Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway

Abstract Background Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive. Methods Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR. Results The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS. Conclusions Our results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

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Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-κB signaling pathway

10.21203/rs.3.rs-70028/v2 ◽

2020 ◽

Author(s):

Yong Zhang ◽

Zhengxia Zha ◽

Wenhua Shen ◽

Dan Li ◽

Naixin Kang ◽

...

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Tca Cycle ◽

Mapk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Trinitrobenzene Sulfonic Acid ◽

Therapeutic Effects ◽

Triterpenoid Saponin ◽

Label Free ◽

Altered Proteins

Abstract Background: Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive.Methods: Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR.Results: The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS.Conclusions: Our results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

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Anemoside B4 ameliorates TNBS-induced colitis involved suppressing the S100A9/NF-κB signaling pathway

10.21203/rs.3.rs-70028/v1 ◽

2020 ◽

Author(s):

Yong Zhang ◽

Zhengxia Zha ◽

Wenhua Shen ◽

Dan Li ◽

Naixin Kang ◽

...

Keyword(s):

Signaling Pathway ◽

Therapeutic Effect ◽

Tricarboxylic Acid Cycle ◽

Tca Cycle ◽

Mapk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Trinitrobenzene Sulfonic Acid ◽

Triterpenoid Saponin ◽

Label Free

Abstract Background Despite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. However, it is unclear which compound in P. chinensis is responsible for the therapeutic effect. Our previous study reported that anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects. Methods Here, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rat were collected for hematology analysis. The effects of anemoside B4 on inflammation-associated mediators were investigated by Enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin staining (HE) staining. Cell proliferation or apoptosis was measured by immunofluorescence technique. The mechanisms of anemoside B4 was investigated using label-free quantitative proteomics. The level of proteins was quantified by western blotting. mRNA expression was quantified by quantitative real-time RT-PCR. Results The results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in the colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins were mainly clustered in tricarboxylic acid cycle (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly downregulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppresses the expression of S100A9 and its downstream genes including TLR4, NF-κB, and p-JNK in colon. In vitro, S100A9 protein could active NF-κB signaling pathway in human intestinal epithelial Caco-2 cells. However, anemoside B4 could inhibit the NF-κB signaling pathway induced by S100A9 protein. Besides, it also inhibited active of NF-κB signaling pathway stimulated by LPS or IL-6. Conclusions Our results demonstrate that anemoside B4 prevents TNBS-induced colitis involved inhibiting the NF-κB signaling pathway through inactivating S100A9 suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

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Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1388-4 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 10

Author(s):

Shan Lei ◽

Zhiwei He ◽

Tengxiang Chen ◽

Xingjun Guo ◽

Zhirui Zeng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Migration And Invasion ◽

Potential Biomarker

Abstract Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

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Network Pharmacology and Pharmacological Evaluation Reveals the Mechanism of the Sanguisorba Officinalis in Suppressing Hepatocellular Carcinoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.618522 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nan Jiang ◽

Hong Li ◽

Yueshan Sun ◽

Jing Zeng ◽

Fei Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Signaling Pathways ◽

Enrichment Analysis ◽

Mapk Signaling ◽

Migration And Invasion ◽

Network Pharmacology ◽

Therapeutic Effects ◽

Sanguisorba Officinalis

Background:Sanguisorba Officinalis L. (SO) is a well-known traditional Chinese medicine (TCM), commonly applied to treat complex diseases, such as anticancer, antibacterial, antiviral, anti-inflammatory, anti-oxidant and hemostatic effects. Especially, it has been reported to exert anti-tumor effect in various human cancers. However, its effect and pharmacological mechanism on hepatocellular carcinoma (HCC) remains unclear.Methods: In this study, network pharmacology approach was applied to characterize the underlying mechanism of SO on HCC. Active compounds and potential targets of SO, as well as related genes of HCC were obtained from the public databases, the potential targets and signaling pathways were determined by protein-protein interaction (PPI), gene ontology (GO) and pathway enrichment analyses. And the compound-target and target-pathway networks were constructed. Subsequently, in vitro experiments were also performed to further verify the anticancer effects of SO on HCC.Results: By using the comprehensive network pharmacology analysis, 41 ingredients in SO were collected from the corresponding databases, 12 active ingredients screened according to their oral bioavailability and drug-likeness index, and 258 potential targets related to HCC were predicted. Through enrichment analysis, SO was found to show its excellent therapeutic effects on HCC through several pathways, mainly related to proliferation and survival via the EGFR, PI3K/AKT, NFκB and MAPK signaling pathways. Additionally, in vitro, SO was found to inhibit cell proliferation, induce apoptosis and down-regulate cell migration and invasion in various HCC cells. Moreover, western blot analysis showed that SO treatment down-regulated the expression of p-EGFR, p-PI3K, p-AKT, p-NFκB and p-MAPK proteins in HepG2 cells. These results validated that SO exerted its therapeutic effects on HCC mainly by the regulation of cell proliferation and survival via the EGFR/MAPK and EGFR/PI3K/AKT/NFκB signaling pathways.Conclusion: Taken together, this study, revealed the anti-HCC effects of SO and its potential underlying therapeutic mechanisms in a multi-target and multi-pathway manner.

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Preclinical study of MEK1/2 inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.240 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 240-240

Author(s):

Junyao Xu ◽

Jennifer J. Knox ◽

Ming Sound Tsao ◽

Eric Xueyu Chen ◽

Pinjiang Cao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Signaling Pathway ◽

Cell Lines ◽

Preclinical Study ◽

Erk Signaling ◽

Therapeutic Effects ◽

Biliary Cancer

240 Background: MEK1/2 is an integral component of the Ras/Raf/MEK/ERK signaling pathway, implicated in uncontrolled cell proliferation and cell survival, a key hallmark of cancer. AZD6244, a novel inhibitor of MEK1/2, is currently completing Phase II clinical trials in biliary cancer, with modest antitumor activity observed as monotherapy. Gemcitabine is a cytotoxic drug commonly used in biliary cancer therapy but many patients showed early resistance. In this preclinical study, we investigated the sequence-dependent antitumor effects of AZD6244 combined with gemcitabine in biliary cancer models. Methods: Two biliary cancer cell lines (EGI-1 and TFK-1) were used. In vitro the effects of single drug or three combination protocols(concurrently; AZD6244 followed by GEM or Gem followed by AZD6244) on cell proliferation, DNA synthesis, and cell cycle distribution were evaluated by MTS, clonogenic assay, EdU uptake and flow cytometry. Drug interactions were analyzed by Chou-Talaly method. In vivo, 4 tumor models subcutaneously xenografted in SCID mice from the two cell lines and 2 human patients were set up to compare the therapeutic effects of different sequence-scheduled combinations. Results: AZD6244 caused G1-S cell cycle arrest in biliary cancer cells in vitro and in vivo, and this effect is correlated with the MEK/ERK signaling pathway blocking. Synchronized progression of the population through S phase were observed in 15h after removal of AZD6244 in cell culture or 48h after final dose of acute AZD6244 treatment in vivo. Antagonistic or additive effects was observed in vitro when combination were given as concurrently(CI=2.03~2.46) or Gem followed by AZD6244(CI=1.34~1.78). In contrast, a synergistic antiproliferative activity was obtained when AZD6244 was given first followed by a drug-free interval before Gem treatment (CI=0.53~0.69). In vivo, the best therapeutic effects were obtained with the sequence of AZD6244 followed by Gem, compared with concurrent or reverse sequence. Conclusions: This study provides a sound rationale for a Phase II trial of a potentially synergistic sequence of MEK inhibitor AZD6244 followed by gemcitabine in patients with advanced biliary cancer.

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Crocetin suppresses angiogenesis through inhibiting Sonic hedgehog signaling pathway in gastric cancer

10.21203/rs.3.rs-86049/v1 ◽

2020 ◽

Author(s):

Ye Zhou ◽

Mingde Zang ◽

Junyi Hou ◽

Jiangli Wang ◽

Yakai Huang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Sonic Hedgehog ◽

Tube Formation ◽

Cell Counting ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Effects ◽

Shh Signaling ◽

Huvec Cells

Abstract BackgroundCrocetin is an active component of saffron stigma, which has important therapeutic effects on various diseases including tumors, arthritis, hemorrhages, etc. However, the effects of crocetin on gastric cancer (GC) cells and their underlying mechanisms remain unclear.MethodsCell counting kit‑8 (CCK‑8), transwell assays, F-actin staining, tube formation and vasculogenic mimicry (VM) assays were used to examine the effects of crocetin on cell proliferation, migration and angiogenesis in GC. Enzyme linked immunosorbent assay (ELISA) and Western blot assay were performed to evaluate expression level of Sonic hedgehog (Shh) signaling and activation of epithelial‑mesenchymal transition (EMT) in GC cells treated with or without crocetin. Proliferation of xenograft tumors was detected by immunohistochemistry. ResultsCrocetin significantly inhibited tube formation of human umbilical vein endothelial (HUVEC) cells and VM formation of GC cells, as well as its proliferation, invasion and migration. Crocetin destroyed cytoskeleton and mosaic vessels formed by HUVEC and GC cells. Furthermore, we found that crocetin suppressed cell proliferation, migration, EMT, tube and VM formation through inhibiting Shh signaling pathway. Utilization of recombinant Shh reversed the suppressing effects of crocetin on cell proliferation, migration, angiogenesis and EMT. In addition, anti-tumor effect of crocetin was confirmed in xenograft tumors.ConclusionsCrocetin suppressed GC progression by inhibiting cell proliferation, migration and angiogenesis including tubes formed by HUVEC cells and VM vessels formed by GC cells, which were mediated by suppressing Shh signaling pathway. These results indicated that crocetin may function as an effective therapeutic drug against GC.

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Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

10.21203/rs.2.17060/v2 ◽

2020 ◽

Author(s):

Lei Li ◽

Xiang-Hui Wu ◽

Xiao-Jing Zhao ◽

Lu Xu ◽

Cai-Long Pan ◽

...

Keyword(s):

Signaling Pathway ◽

Mapk Signaling ◽

Amyloid Deposition ◽

Microglial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Effects ◽

Inflammatory Phenotype ◽

Β Amyloid ◽

Anti Inflammatory ◽

Behavioral Impairments

Abstract Background : Alzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods : The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, Nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence and flow cytometry analysis. Results : Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro . After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions : Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

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Upregulation of Long Noncoding RNA_GAS5 Suppresses Cell Proliferation and Metastasis in Laryngeal Cancer via Regulating PI3K/AKT/mTOR Signaling Pathway

Technology in Cancer Research & Treatment ◽

10.1177/1533033821990074 ◽

2021 ◽

Vol 20 ◽

pp. 153303382199007

Author(s):

Wenlin Liu ◽

Jiandong Zhan ◽

Rong Zhong ◽

Rui Li ◽

Xiaoli Sheng ◽

...

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Laryngeal Cancer ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Proliferation And Metastasis ◽

Cancer Tissues ◽

Lncrna Gas5

Background: Laryngeal cancer is one of the most common malignant tumors among head and neck cancers. Accumulating studies have indicated that long noncoding RNAs (lncRNAs) play an important role in laryngeal cancer occurrence and progression, however, the functional roles and relative regulatory mechanisms of lncRNA growth arrest-specific transcript 5 (GAS5) in laryngeal cancer progression remain unclear. Methods: The expression of lncRNA GAS5 in both laryngeal cancer tissues and cell lines was evaluated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay. The relationships between lncRNA GAS5 expression and clinical parameters were also analyzed. To determine the biological function of lncRNA GAS5, a lncRNA GAS5-specific plasmid was first transfected into laryngeal cancer cells using lentiviral technology. Cell counting kit-8 assay, flow cytometry, and Transwell assays were used to detect in vitro cell proliferation, apoptosis, cycle distribution, and metastasis abilities, respectively. Furthermore, in vivo cell growth experiments were also performed using nude mice. Additionally, western blotting was performed to identify the underlying regulatory mechanism. Results: In the current study, lncRNA GAS5 was downregulated in laryngeal cancer tissues and its low expression was closely associated with poor tumor differentiation, advanced TNM stage, lymph node metastasis, and shorter overall survival time. In addition, lncRNA GAS5 upregulation significantly inhibited laryngeal cancer cell proliferation both in vitro and in vivo. Moreover, in response to lncRNA GAS5 overexpression, more laryngeal cancer cells were arrested at the G2/M stage, accompanied by increased cell apoptosis rates and suppressed migration and invasion capacities. Mechanistically, our data showed that the overexpression of lncRNA GAS5 significantly regulated the PI3K/AKT/mTOR signaling pathway. Conclusion: LncRNA GAS5 might act as a suppressor gene during laryngeal cancer development, as it suppressed cell proliferation and metastasis by regulating the PI3K/AKT/mTOR signaling pathway; thus, lncRNA GAS5 is a promising therapeutic biomarker for the treatment of laryngeal cancer.

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Bu Shen Zhu Yun Decoction Improves Endometrial Receptivity via VEGFR-2-Mediated Angiogenesis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/3949824 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Li Li ◽

Huabo Jiang ◽

Xuecong Wei ◽

Dandan Geng ◽

Ming He ◽

...

Keyword(s):

Signaling Pathway ◽

Embryo Implantation ◽

Mapk Signaling ◽

Endometrial Receptivity ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Cell Counting ◽

Nuclear Antigen ◽

Vitro Fertilization

Vascular endothelial growth factor receptor-2 (VEGFR-2) regulates the mitogen-activated protein kinase (MAPK) signaling pathway and plays an important role in angiogenesis. Bu Shen Zhu Yun decoction (BSZYD) can improve endometrial receptivity and embryo implantation rates in patients undergoing in vitro fertilization. However, whether BSZYD improves endometrial receptivity via angiogenesis remains unclear. Here, we investigated the effects of BSZYD on the proliferation, migration, and angiogenesis of human endometrial microvascular endothelial cells (HEMECs) and found that BSZYD upregulated the expression of cyclin D1, matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen (PCNA) in HEMECs. Cell Counting Kit 8 assay, scratch-wound assay, and Tube Formation Assay results showed that BSZYD promoted the proliferation, migration, and angiogenesis of HEMECs. Western blot analysis results revealed the activation of the MAPK signaling pathway by BSZYD through the upregulation of VEGF and VEGFR-2 expression. Together, these findings highlight the novel mechanism underlying BSZYD-mediated improvement in endometrial receptivity through the MAPK signaling pathway.

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HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

International Journal of Molecular Sciences ◽

10.3390/ijms19103153 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3153 ◽

Cited By ~ 6

Author(s):

J. Muñoz-Bello ◽

Leslie Olmedo-Nieva ◽

Leonardo Castro-Muñoz ◽

Joaquín Manzo-Merino ◽

Adriana Contreras-Paredes ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Transcriptional Activation ◽

Target Genes ◽

Promote Cell Proliferation ◽

E6 And E7 ◽

Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

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