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

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.

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

2021 ◽  
Vol 16 (1) ◽  
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

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.

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

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.

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

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.

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

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.

scholarly journals Integrated Network and Experimental Pharmacology for Deciphering the Medicinal Substances and Multiple Mechanisms of Duhuo Jisheng Decoction in Osteoarthritis Therapy

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Wenyu Xiao ◽  
Weibing Sun ◽  
Hui Lian ◽  
Juexin Shen
Keyword(s):  
Signaling Pathway ◽  
Mapk Signaling ◽  
Herbal Remedies ◽  
Chondrocyte Apoptosis ◽  
Therapeutic Effects ◽  
Integrated Network ◽  
Experimental Pharmacology ◽  
Joint Disorder ◽  
Medicinal Substances ◽  
Long Time

Osteoarthritis (OA) is currently the most common joint disorder worldwide. In last decades, herbal remedies have achieved a significant advancement in the treatment of OA. Duhuo Jisheng Decoction (DHJS), an herbal formula consisting of 15 medicinal herbs, has a long-time practice in OA therapy in China. However, its therapeutic mechanisms have not been comprehensively elucidated. In the present work, integrated network and experimental pharmacology were performed for investigating the therapeutic substances and mechanisms of DHJS. Based on network analysis, the contribution of each herb to OA therapy was evaluated. Furthermore, a series of potential targets and signaling pathways were enriched, which could be involved in the therapeutic effects and mechanisms of DHJS. Further experimental results indicated that DHJS attenuated TNFα, IL-6, MMP-1, MMP-9, MMP-13, and ADAMTs-5 expression, inhibited NF-κB and p38 MAPK signaling pathway, activated AMPK-SIRT1 signaling pathway, and suppressed chondrocyte apoptosis, which synergistically contributed to OA therapy. Our work demonstrated that DHJS could be very promising for OA therapy through synergistically acting on multitargets and multipathways.

scholarly journals Proteomic Analysis of Radiation-Induced Acute Liver Damage in a Rabbit Model

Dose-Response ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 155932581988950 ◽  
Author(s):  
Lingong Jiang ◽  
Huimin Jia ◽  
Zhicheng Tang ◽  
Xiaofei Zhu ◽  
Yangsen Cao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Liver Damage ◽  
Rabbit Model ◽  
Mapk Signaling ◽  
Differentially Expressed ◽  
Mitogen Activated Protein Kinase ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Radiation Induced ◽  
Liver Tissues

Radiation-induced liver damage (RILD) has become a limitation in radiotherapy for hepatocellular carcinoma. We established a rabbit model of RILD by CyberKnife. Electron microscopy analysis revealed obvious nuclear atrophy and disposition of fat in the nucleus after irradiation. We then utilized a mass spectrometry-based label-free relative quantitative proteomics approach to compare global proteomic changes of rabbit liver in response to radiation. In total, 2365 proteins were identified, including 338 proteins that were significantly dysregulated between irradiated and nonirradiated liver tissues. These differentially expressed proteins included USP47, POLR2A, CSTB, MCFD2, and CSNK2A1. Real-time polymerase chain reaction confirmed that USP47 and CABLES1 transcripts were significantly higher in irradiated liver tissues, whereas MCFD2 and CSNK2A1 expressions were significantly reduced. In Clusters of Orthologous Groups of proteins analysis, differentially expressed proteins were annotated and divided into 24 categories, including posttranslational modification, protein turnover, and chaperones. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the enriched pathways in dysregulated proteins included the vascular endothelial growth factors (VEGF) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the adipocytokine signaling pathway. The identification of proteins and pathways is crucial toward elucidating the radiation response process of the liver, which may facilitate the discovery of novel therapeutic targets.

scholarly journals miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway

2018 ◽  
Vol 26 (3) ◽  
pp. 363-372 ◽  
Author(s):  
Xiaowen Chen ◽  
Jianli Chen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Luciferase Reporter ◽  
And Migration ◽  
Mcf 7

This study intended to investigate the effects of miR-3188 on breast cancer and to reveal the possible molecular mechanisms. miR-3188 was upregulated and TUSC5 was downregulated in breast cancer tissues and MCF-7 cells compared to normal tissue and MCF-10 cells. After MCF-7 cells were transfected with miR-3188 inhibitor, cell proliferation and migration were inhibited, whereas apoptosis was promoted. Luciferase reporter assay suggested that TUSC5 was a target gene of miR-3188. In addition, miR-3188 overexpression increased the p-p38 expression, while miR-3188 suppression decreased the p-p38 expression significantly. miR-3188 regulated breast cancer progression via the p38 MAPK signaling pathway. In conclusion, miR-3188 affects breast cancer cell proliferation, apoptosis, and migration by targeting TUSC5 and activating the p38 MAPK signaling pathway. miR-3188 may serve as a potential therapeutic agent for the treatment of breast cancer.

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

2019 ◽  
Vol 38 (1) ◽  
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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