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

2019 ◽  
Author(s):  
Lei Li ◽  
Xiang-Hui Wu ◽  
Xiao-Jing Zhao ◽  
Lu Xu ◽  
Cai-Long Pan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Amyloid Deposition ◽  
Microglial Cells ◽  
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. 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 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 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.

The defense response of Caenorhabditis elegans to Cutibacterium acnes SK137 via the TIR-1-p38 MAPK signaling pathway

2021 ◽  
Author(s):  
Ayano Tsuru ◽  
Yumi Hamazaki ◽  
Shuta Tomida ◽  
Mohammad Shaokat Ali ◽  
Eriko Kage-Nakadai
Keyword(s):  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Defense Response ◽  
Mapk Pathway ◽  
Defense Responses ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Healthy Skin ◽  
Cutibacterium Acnes

Abstract Cutibacterium acnes plays roles in both acne disease and healthy skin ecosystem. We observed that mutations in the tir-1/SARM1 and p38 MAPK cascade genes significantly shortened Caenorhabditis elegans lifespan upon Cutibacterium acnes SK137 infection. Antimicrobial molecules were induced by SK137 in a TIR-1-dependent manner. These results suggest that defense responses against SK137 involve the TIR-1-p38 MAPK pathway in Caenorhabditis elegans.

scholarly journals PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2420
Author(s):  
Minju Lee ◽  
Gee-Hye Kim ◽  
Miyeon Kim ◽  
Ji Min Seo ◽  
Yu Mi Kim ◽  
...  
Keyword(s):  
Scale Up ◽  
Therapeutic Effects ◽  
Arginase 1 ◽  
Inflammatory Phenotype ◽  
Monosodium Iodoacetate ◽  
M1 Phenotype ◽  
Interleukin 1Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Inflammatory Macrophages

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.

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.

Fermented ginseng attenuates lipopolysaccharide-induced inflammatory responses by activating the TLR4/MAPK signaling pathway and remediating gut barrier

2021 ◽  
Author(s):  
Jingjing Fan ◽  
Sitong Liu ◽  
Zhiyi Ai ◽  
Yiying Chen ◽  
Yonghong Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Physiological Effect ◽  
Mapk Signaling Pathway ◽  
Gut Barrier ◽  
Fermented Ginseng ◽  
Anti Inflammatory

Generally, ginsenosides have the physiological effect of an anti-inflammatory immunity.

scholarly journals Estrogen Enhances Matrix Synthesis in Nucleus Pulposus Cell through the Estrogen Receptor β-p38 MAPK Pathway

2016 ◽  
Vol 39 (6) ◽  
pp. 2216-2226 ◽  
Author(s):  
Pei Li ◽  
Yuan Xu ◽  
Yibo Gan ◽  
Liyuan Wang ◽  
Bin Ouyang ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Matrix Synthesis ◽  
P38 Mapk Pathway ◽  
Collagen Ii

Background/Aims: Matrix homeostasis within the disc nucleus pulposus (NP) tissue is important for disc function. Increasing evidence indicates that sex hormone can influence the severity of disc degeneration. This study was aimed to study the role of 17β-estradiol (E2) in NP matrix synthesis and its underlying mechanism. Methods: Rat NP cells were cultured with (10-5, 10-7 and 10-9 M) or without (control) E2 for48 hours. The estrogen receptor (ER)-β antagonist PHTPP and ERβ agonist ERB 041 were used to investigate the role mediated by ERβ. The p38 MAPK inhibitor SB203580 was used to investigate the role of p38 MAPK signaling pathway. Gene and protein expression of SOX9, aggrecan and collagen II, glycosaminoglycan (GAG) content, and immunostaining assay for aggrecan and collagen II were analyzed to evaluate matrix production in rat NP cells. Results: E2 enhanced NP matrix synthesis in a concentration-dependent manner regarding gene and proetin expression of SOX9, aggrecan and collagen II, protein deposition of aggrecan and collagen II, and GAG content. Moreover, activation of p38 MAPK signaling pathway was increased with elevating E2 concentration. Further analysis indicated that ERB 041 and PHTPP could respectively enhance and suppress effects of E2 on matrix synthesis in NP cells, as well as activation of p38 MAPK pathway. Additionally, inhibition of p38 MAPK signaling pathway significantly abolished the effects of E2 on matrix synthesis. Conclusion: E2 can enhance matrix synthesis of NP cells and the ERβ/p38 MAPK pathway is involved in this regulatory process.

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.

The CML-Microvesicles Are Enriched with Mirnas Regulating MAPK Signaling Pathway.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2786-2786
Author(s):  
Xiaomei Chen ◽  
Wei Xiong ◽  
Fang Liu ◽  
Shiang Huang ◽  
Sun Yanqing ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
K562 Cells ◽  
Gene Interaction ◽  
Mapk Signaling ◽  
Interaction Networks ◽  
Regulatory Effect ◽  
Gene Interaction Networks ◽  
Microrna Gene

Abstract Abstract 2786 Leukemia-cell-derived microvesicles (MVs) act as vehicles for exchange of genetic information between leukemia and nomal cells, engendering a favorable microenvironment for leukemia development. Within the leukemia mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. MVs contain microRNAs that could be transferred to target cells inducing epigenetic changes. MicroRNAs are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML)-derived MVs. Given the attributes of MVs and microRNAs in leukemia progression, we therefore aimed to investigate a possible regulatory effect of microRNAs upon MVs as a mean to uncover molecular events involved in promotion of leukemogenesis by MVs. Hnece, we determined the miRNA expression profiles of CML-derived MVs and their parental cells using Agilent miRNA microarray analysis. The six miRNAs obtained by microarray profiling were validated using real-time PCR. The potential targets of the differentially expressed microRNAs were predicted using computational searches. Bioinformatic analyses of the predicted target genes were done for further research. We identified 104 microRNAs aberrantly expressed in both CML-derived MVs and their parental cells, indicating that CML-derived MVs miRNA is the mini version of the parental cells. Target gene-related pathway analyses showed that majority of the 104 microRNAs involved in the signaling pathways associated with leukemia, especially the mitogen-activated protein kinase (MAPK) signaling pathways. We found 34 microRNAs targeted 44 genes of the MAKP pathway, suggesting that the MAPK signaling pathway may commonly function together. By further conducting microRNA gene network analysis, we found that the miR-15a/b, miR-16, miR-17and miR-30 families are likely to play key roles in the regulation of MAPK pathways. The figure showed microRNA-gene interaction networks related to the pathway. The has-miR-30 family (except for hsa-miR-30a hsa-miR-30d) showed that the most target mRNAs, with degrees from 6 to 9, while hsa-miR-17, hsa-miR-16 and hsa-miR-15a/b occupy an important position in the MAPK pathway. The seven microRNAs might play an important role in the pathogenesis of CML. The MAPK pathway is a common point of convergence of many different mitogenic and anti-apoptotic signal transduction pathways in hematopoietic, as well as epithelial, cancer cells and can now be clinically targeted by highly selective small molecule inhibitors. Such deregulation of MAPK pathways contributes to BCR-ABL leukemogenesis, and their targeting with selective inhibitors provides an approach to enhance anti-leukemic responses and/or overcome leukemic cell resistance in CML. A large body of evidence has established that RAS/MAPK signaling contribute to the survival of BCR-ABL positive cells under imatinib selection pressure. It is evident that release of microRNAs from the lumen of MVs can induce activation of specific signal transduction cascades and influence the physiologic state of recipient cells. So the MVs derived from leukemia cells may weaken or enhance the expression of mRNA involved in MAPK pathway in recipient cells, and come to remodel the leukemia niche. In conclusion, we first demonstrated that CML-MVs were enriched with expression changes of distinct sets of miRNAs regulating MAPK sinaling pathway. MAPK sinaling pathway were active in CML-MVs and may commonly function together. We believe that this new correlation among MVs, microRNAs and MAPK pathway can be exploited to both better understand leukemia progression and also suggest novel therapies for leukemias. Fig 1. microRNA-gene interaction networks of MAPK pathway. Blue nodes represent microRNA co-eppressed in MVs from K562 cells and K562 cells, red nodes represent target mRNA. Edges show the regulatory effect of microRNA on mRNA. Fig 1. microRNA-gene interaction networks of MAPK pathway. Blue nodes represent microRNA co-eppressed in MVs from K562 cells and K562 cells, red nodes represent target mRNA. Edges show the regulatory effect of microRNA on mRNA. Disclosures: No relevant conflicts of interest to declare.

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