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Article ; Online: Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats.

Duan, Chenxia / Zhu, Yi / Zhang, Zhuoliang / Wu, Tiantian / Shen, Mengwei / Xu, Jinfu / Gao, Wenxin / Pan, Jianhua / Wei, Lei / Su, Huibin / Shi, Chenghuan

Molecular pain

2024 Volume 20, Page(s) 17448069241239231

Abstract: ... CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development ... explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord ... of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection ...

Abstract	Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.
MeSH term(s)	Humans ; Rats ; Animals ; Cancer Pain/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Rats, Sprague-Dawley ; Pain/metabolism ; Bone Neoplasms/complications ; Spinal Cord/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Spinal Cord Dorsal Horn/metabolism ; Analgesics/pharmacology ; Hyperalgesia/metabolism ; Ketamine
Chemical Substances	Esketamine (50LFG02TXD) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Analgesics ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2174252-2
ISSN	1744-8069 ; 1744-8069
ISSN (online)	1744-8069
ISSN	1744-8069
DOI	10.1177/17448069241239231
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Article ; Online: Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Zanyan Zhao / Xiangpu Wang / Yu Ma / Xiaohong Duan

International Journal of Molecular Sciences, Vol 25, Iss 1, p

2024 Volume 637

Abstract: ... sequencing revealed the upregulation of genes, such as Fos , Src , Jun , and various integrin subunits ... that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos - Jun - Src - Integrin ...

Abstract	The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout ( Atp6v1h +/- ) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h +/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos , Src , Jun , and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos - Jun - Src - Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h ’s role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.
Keywords	osteoporosis ; Atp6v1h ; Fos-Jun-Src-Integrin pathway ; tail suspension model ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570 ; 616
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: NF‑κB regulates HSF1 and c‑Jun activation in heat stress‑induced intestinal epithelial cell apoptosis.

Li, Jun / Liu, Yanan / Duan, Pengkai / Yu, Rongguo / Gu, Zhengtao / Li, Li / Liu, Zhifeng / Su, Lei

Molecular medicine reports

2018 Volume 17, Issue 2, Page(s) 3388–3396

Abstract: ... The levels of heat stress‑induced c‑Jun phosphorylation were also examined: Knockdown of p65 resulted ... in a reduction of c‑Jun phosphorylation, whereas p65 overexpression resulted in increased phosphorylation ... apoptosis. Cells pretreated with c‑Jun peptide, an inhibitor of c‑Jun activation, exhibited a significant ...

Abstract	Heat stress may induce intestinal epithelial cell apoptosis; however, the molecular mechanisms have not yet been identified. The present study used IEC‑6 rat small intestinal epithelial cells to investigate heat stress‑induced production of reactive oxygen species (ROS), which may be involved in nuclear factor (NF)‑κB activation during heat stress. IEC‑6 cells were transfected with NF‑κB p65‑specific small interfering RNA (siRNA), and observed a significant increase in cell apoptosis and caspase‑3 cleavage; however, in cells transfected with adenovirus that constitutively overexpressed p65, the opposite results were obtained. Furthermore, p65 knockdown increased the heat stress‑induced expression and activity of heat shock transcription factor 1 (HSF1); conversely, p65 overexpression slightly decreased HSF1 activity. The levels of heat stress‑induced c‑Jun phosphorylation were also examined: Knockdown of p65 resulted in a reduction of c‑Jun phosphorylation, whereas p65 overexpression resulted in increased phosphorylation. Furthermore, siRNA‑mediated knockdown of HSF1 in IEC‑6 cells significantly increased heat stress‑induced apoptosis. Cells pretreated with c‑Jun peptide, an inhibitor of c‑Jun activation, exhibited a significant reduction in apoptosis. These findings indicated that heat stress stimulation in IEC‑6 cells induced the pro‑apoptotic role of NF‑κB by regulating HSF1 and c‑Jun activation.
MeSH term(s)	Animals ; Apoptosis ; Cell Line ; Heat Shock Transcription Factors/immunology ; Heat-Shock Response ; Intestinal Mucosa/cytology ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; NF-kappa B/immunology ; Proto-Oncogene Proteins c-jun/immunology ; Rats ; Reactive Oxygen Species/immunology
Chemical Substances	Heat Shock Transcription Factors ; Hsf1 protein, rat ; NF-kappa B ; Proto-Oncogene Proteins c-jun ; Reactive Oxygen Species
Language	English
Publishing date	2018-02
Publishing country	Greece
Document type	Journal Article
ISSN	1791-3004
ISSN (online)	1791-3004
DOI	10.3892/mmr.2017.8199
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Article ; Online: A network pharmacology-based exploration of the active compounds and potential drug targets of Si-Jun-Zi decoction in the treatment of cutaneous squamous cell carcinoma.

Qin, Si / Zhang, Lan-Yue / Zhang, Hao-Bin / Shi, Si-Man / Zhou, Xin / Lu, Zhen-Yu / Duan, Yi-Xue / Huang, Wen-Bin / Wen, Ju

Translational cancer research

2022 Volume 11, Issue 8, Page(s) 2887–2901

Abstract: ... then employed a data mining method to analyze drug combinations of Si-Jun-Zi (SJZ) decoction. Multiple databases ...

Abstract	Background: Cutaneous squamous cell carcinoma (cSCC), a kind of skin cancer with high rates of morbidity and mortality, occurs frequently in the clinic. Although early surgical treatment can achieve good results, there is no effective prevention and treatment for the recurrence and metastasis of cSCC. As a useful resource to protect humans from disease, traditional Chinese medicine (TCM) has been adopted by clinicians for thousands of years. Methods: In this study, we collected a Chinese medicine formula and then employed a data mining method to analyze drug combinations of Si-Jun-Zi (SJZ) decoction. Multiple databases were used in this study to predict various ingredients, compounds, and their targets in the decoction. The potential targets of cSCC were also obtained from the database in the same way. In addition, as bioinformatics analysis methods, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used in our research as supplementary means to network pharmacology. Finally, we used ultra-performance liquid chromatography (UPLC) fingerprinting to analyze the effective components of the TCM decoction. Results: We detected 559 active compounds from Ginseng, Largehead Atractylodes, India Bread, and Glycyrrhiza Inflata, and selected 136 molecules under specific conditions. The mechanisms of the TCM formula were illustrated by the network pharmacology, such as compounds-herb network, compounds-target network, disease-target network, and target-target interaction network, as well as characteristics of the TCM. Then, GO analysis and KEGG analysis were performed on the compounds in the network using multiple methods of data mining and bioinformatics, and 10 candidate targets were identified. In addition, the UPLC fingerprinting method was used to analyze the components of SJZ decoction. Conclusions: Network pharmacology was performed to investigate the characteristics and mechanism of SJZ decoction, and a bioinformatics method was used to analyze the relationship between the effective compounds of the SJZ TCM decoction and cSCC-related specific targets and pathways, to find a variety of candidate compounds with multi-target activity.
Language	English
Publishing date	2022-08-31
Publishing country	China
Document type	Journal Article
ZDB-ID	2901601-0
ISSN	2219-6803 ; 2218-676X
ISSN (online)	2219-6803
ISSN	2218-676X
DOI	10.21037/tcr-22-1716
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Article ; Online: AMOTL2 inhibits JUN Thr239 dephosphorylation by binding PPP2R2A to suppress the proliferation in non-small cell lung cancer cells.

Cui, Renjie / Jiang, Nan / Zhang, Meiqin / Du, Sichen / Ou, Huayuan / Ge, Runsheng / Ma, Duan / Zhang, Jin

Biochimica et biophysica acta. Molecular cell research

2020 Volume 1868, Issue 1, Page(s) 118858

Abstract: ... lung tumor cells. The proto-oncogene JUN is a key subunit of activator protein-1 (AP-1 ... increase in JUN T239 phosphorylation. AMOTL2 bound PPP2R2A in cytoplasm, which reduced nuclear localization ... growth in NSCLC cells and function in the AMOTL2-PPP2R2A-JUN axis, in which AMOTL2 inhibits the entry ...

Abstract	Protein phosphatase 2A (PP2A) complex comprises an extended family of intracellular protein serine/threonine phosphatases, that participate in different signaling transduction pathways. Different functions of PP2As are determined by the variety of regulatory subunits. In this study, CRISPR/Cas9-mediated loss-of-function screen revealed that PPP2R2A downregulation suppressed cell growth in NSCLC cells. AMOTL2 was identified and confirmed as a novel binding partner of PPP2R2A in NSCLC cells by mass spectrometry, CO-IP, GST pull-down and immunofluorescence. Upregulation of AMOTL2 also led to cell proliferation delay in human and mouse lung tumor cells. The proto-oncogene JUN is a key subunit of activator protein-1 (AP-1) transcription factor which plays crucial role in regulating tumorigenesis and its activity is negatively regulated by the phosphorylation at T239. Our results showed that either AMOTL2 upregulation or PPP2R2A downregulation led to great increase in JUN T239 phosphorylation. AMOTL2 bound PPP2R2A in cytoplasm, which reduced nuclear localization of PPP2R2A. In conclusion, AMOTL2 and PPP2R2A act respectively as negative and positive regulator of cell growth in NSCLC cells and function in the AMOTL2-PPP2R2A-JUN axis, in which AMOTL2 inhibits the entry of PPP2R2A into the nucleus to dephosphorylate JUN at T239.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Carrier Proteins/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; MAP Kinase Signaling System/genetics ; Phosphorylation/genetics ; Protein Phosphatase 2/genetics ; Proto-Oncogene Proteins c-jun/genetics ; Transcription Factor AP-1/genetics ; Up-Regulation
Chemical Substances	AMOTL2 protein, human ; Carrier Proteins ; JUN protein, human ; PPP2R2A protein, human ; Proto-Oncogene Proteins c-jun ; Transcription Factor AP-1 ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2020-09-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2020.118858
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Article ; Online: Delayed Treatment With 4-Methylpyrazole Protects Against Acetaminophen Hepatotoxicity in Mice by Inhibition of c-Jun n-Terminal Kinase.

Akakpo, Jephte Y / Ramachandran, Anup / Duan, Luqi / Schaich, Matthew A / Jaeschke, Matthew W / Freudenthal, Bret D / Ding, Wen-Xing / Rumack, Barry H / Jaeschke, Hartmut

Toxicological sciences : an official journal of the Society of Toxicology

2019 Volume 170, Issue 1, Page(s) 57–68

Abstract: ... alanine aminotransferase activities and reduced areas of necrosis. 4MP prevented c-Jun c-Jun N-terminal kinase (JNK ...

Abstract	Acetaminophen (APAP) overdose is the most common cause of hepatotoxicity and acute liver failure in the United States and many western countries. However, the only clinically approved antidote, N-acetylcysteine, has a limited therapeutic window. 4-Methylpyrazole (4MP) is an antidote for methanol and ethylene glycol poisoning, and we have recently shown that cotreatment of 4MP with APAP effectively prevents toxicity by inhibiting Cyp2E1. To evaluate if 4MP can be used therapeutically, C57BL/6J mice were treated with 300 mg/kg APAP followed by 50 mg/kg 4MP 90 min later (after the metabolism phase). In these experiments, 4MP significantly attenuated liver injury at 3, 6, and 24 h after APAP as shown by 80%-90% reduction in plasma alanine aminotransferase activities and reduced areas of necrosis. 4MP prevented c-Jun c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, and reduced mitochondrial oxidant stress and nuclear DNA fragmentation. 4MP also prevented JNK activation in other liver injury models. Molecular docking experiments showed that 4MP can bind to the ATP binding site of JNK. These data suggest that treatment with 4MP after the metabolism phase effectively prevents APAP-induced liver injury in the clinically relevant mouse model in vivo mainly through the inhibition of JNK activation. 4MP, a drug approved for human use, is as effective as N-acetylcysteine or can be even more effective in cases of severe overdoses with prolonged metabolism (600 mg/kg). 4MP acts on alternative therapeutic targets and thus may be a novel approach to treatment of APAP overdose in patients that complements N-acetylcysteine.
MeSH term(s)	Acetaminophen/toxicity ; Animals ; Chemical and Drug Induced Liver Injury/enzymology ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/prevention & control ; Fomepizole/administration & dosage ; Fomepizole/therapeutic use ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Male ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Protein Binding ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/therapeutic use ; Time-to-Treatment
Chemical Substances	Protein Kinase Inhibitors ; Acetaminophen (362O9ITL9D) ; Fomepizole (83LCM6L2BY) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2019-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfz077
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Article: Delayed Treatment With 4-Methylpyrazole Protects Against Acetaminophen Hepatotoxicity in Mice by Inhibition of c-Jun n-Terminal Kinase

Akakpo, Jephte Y / Ramachandran, Anup / Duan, Luqi / Schaich, Matthew A / Jaeschke, Matthew W / Freudenthal, Bret D / Ding, Wen-Xing / Rumack, Barry H / Jaeschke, Hartmut

Toxicological sciences. 2019 July 01, v. 170, no. 1

2019

Abstract: ... alanine aminotransferase activities and reduced areas of necrosis. 4MP prevented c-Jun c-Jun N-terminal kinase (JNK ...

Abstract	Acetaminophen (APAP) overdose is the most common cause of hepatotoxicity and acute liver failure in the United States and many western countries. However, the only clinically approved antidote, N-acetylcysteine, has a limited therapeutic window. 4-Methylpyrazole (4MP) is an antidote for methanol and ethylene glycol poisoning, and we have recently shown that cotreatment of 4MP with APAP effectively prevents toxicity by inhibiting Cyp2E1. To evaluate if 4MP can be used therapeutically, C57BL/6J mice were treated with 300 mg/kg APAP followed by 50 mg/kg 4MP 90 min later (after the metabolism phase). In these experiments, 4MP significantly attenuated liver injury at 3, 6, and 24 h after APAP as shown by 80%–90% reduction in plasma alanine aminotransferase activities and reduced areas of necrosis. 4MP prevented c-Jun c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, and reduced mitochondrial oxidant stress and nuclear DNA fragmentation. 4MP also prevented JNK activation in other liver injury models. Molecular docking experiments showed that 4MP can bind to the ATP binding site of JNK. These data suggest that treatment with 4MP after the metabolism phase effectively prevents APAP-induced liver injury in the clinically relevant mouse model in vivo mainly through the inhibition of JNK activation. 4MP, a drug approved for human use, is as effective as N-acetylcysteine or can be even more effective in cases of severe overdoses with prolonged metabolism (600 mg/kg). 4MP acts on alternative therapeutic targets and thus may be a novel approach to treatment of APAP overdose in patients that complements N-acetylcysteine.
Keywords	DNA fragmentation ; acetaminophen ; acetylcysteine ; adenosine triphosphate ; alanine transaminase ; antidotes ; binding sites ; computer simulation ; enzyme activity ; enzyme inhibition ; ethylene glycol ; hepatotoxicity ; humans ; liver ; liver failure ; metabolism ; methanol ; mitochondria ; mitogen-activated protein kinase ; necrosis ; nuclear genome ; overdose ; patients ; poisoning ; pyrazoles ; United States
Language	English
Dates of publication	2019-0701
Size	p. 57-68.
Publishing place	Oxford University Press
Document type	Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfz077
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Article ; Online: MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239.

Shi, Qiqing / Xiong, Bo / Zhong, Jing / Wang, Huihui / Ma, Duan / Miao, Changhong

Molecular immunology

2017 Volume 88, Page(s) 79–88

Abstract: ... leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction ... of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK ... through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally ...

Abstract	TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression.
MeSH term(s)	Animals ; Cell Cycle Proteins/metabolism ; Cell Line ; Cytokines/biosynthesis ; DNA-Binding Proteins/metabolism ; HEK293 Cells ; Humans ; Inflammation/immunology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Oncogene Proteins/metabolism ; Phosphorylation/physiology ; Protein Phosphatase 2/metabolism ; Protein Transport/physiology ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; Transcription Factor AP-1/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Cell Cycle Proteins ; Cytokines ; DNA-Binding Proteins ; Lipopolysaccharides ; MFHAS1 protein, human ; Oncogene Proteins ; TLR4 protein, human ; Toll-Like Receptor 4 ; Transcription Factor AP-1 ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; PPP2CA protein, human (EC 3.1.3.16) ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2017
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2017.06.017
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Article ; Online: Porphyromonas gingivalis-induced reactive oxygen species activate JAK2 and regulate production of inflammatory cytokines through c-Jun.

Wang, Huizhi / Zhou, Huaxin / Duan, Xiaoxian / Jotwani, Ravi / Vuddaraju, Himabindu / Liang, Shuang / Scott, David A / Lamont, Richard J

Infection and immunity

2014 Volume 82, Issue 10, Page(s) 4118–4126

Abstract: ... the production of IL-6 and IL-1β. ROS-mediated phosphorylation of JAK2 induced the phosphoactivation of c-Jun ... amino-terminal protein kinase (JNK) and the downstream transcriptional regulator c-Jun. Inhibition ... pharmacological inhibition or siRNA-mediated gene silencing of JNK or c-Jun mimicked the effect of JAK2 inhibition ...

Abstract	Pathogen-induced reactive oxygen species (ROS) play a crucial role in host innate immune responses through regulating the quality and quantity of inflammatory mediators. However, the underlying molecular mechanisms of this effect have yet to be clarified. In this study, we examined the mechanism of action of ROS stimulated by Porphyromonas gingivalis in gingival epithelial cells. P. gingivalis induced the rapid production of ROS, which lead to the phosphorylation of JAK2 and increased levels of secreted proinflammatory cytokines interleukin-6 (IL-6) and IL-1β. Neutralization of ROS by N-acetyl-l-cysteine (NAC) abrogated the phosphorylation of JAK2 and suppressed the production of IL-6 and IL-1β. ROS-mediated phosphorylation of JAK2 induced the phosphoactivation of c-Jun amino-terminal protein kinase (JNK) and the downstream transcriptional regulator c-Jun. Inhibition of JAK2, either pharmacologically or by small interfering RNA (siRNA), reduced both the phosphorylation of these molecules and the production of proinflammatory cytokines in response to P. gingivalis. Furthermore, pharmacological inhibition or siRNA-mediated gene silencing of JNK or c-Jun mimicked the effect of JAK2 inhibition to suppress P. gingivalis-induced IL-6 and IL-1β levels. The results show that ROS-mediated activation of JAK2 is required for P. gingivalis-induced inflammatory cytokine production and that the JNK/c-Jun signaling axis is involved in the ROS-dependent regulation of IL-1β and IL-6 production.
MeSH term(s)	Cells, Cultured ; Epithelial Cells/immunology ; Epithelial Cells/microbiology ; Humans ; Interleukin-1beta/biosynthesis ; Interleukin-6/biosynthesis ; JNK Mitogen-Activated Protein Kinases/metabolism ; Janus Kinase 2/metabolism ; Phosphorylation ; Porphyromonas gingivalis/immunology ; Protein Processing, Post-Translational ; Reactive Oxygen Species/toxicity
Chemical Substances	Interleukin-1beta ; Interleukin-6 ; Reactive Oxygen Species ; JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2014-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.02000-14
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Article: MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239

Shi, Qiqing / Bo Xiong / Jing Zhong / Huihui Wang / Duan Ma / Changhong Miao

Molecular Immunology. 2017 Aug., v. 88

2017

Abstract	TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression.
Keywords	Toll-like receptor 4 ; cytoplasm ; dephosphorylation ; fluorescent antibody technique ; genes ; inflammation ; innate immunity ; interleukin-6 ; mitogen-activated protein kinase ; phosphorylation ; precipitin tests ; signal transduction
Language	English
Dates of publication	2017-08
Size	p. 79-88.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2017.06.017
Database	NAL-Catalogue (AGRICOLA)

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