Inhibition of the p38 MAPK pathway sensitizes human gastric cells to doxorubicin treatment in vitro and in vivo

Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N = 16) or streptozotocin intraperitoneally (DM, N = 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10−6 M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HG-stimulated MC by 70 and 91%, respectively ( P < 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased ( P < 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC ( P < 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis.

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Erucic acid from Isatis indigotica Fort. suppresses influenza A virus replication and inflammation in vitro and in vivo through modulation of NF-κB and p38 MAPK pathway

Journal of Pharmaceutical Analysis ◽

10.1016/j.jpha.2019.09.005 ◽

2020 ◽

Vol 10 (2) ◽

pp. 130-146 ◽

Cited By ~ 3

Author(s):

Xiaoli Liang ◽

Yuan Huang ◽

Xiping Pan ◽

Yanbing Hao ◽

Xiaowei Chen ◽

...

Keyword(s):

Erucic Acid ◽

P38 Mapk ◽

Influenza A Virus ◽

Virus Replication ◽

Influenza A ◽

Mapk Pathway ◽

Isatis Indigotica ◽

P38 Mapk Pathway

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Gold Nanoparticles Combined Human β-Defensin 3 Gene-Modified Human Periodontal Ligament Cells Alleviate Periodontal Destruction via the p38 MAPK Pathway

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.631191 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lingjun Li ◽

Yangheng Zhang ◽

Min Wang ◽

Jing Zhou ◽

Qian Zhang ◽

...

Keyword(s):

Gold Nanoparticles ◽

Osteogenic Differentiation ◽

P38 Mapk ◽

Periodontal Ligament ◽

Mapk Pathway ◽

Periodontal Regeneration ◽

Periodontal Ligament Cells ◽

Human Periodontal Ligament Cells ◽

P38 Mapk Pathway

Periodontitis is a chronic inflammatory disease with plaques as the initiating factor, which will induce the destruction of periodontal tissues. Numerous studies focused on how to obtain periodontal tissue regeneration in inflammatory environments. Previous studies have reported adenovirus-mediated human β-defensin 3 (hBD3) gene transfer could potentially enhance the osteogenic differentiation of human periodontal ligament cells (hPDLCs) and bone repair in periodontitis. Gold nanoparticles (AuNPs), the ideal inorganic nanomaterials in biomedicine applications, were proved to have synergetic effects with gene transfection. To further observe the potential promoting effects, AuNPs were added to the transfected cells. The results showed the positive effects of osteogenic differentiation while applying AuNPs into hPDLCs transfected by adenovirus encoding hBD3 gene. In vivo, after rat periodontal ligament cell (rPDLC) transplantation into SD rats with periodontitis, AuNPs combined hBD3 gene modification could also promote periodontal regeneration. The p38 mitogen-activated protein kinase (MAPK) pathway was demonstrated to potentially regulate both the in vitro and in vivo processes. In conclusion, AuNPs can promote the osteogenic differentiation of hBD3 gene-modified hPDLCs and periodontal regeneration via the p38 MAPK pathway.

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PB1692 G-CSF ACTIVATING P38 MAPK PATHWAY ENHANCES THE ANTI-LEUKEMIC ACTIVITY OF ARSENIC TRIOXIDE IN VITRO THROUGH UP-REGULATING AQP9 EXPRESSION

HemaSphere ◽

10.1097/01.hs9.0000565284.14988.dc ◽

2019 ◽

Vol 3 (S1) ◽

pp. 779

Author(s):

A. Wang ◽

J. Wang ◽

X. Li ◽

H. Pu ◽

L. Xu ◽

...

Keyword(s):

Arsenic Trioxide ◽

P38 Mapk ◽

Mapk Pathway ◽

P38 Mapk Pathway

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Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

Biochemical Journal ◽

10.1042/bj20080599 ◽

2008 ◽

Vol 413 (3) ◽

pp. 429-436 ◽

Cited By ~ 134

Author(s):

Yan Zeng ◽

Heidi Sankala ◽

Xiaoxiao Zhang ◽

Paul R. Graves

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Kinase Inhibitor ◽

Mapk Pathway ◽

Phosphorylation Site ◽

Mitogen Activated Protein Kinase ◽

Processing Bodies ◽

Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

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The Role of Signaling Pathways of Inflammation and Oxidative Stress in Development of Senescence and Aging Phenotypes in Cardiovascular Disease

Cells ◽

10.3390/cells8111383 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1383 ◽

Cited By ~ 17

Author(s):

John Papaconstantinou

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

P38 Mapk ◽

Mapk Pathway ◽

Pharmacological Intervention ◽

Mapk Activity ◽

Chain Complexes ◽

Stress Signals

The ASK1-signalosome→p38 MAPK and SAPK/JNK signaling networks promote senescence (in vitro) and aging (in vivo, animal models and human cohorts) in response to oxidative stress and inflammation. These networks contribute to the promotion of age-associated cardiovascular diseases of oxidative stress and inflammation. Furthermore, their inhibition delays the onset of these cardiovascular diseases as well as senescence and aging. In this review we focus on whether the (a) ASK1-signalosome, a major center of distribution of reactive oxygen species (ROS)-mediated stress signals, plays a role in the promotion of cardiovascular diseases of oxidative stress and inflammation; (b) The ASK1-signalosome links ROS signals generated by dysfunctional mitochondrial electron transport chain complexes to the p38 MAPK stress response pathway; (c) the pathway contributes to the sensitivity and vulnerability of aged tissues to diseases of oxidative stress; and (d) the importance of inhibitors of these pathways to the development of cardioprotection and pharmaceutical interventions. We propose that the ASK1-signalosome regulates the progression of cardiovascular diseases. The resultant attenuation of the physiological characteristics of cardiomyopathies and aging by inhibition of the ASK1-signalosome network lends support to this conclusion. Importantly the ROS-mediated activation of the ASK1-signalosome p38 MAPK pathway suggests it is a major center of dissemination of the ROS signals that promote senescence, aging and cardiovascular diseases. Pharmacological intervention is, therefore, feasible through the continued identification of potent, non-toxic small molecule inhibitors of either ASK1 or p38 MAPK activity. This is a fruitful future approach to the attenuation of physiological aspects of mammalian cardiomyopathies and aging.

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B7-H1(PD-L1) confers chemoresistance through ERK and p38 MAPK pathway in tumor cells

10.1101/308601 ◽

2018 ◽

Cited By ~ 1

Author(s):

Xiaosheng Wu ◽

Yanli Li ◽

Xin Liu ◽

Siyu Cao ◽

Susan M. Harrington ◽

...

Keyword(s):

Tumor Cells ◽

P38 Mapk ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Dependent Manner ◽

Intracellular Signaling Pathway ◽

Development Of Resistance ◽

P38 Mapk Pathway

ABSTRACTDevelopment of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of patients with cancer. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance remains underestimated. It has been recently observed that overexpression of B7-H1(PD-L1) confers chemoresistance in human cancers, however the underlying mechanisms are unclear. Here we show that the development of chemoresistance depends on the increased activation of ERK pathway in tumor cells overexpressing B7-H1. Conversely, B7-H1 deficiency renders tumor cells susceptible to chemotherapy in a cell-context dependent manner through activation of the p38 MAPK pathway. B7-H1 in tumor cells associates with the catalytic subunit of a DNA-dependent serine / threonine protein kinase (DNA-PKcs). DNA-PKcs is required for the activation of ERK or p38 MAPK in tumors expressing B7-H1, but not in B7-H1 negative or B7-H1 deficient tumors. Ligation of B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast tumor cells to cisplatin therapy in vivo. Our results suggest that B7-H1(PD-L1) expression in cancer cells modifies their chemosensitivity towards certain drugs and targeting B7-H1 intracellular signaling pathway is a new way to overcome cancer chemoresistance.

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