Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer最新文献

{"title":"Anti-Cancer Role of Ellagic Acid by Modulating the Altered PI3K/PTEN/Akt Pathway in Bladder Cancer.","authors":"Satya Sahay, Deepika Trehan, Ranbala Kumari, Jyoti Sharma, Pawan Vasudeva, Niraj Kumar, Usha Agrawal","doi":"10.1615/JEnvironPatholToxicolOncol.2024053383","DOIUrl":"https://doi.org/10.1615/JEnvironPatholToxicolOncol.2024053383","url":null,"abstract":"<p><p>Bladder cancer (BCa) is approximately the fourth most prevalent diagnosed cancer in men and is three times less common in women. Therefore, identifying biomarkers, developing more effective therapeutic strategies, and understanding the mechanisms underlying BCa tumor growth and progression are urgently required to improve survival rates. Therefore, we aim to investigate the expression of PTEN/Akt in tissue samples of both non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) patients (n = 70) and human BCa cell lines T24 and 5637, along with the potent role of ellagic acid (EA) in the modulation of the PTEN/Akt pathway and the resulting therapeutic potential. Results showed low-intensity nuclear or cytoplasmic PTEN staining or loss of PTEN expression in tumor cells and overexpression of p-Akt (Ser-473) with high intensity in the nucleus or cytoplasm. EA treatment of T24 and 5637 cells reduced cell viability, inflammation (NF-κB, COX-2), invasion (MMP-9), induced the caspase (cas-3 and cas-9) cascade signaling pathway, and induced cell apoptosis along with the suppression of the PI3K/PTEN/Akt signaling pathway after 48h in a dose-dependent manner. Thus, these data suggested that the EA showed a strong potential anti-cancer effect in T24 and 5637 cells. In conclusion, the expression of PTEN/p-Akt and the inverse relation indicated an alteration of the PTEN/Akt pathway, and such cases could benefit from treatment with EA in BCa.</p>","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"44 2","pages":"57-69"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA PTCSC1 Promotes TRAIL Resistance through FOXO3a Pathway in HCT116 and SW480 Cells.","authors":"Changcheng Wang, Jia Guo, Zengan Wu","doi":"10.1615/JEnvironPatholToxicolOncol.2024053010","DOIUrl":"https://doi.org/10.1615/JEnvironPatholToxicolOncol.2024053010","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a malignant tumor that affects patients worldwide, and its mortality rate is high. Although treatments that activate TNF-associated apoptosis-inducing ligand (TRAIL)-induced apoptosis have shown some efficacy, many CRC patients are resistant to TRAIL therapy. Our findings indicated that the lncRNA PTCSC1 is over-expressed in CRC. However, the mechanism underlying resistance to PTCSC1 in CRC is unclear. In this work, we determined the role of PTCSC1 in TRAIL-resistant CRC patients and explored possible molecular mechanisms. We found that TRAIL-sensitive HCT116 and SW480 cells expressed relatively lower levels of PTCSC1 than TRAIL-resistant HT-29 and caco-2 cells. Increased expression of PTCSC1 was here found to inhibited TRAIL-induced apoptosis in HCT116 and SW480 cells. Decreased expression of PTCSC1 increased TRAIL-induced apoptosis in HT-29 and caco-2 cells. The level of expression of PTCSC1 was related to their sensitivity to TRAIL-induced apoptosis. Furthermore, PTCSC1 decreased the expression of Death Receptor 4 (DR4) while increased the activation of serine/threonine kinase 1 (AKT) and Forkhead Box O3a (FOXO3a). Our findings therefore support the idea that targeting PTCSC1 function may represent a strategy to overcome TRAIL resistance in CRC through the DR4/AKT/FOXO3a pathway.</p>","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"44 2","pages":"31-39"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying circRNA-miRNA-mRNA Networks Associated with Osimertinib Resistance in Lung Adenocarcinoma by Analyzing Microarray Datasets.","authors":"Fen Liu, Xiyan Wang, Wenjun Tian, Xueli Dong, Guanghai Wang","doi":"10.1615/JEnvironPatholToxicolOncol.2024054531","DOIUrl":"https://doi.org/10.1615/JEnvironPatholToxicolOncol.2024054531","url":null,"abstract":"<p><strong>Background: </strong>This study was to screen for circRNAs associated with osimertinib resistance in lung adenocarcinoma (LUAD) and establish a circRNA-miRNA-mRNA ceRNA network.</p><p><strong>Methods: </strong>DESeq2 analysis was used to identify circRNAs in GEO database associated with osimertinib resistance in LUAD. Differentially expressed miRNAs in LUAD intersected with the target miRNAs of circRNA. Predicted target gene for miRNAs were overlapped with the co-expressed genes of EGFR. Hsa_circ_0078465/miR-183-5p/NRAS axis was validated in cells.</p><p><strong>Results: </strong>Osimertinib resistance-related circRNAs in LUAD were linked to six differentially expressed miRNAs and 35 EGFR-related mRNAs. NRAS was the hub gene. These mRNAs were associated with cell motility regulation, non-small cell lung cancer and EGFR tyrosine kinase inhibitor resistance pathway. The cell proliferation and migration assays confirmed the promoting role of hsa_circ_0078465/miR-183-5p/NRAS axis in osimertinib-resistant cells.</p><p><strong>Conclusion: </strong>A circRNA-miRNA-mRNA network associated with osimertinib resistance in LUAD proposed hsa_ circ_0078465/miR-183-5p/NRAS axis.</p>","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"44 2","pages":"71-83"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Ion Channel-Associated Prognostic Biomarkers for Lung Adenocarcinoma.","authors":"Yunfei Liu, Yanpeng Wang, Taoli Chen, Junzhao Sui, Wanping Xia, Qichuan Wang","doi":"10.1615/JEnvironPatholToxicolOncol.2024053959","DOIUrl":"https://doi.org/10.1615/JEnvironPatholToxicolOncol.2024053959","url":null,"abstract":"<p><p>Expression and functional dysregulation of ion channel genes are correlated with an unfavorable prognosis in lung adenocarcinoma (LUAD). Ion channel signature for predicting the prognosis of individuals with LUAD. 94 ion channel-related differentially expressed genes in LUAD were identified from TCGA-LUAD, and ion channel-based LUAD risk model was established and validated using the GEO cohort. Survival analysis outcomes demonstrated that low-risk LUAD patients were accompanied with higher survival rates. Cox analysis manifested that LUAD prognostic risk score was an independent prognosticactor. We plotted a nomogram with clinical utility based on LUAD risk score and clinical factors. Differentially expressed genes in LUAD patients of different risk groups were enriched in biological functions and signaling pathways related to ion channels, cancer transcription dysregulation, and immunity. Immune infiltration results suggested that LUAD patients with low risk scores exhibited better immune cell infiltration and function. Prediction results of immunotherapy response showed that LUAD patients with low risk scores had a higher chance of benefiting from immunotherapy. The drug prediction results showed that individuals with LUAD in the low-risk group were more sensitive to paclitaxel, BI 2536, pyrimethamine, and VX-680, while individuals with LUAD in the high-risk group to erlotinib, sorafenib, panitumumab, PHA-665752, and roscovitine. In summary, ion channel-related genes can provide valuable information for prognosis assessment and drug treatment of LUAD patients.</p>","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"44 2","pages":"41-55"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Gene-Regulatory Networks and Potential Therapeutic Drugs Based on ELF3 Expression in Cholangiocarcinoma.","authors":"Cui Zhang, Mengting Tong, Guangpeng Chen, Yong Dong, Da Li","doi":"10.1615/JEnvironPatholToxicolOncol.2024052875","DOIUrl":"https://doi.org/10.1615/JEnvironPatholToxicolOncol.2024052875","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a life-threatening malignancy, and there is an urgent need for new biomarkers to improve the prognosis of patients. The expression of ELF3 in CCA tumor and non-tumor tissues was examined in two cohorts. ELF3 expression and the methylation level of its promoter in CCA patients with various clinicopathological features were analyzed using the UALCAN website. Co-expressed genes significantly associated with ELF3 were screened using the LinkedOmics website. A protein-protein interaction (PPI) network for these co-expressed genes was constructed using the STRING website. Core co-expressed genes correlated with ELF3 were identified through random walk with restart (RWR) analysis. GeneMANIA was utilized to analyze the major biological functions within networks of kinases and TFs mediated by ELF3. Potential targeted drugs for CCA treatment were screened using the Connectivity Map (CMAP) database. ELF3 expression in CCA tissue was significantly increased compared with that in normal tissue. Among CCA patients with distinct clinicopathological features, ELF3 expression was notably elevated in tumor tissues compared to normal tissue, while ELF3 promoter's methylation levels in tumor tissue were significantly decreased. In total, 307 co-expressed genes, evidently relevant to ELF3, were identified through LinkedOmics analysis. RWR analysis revealed 61 co-expressed genes closely associated with ELF3. Enrichment analysis indicated that these genes control cell junctions and epithelial cell differentiation. GeneMANIA analysis uncovered that ELF3-involved regulatory networks of kinases and TFs were primarily linked to the regulation of immune cells and cell adhesion. CMAP analysis identified 10 potential small molecules for CCA treatment including 4 existing drugs used for other diseases. ELF3 shows promise as a diagnostic marker for CCA, and the drugs we have identified hold great potential for the treatment of this fatal disease.</p>","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"44 2","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP3-Inflammasome Gene Variations in the Risk of Type 2 Diabetes.","authors":"C. Ozbayer, H. Kurt, Emine Yagci, M. Kebapçı, H. Gunes, I. Degirmenci","doi":"10.1615/jenvironpatholtoxicoloncol.2021040001","DOIUrl":"https://doi.org/10.1615/jenvironpatholtoxicoloncol.2021040001","url":null,"abstract":"Inflammation is the natural immunological response of an organism against any harmful, foreign or destructive effect to heal and repair damaged tissue. The nod-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is one of the main components of the inflammatory mechanism and is associated with many inflammatory diseases, but it is also closely related to metabolic abnormalities, such as type 2 diabetes mellitus (T2DM), insulin resistance and obesity. NLRP3 activates inflammation and causes interleukin-1β release, exogenous and endogenous danger signals, as well as insulin resistance. In this direction, we focus on the gene structure of NLRP3 in diabetes and accordingly, we aim to determine the relationship between eight gene variations in the NLRP3 gene and T2DM. We investigated the rs10802501, rs10733113, rs10754558, rs10925026, rs10925027, rs35829419, rs4612666 and rs4925659 single-nucleotide polymorphisms of NLRP3 gene using the Sequenom MassARRAY system in 100 T2DM patients and 100 control individuals. There were no significant differences between T2DM risk and the genotype frequencies of rs10802501, rs10733113, rs35829419 and rs10925026 variants (p > 0.05). However, significant genotype frequencies were determined for rs10925027 (p = 0.0013) and rs4925659 (p < 0.001). For the risk allele G of the rs10754558 variant, significant differences were found in the heterozygous and dominant model (p = 0.036, p = 0.033). The genotype distribution of the rs4612666 variant was significant only in the heterozygous model (p = 0.047). In this hospital-based case-control study, rs10925027, rs4925659 and rs10754558 variants were found to be closely related to T2DM risk. The rs10925027 CC genotype, rs4925659 GG genotype, rs10754558 GG and GC+GG genotypes of the NLRP3 were determined as important risk factors for the T2DM.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"112 1","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82465984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Features of Coronavirus and the COVID-19 Pandemic's Impact in India.","authors":"Ankur Jaiswal, V. Babu, M. Sethi, Basant Baishya, Pallavi Jaiswal, R. Joshi, Sudhir Jugran, B. Ramola, Avnish Kumar","doi":"10.1615/jenvironpatholtoxicoloncol.2022035706","DOIUrl":"https://doi.org/10.1615/jenvironpatholtoxicoloncol.2022035706","url":null,"abstract":"The rapid transmission of COVID-19 infection around the world in a brief timeframe has caused an exponential decline in street traffic and other industrial activities in various parts of the world. The confined human collaboration with the nature at the time of this emergency has shown up as an advantage for Mother Nature after COVID-19 flare because the air present in the atmosphere and water flowing in river streams is upgrading and untamed life is blossoming. India, being consistently seen as the center of contamination due to a tremendous population, overwhelming road traffic and industries which contribute to heavy pollution prompting rise in air quality index for almost all the big cities of the country. However, after the announcement of lockdown because of COVID-19, the air quality begun to upgrade and other environmental variables, for example, water quality in streams and waterways have begun offering a positive hint towards restoration. This review gives a brief knowledge on the structure and genomic organization of novel coronavirus as well as it focuses on alterations in air and water quality along with its environmental consequences at specific locations of the country during lockdown due to this pandemic circumstance.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"1 1","pages":"37-46"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83033154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abies spectabilis-Mediated Silver Nanoparticles Inhibits Cell Growth and Promotes Apoptosis in Breast Cancer MCF-7 Cells.","authors":"Guanghui Ren, Xiaoyan Hao, Shuyi Yan, Jun Chen, Guobin Qiu, K. Ang, Mohd Islahuddin Mohd Tamrin","doi":"10.1615/jenvironpatholtoxicoloncol.2021039805","DOIUrl":"https://doi.org/10.1615/jenvironpatholtoxicoloncol.2021039805","url":null,"abstract":"Breast cancer is the second most cause of mortality among women worldwide due to the uncontrolled proliferation of tumor cells in the mammary epithelial tissues. The silver nanoparticles were formulated from the Abies spectabilis leaf (AS-AgNPs) and characterized by various practices like UV-vis spectroscopy, FTIR, SEM, and XRD. The in vitro anticancer potential of fabricated AS-AgNPs against the MCF-7 cells were analyzed. The MTT test was executed to investigate the cytotoxic nature of fabricated AS-AgNPs against MCF-7 cells. The magnitudes of ROS accumulation and MMP level in the AS-AgNPs supplemented MCF-7 cells were studied using fluorescent staining techniques. Caspase activities were studied using assay kits. The contents of oxidative stress and antioxidant biomarker (TBARS, SOD, CAT, and GSH) levels were scrutinized by standard methods. The expressions of apoptotic markers like Bax and Bcl-2 in the AS-AgNPs administered MCF-7 cells were detected by RT-PCR assay. The MTT findings showed that both extract and fabricated AS-AgNPs remarkably decreased the MCF-7 cells. Nonetheless, both plant extract and AS-AgNPs did not affect the cell viability of MCF-10A cells. Furthermore, the fabricated AS-AgNPs improved the ROS accumulation, and depleted the MMP status in the MCF-7 cells. AS-AgNPs administered MCF-7 cells demonstrated the improved TBARS content and depleted antioxidants. The treatment with AS-AgNPs considerably elevated the caspase-9 and -3 activities and Bax expression, while decreasing the Bcl-2 expression in MCF-7 cells. Hence the current investigation reports that the formulated AS-AgNPs exhibited remarkable in vitro anticancer action against MCF-7 cells through increased ROS, oxidative stress, and apoptotic protein expression. The fabricated AS-AgNPs could be a possible anticancer remedy in the future.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"39 1","pages":"73-83"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75430072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Targets of Nimbolide for Anti-Cancer Therapy: An Updated Review.","authors":"P. Elumalai, D. Ezhilarasan, S. Raghunandhakumar","doi":"10.1615/jenvironpatholtoxicoloncol.2021040263","DOIUrl":"https://doi.org/10.1615/jenvironpatholtoxicoloncol.2021040263","url":null,"abstract":"Cancer is a major cause of death worldwide with an increasing incidence rate and is considered a major public health problem. Distance metastasis to other tissues, high toxicity, and drug resistance of cancer cells to chemotherapy demand novel therapeutic approaches to treat cancer. Natural compounds from medicinal plants have been studied for therapeutic use in various malignancies. Nimbolide is an active principal compound from Azadirachta indica, which is an Asian traditional medicinal plant utilized historically as a remedy for a variety of diseases due to its antioxidant, anti-inflammatory, anti-cancer, and antimicrobial properties. It is a limonoid triterpene possessing potent anti-cancer effects in various types of cancers. It has been reported to induce multiple cytotoxic effects in tumor cells by modulating the cell proliferation, cell cycle, apoptosis, and metastasis by altering the various molecular signaling pathways. In the present review, we summarized all the in vitro and in vivo studies reporting the molecular targets of nimbolide for the therapeutic approaches in different types of cancer cells. We analyzed research publications up to September 2021 on the effect of nimbolide in various malignancies and the molecular mechanism of action. Nimbolide targets different signaling pathways including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin like growth factor (IGF), Wingless and INT-1 (Wnt)/β-catenin, mitogen-activated protein kinases (MAPK)/c-Jun N-terminal kinases (JNK), phosphoinositide 3-kinase (PI3K)/AKT, tumor necrosis factor-α (TNF-α)/nuclear factor kappa B (NF-κβ), and death receptor 5 (DR5) in several cancer cells. Nimbolide's widespread availability and absence of side effects, as well as understanding the molecular mechanism of nimbolide's action, will be useful to develop a therapeutic agent against cancer.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"56 1","pages":"69-88"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83398543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rk2 Protects against Ulcerative Colitis via Inactivating ERK/MEK Pathway by SIRT1.","authors":"Xiaodong Huang, Jianwei Xiao, Mudan Wen, Jing-Tao Liang","doi":"10.1615/jenvironpatholtoxicoloncol.2021039648","DOIUrl":"https://doi.org/10.1615/jenvironpatholtoxicoloncol.2021039648","url":null,"abstract":"BACKGROUND Chinese traditional medicine is widely used in the treatment of ulcerative colitis (UC). Ginsenoside Rk2 is a newly discovered dammarane triterpenoid saponin isolated from ginseng. Our study aimed to investigate the effects of Ginsenoside Rk2 on UC. METHODS Human clones of colorectal adenocarcinoma Caco-2 cells and human intestinal epithelial THP-1 cells were co-cultured to establish a UC model in vitro. Cell viability and apoptosis were analyzed by cell counting kit 8 (CCK-8) and flow cytometry assay, respectively. Inflammatory cytokines' mRNA levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot was applied to examine the protein expression of apoptosis-associated proteins and the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MEK) pathway. Furthermore, fisetin, an ERK kinase activator, was used to carry out rescue experiment. SRT1720, an activator of SIRT1, was applied to increase the SIRT1 protein levels while SIRT1 inhibitor nicotinamide (NAM) exerted the opposite effect. RESULTS Ginsenoside Rk2 promoted cell viability, suppressed cell apoptosis, and reduced the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α (TNF-α) of HT-29 cells in UC model in a concentration-dependent manner. Meanwhile, the inhibitory effects of Ginsenoside Rk2 on the ERK/MEK pathway strengthened with the increase of concentration, and was verified by fisetin application. Furthermore, the upregulation of SIRT1 induced by Ginsenoside Rk2 prompted dephosphorylation of ERK and MEK to attenuate ERK/MEK pathway activation and reduced inflammatory progress, which was confirmed by SRT1720 as well as NAM. CONCLUSIONS Ginsenoside Rk2 inactivated ERK/MEK pathway by regulating SIRT1 to restore the cellular function of human intestinal epithelial THP-1 cells. Therefore, Ginsenoside Rk2 may be effective in the treatment of UC.","PeriodicalId":94332,"journal":{"name":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","volume":"36 1","pages":"89-98"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84974243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}