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

2018 ◽  
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.

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

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.

Tougu Xiaotong capsules may inhibit p38 MAPK pathway-mediated inflammation: In vivo and in vitro verification

2020 ◽  
Vol 249 ◽  
pp. 112390 ◽  
Author(s):  
Xihai Li ◽  
Zhenli Zhang ◽  
Wenna Liang ◽  
Jianwei Zeng ◽  
Xiang Shao ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Mapk Pathway

scholarly journals Autophagy Protects from Raddeanin A-Induced Apoptosis in SGC-7901 Human Gastric Cancer Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yu-hao Teng ◽  
Jie-pin Li ◽  
Shen-lin Liu ◽  
Xi Zou ◽  
Liang-hua Fang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Human Gastric Cancer ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Inhibition Of Proliferation ◽  
P38 Mapk Pathway ◽  
Induced Apoptosis ◽  
Dose Dependent

Raddeanin A (RA) is an extractive fromAnemone raddeana Regel, a traditional Chinese medicine. The aim of this study is to assess the efficacy of RA against human gastric cancer (GC) cells (SGC-7901) and explore its mechanism. MTT assay showed that RA inhibition of proliferation of SGC-7901 cells increased in a dose-dependent manner. Flow cytometry analysis and Hoechst 33258 staining showed that RA induced apoptosis on SGC-7901 cells. Meanwhile, it induced autophagy. Western blotting analysis showed that the RA induces apoptosis and autophagy by activating p38 MAPK pathway and inhibiting mTOR pathway. Further studies showed that autophagy inhibition could protect from RA-induced apoptosis in SGC-7901 cells. In conclusion, RA can induce SGC-7901 cell apoptosis and autophagy by activating p38 MAPK pathway. And autophagy can protect SGC-7901 cells from apoptosis induced by RA.

Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway

2007 ◽  
Vol 86 (6) ◽  
pp. 331-344 ◽  
Author(s):  
Haitao Wu ◽  
Xuan Wang ◽  
Shuhong Liu ◽  
Yan Wu ◽  
Tong Zhao ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Myogenic Differentiation ◽  
P38 Mapk Pathway

Abstract 17211: Targeting Mitogen-Activated Kinase Alleviates Free Heme-Induced Endothelial Barrier Dysfunction and Vascular Leakage in Lungs

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Joel James ◽  
Mathews Valuparampil Varghes ◽  
Marina zemskova ◽  
Olga Rafikova ◽  
Ruslan Rafikov
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Vascular Leakage ◽  
Endothelial Barrier ◽  
Contributory Factor ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
P38 Mapk Pathway ◽  
Free Heme

Introduction: Several studies confirm that free heme in circulation due to hemolysis causes endothelial barrier dysfunction. We recently demonstrated that hemolysis-induced vascular leakage with barrier dysfunction was a contributory factor to the development of pulmonary hypertension (PH). However, the precise molecular mechanisms involved in the pathology of heme induced barrier disruption still remains to be elucidated. Hypothesis: Previous studies by us showed that free heme activated the p38/MAPK pathway. Therefore, we hypothesized that targeting mitogen-activated protein kinase kinase 3 (MKK3) a key regulator of this pathway would alleviate heme induced vascular leakage. Methods: Barrier dysfunction in human micro-vascular endothelial cells (HLMVEC) was monitored using noninvasive electrical impedance and immunostaining. We used an MKK3 knockout mouse model to assess the efficacy of targeting the p38/MAPK pathway. Results: We found a rapid drop in the HLMVEC barrier integrity with heme, in a dose dependent manner (p<0.05). Investigating the barrier proteins showed that heme significantly affected the tight junction proteins, zona occludens-1, claudin1, and claudin5 (p<0.05). We also found the p38MAPK/HSP27 pathway, involved in regulating the endothelial cytoskeleton remodeling, to be significantly altered with heme treatment, both in the HLMVEC and mice (p<0.05). However, heme treated mice showed no significant change in E-selectin, ICAM1 and VCAM1, indicating that the primary rapid target of heme was the p38/MAPK pathway and not the inflammatory pathways. Finally, injecting mice with heme-FITC-dextran and then following its release into the lungs demonstrated that the MKK3 KO significantly prevented heme induced vascular leakage (p<0.05). Conclusion: We demonstrate that heme induces a rapid barrier dysfunction by disruption of endothelial barrier proteins via the p38/MAPK pathway. Also, knocking out MKK3, a crucial regulator of the p38/MAPK pathway significantly decreased heme induced vascular leakage, a contributory factor to PH. Taken together, our results show that targeting the MKK3/p38MAPK axis represents a decisive treatment strategy in alleviating heme induced barrier dysfunction in cardiovascular diseases.

scholarly journals Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

2015 ◽  
Vol 112 (5) ◽  
pp. E497-E505 ◽  
Author(s):  
Elisa Duregotti ◽  
Samuele Negro ◽  
Michele Scorzeto ◽  
Irene Zornetta ◽  
Bryan C. Dickinson ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Motor Axon ◽  
Nerve Terminals ◽  
Axon Terminals ◽  
Terminal Degeneration

An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin-treated primary neurons release signaling molecules derived from mitochondria: hydrogen peroxide, mitochondrial DNA, and cytochrome c. These molecules activate isolated primary Schwann cells, Schwann cells cocultured with neurons and at neuromuscular junction in vivo through the MAPK pathway. We propose that this inter- and intracellular signaling is involved in triggering the regeneration of peripheral nerve terminals affected by other forms of neurodegenerative diseases.

scholarly journals IL-1β Promotes A7r5 and HASMC Migration and Invasion via the p38-MAPK/Ang2 Pathway

2022 ◽  
Author(s):  
anyu Xu ◽  
jingchun Pei ◽  
Yunhong Yang ◽  
Baotong Hua ◽  
Jing Wang
Keyword(s):  
Cell Migration ◽  
Cyclin D1 ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Cell Migration And Invasion ◽  
Invasion And Migration

Abstract Background: The migration, proliferation, and inflammatory factor secretion of vascular smooth muscle cells (VSMCs) are involved in the important pathological processes of several vascular occlusive diseases, including coronary atherosclerosis (CAS). IL-1β, as a bioactive mediator of VSMC synthesis and secretion, can promote the pathological progress of CAS. In this study, we further explored the underlying molecular mechanisms by which IL-1β regulates VSMC migration, invasion.Methods: We pretreated A7r5 and HASMC with IL-1β for 24 hours, and measured the expression of IL-1β, PCNA, cyclin D1, MMP2 and MMP9 in the cells by Western blotting. Cell migration and invasion ability were measured by Transwell and wound healing assays. Cell viability was measured by an MTT assay. Results: We found that IL-1β up-regulated the expression of proliferation-related proteins (PCNA and Cyclin D1) in A7r5 and HASMC, and induces the secretion of MMP2 and MMP9, promotes cell invasion and migration. In addition, in A7r5 and HASMCs treated with IL-1β, the expression of Ang2 increased in a time-dependent manner, transfection with si-Ang2 suppressed cell migration and invasion, with down-regulated MMP2 and MMP9 expression. In parallely, we further found that the p38-MAPK pathway is activated in cells induced by IL-1β, p38-MAPK inhibitors can down-regulate the expression of Ang2. Conclusions: These data demonstrated that IL-1β promotes A7r5 and HASMC migration and invasion via the p38-MAPK/Ang2 pathway.

scholarly journals Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway

2021 ◽  
Vol 22 (16) ◽  
pp. 8720
Author(s):  
Simon Kwoon Ho Chow ◽  
Can Cui ◽  
Keith Yu Kin Cheng ◽  
Yu Ning Chim ◽  
Jinyu Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Fracture Healing ◽  
P38 Mapk ◽  
Osteoporotic Fracture ◽  
Mechanical Stimulation ◽  
Mapk Pathway ◽  
Acute Inflammatory Response ◽  
P38 Mapk Pathway ◽  
Response Expression

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

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