of the inflammatory cytokines IL-1β and IL-6. Mechanistic studies revealed that the target of cinacalcet was neurokinin-1 receptor (NK1R) and their binding was confirmed by a DARTs assay. Furthermore, the inhibition of NK-κB P65 activation was found to occur via the suppression of PKCδ/ERK/P65 signaling mediated by cinacalcet.Conclusion: Cinacalcet inhibits the activation of NF-κB and reduces the production of inflammatory cytokines by suppressing the PKCδ/ERK/P65 signaling pathway via targeting NK1R, suggesting that it can be used to treat inflammatory diseases, particularly colitis.

scholarly journals Transcriptomic Analysis Implicates the p53 Signaling Pathway in the Establishment of HIV-1 Latency in Central Memory CD4 T Cells in an In Vitro Model

2016 ◽  
Vol 12 (11) ◽  
pp. e1006026 ◽  
Author(s):  
Cory H. White ◽  
Bastiaan Moesker ◽  
Nadejda Beliakova-Bethell ◽  
Laura J. Martins ◽  
Celsa A. Spina ◽  
...  
Keyword(s):  
T Cells ◽  
Signaling Pathway ◽  
Cd4 T Cells ◽  
In Vitro Model ◽  
P53 Signaling ◽  
Vitro Model ◽  
Memory Cd4 T Cells ◽  
P53 Signaling Pathway ◽  
Hiv 1

scholarly journals Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanrui Ma ◽  
Jiaqing Xiang ◽  
Guixiao Huang ◽  
Yaxi Zhao ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Cholestatic Liver Disease ◽  
P53 Signaling ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Cholestatic Liver Injury ◽  
P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

scholarly journals Absence of miR-378d Promoted The Malignant Phenotype of ESCC Through The AKT-β-Catenin and Hippo-p53 Signaling Pathway

2020 ◽  
Author(s):  
Jie Peng ◽  
Juan Yu ◽  
Jianli Liu ◽  
Haixiang Wei ◽  
Haixia Song ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Stem Cell Marker ◽  
Poor Prognostic Factor ◽  
P53 Expression ◽  
Mesenchymal Transition ◽  
P53 Signaling ◽  
P53 Signaling Pathway

Abstract Background: Chemoresistance is an important cause of malignant progression of esophageal squamous cell carcinomas (ESCCs). miR-378d is sharply reduced in paclitaxel (PTX)-resistance esophageal cancer cells by gene-expression profile analysis (RNA-Seq), but the mechanism of miR-378d-mediated tumor progression is unclear. Patients and methods: Herein, we detected miR-378d expression in 596 ESCC patients by in situ hybridization. Results showed that low miR-378d expression was associated with poor prognosis of ESCC patients, and that miR-378d absence enhanced carcinogenesis by promoting chemoresistance, colony formation, EMT, invasion, and metastasis. Results: Furthermore, miR-378d can target downregulated AKT1 expression by binding to the AKT1 mRNA 3′UTR, inactivating the AKT-β-catenin signaling pathway, and reducing the epithelial–mesenchymal transition marker Vimentin and the cancer stem cell marker ALDH1A1. miR-378d silencing in ESCC cells also promoted polyploidy formation in vitro and in vivo, and miR-378d inhibition suppressed the Hippo-p53 signaling pathway. Consequnetly, YAP and TAZ protein accumulated in nuclei and p53 expression decreased, which may promote the formation of ploidy tumor cells. Conclusions: Therefore, low miR-378d expression is a poor prognostic factor of ESCC patients and promotes polyploidy and cancer progression by activating AKT-β-catenin and suppressing the Hippo-p53 signaling pathway.

scholarly journals Effects of FM0807, a novel curcumin derivative, on lipopolysaccharide-induced inflammatory factor release via the ROS/JNK/p53 pathway in RAW264.7 cells

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Yilong Wu ◽  
Zhiwei Liu ◽  
Weifang Wu ◽  
Su Lin ◽  
Nanwen Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Activity ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Inflammatory Factor ◽  
P53 Signaling ◽  
Anti Inflammatory ◽  
P53 Signaling Pathway ◽  
Curcumin Derivative

Purpose: Sepsis is a systemic inflammatory response caused by infection. Curcumin is known to have antioxidant and anti-inflammatory activities. FM0807, a curcumin derivative, was investigated in the present study to determine its effect on cytokines and the possible molecular mechanism. Main methods: The experiments were carried out in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cell viability was measured by MTT assay. ELISA, Griess assays, fluorescence-based quantitative PCR, flow cytometric analysis, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) experiments, and Western blotting were carried out to assess the potential effects of FM0807 on LPS-induced RAW 264.7 cells. Significant findings: FM0807 had no cytotoxic effects on RAW 264.7 cells. Furthermore, pretreatment with FM0807 inhibited the inflammatory factor tumor necrosis factor-α (TNF-α), interleukin (IL) 1β (IL-1β), IL-6, and inducible nitric oxide synthase (iNOS) at the protein and gene levels. FM0807 also inhibited the production of reactive oxygen species (ROS) and apoptosis. In addition, the activation of the ROS/JNK (c-jun NH2-terminal kinase)/p53 signaling pathway was inhibited by FM0807 in RAW 264.7 cells in vitro. Conclusion: FM0807 has anti-inflammatory activity in vitro, which suggests a potential clinical application in sepsis. The anti-inflammatory activity of FM0807 may be mediated by the ROS/JNK/p53 signaling pathway.

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