scholarly journals The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Yan Guo ◽  
Xiaobo Xu ◽  
Jingyi Huang ◽  
Zhen Wang ◽  
Zhenzhong Li ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Interleukin 1 ◽  
First Line ◽  
Satellite Glial Cell ◽  
P38mapk Signaling ◽  
Mechanical Thresholds ◽  
The Relationship ◽  
P2x7r Activation ◽  
Necrosis Factor ◽  
P38 Pathway

The proteasome inhibitor bortezomib (BTZ) is a potent first-line anticancer drug for multiple myeloma; nonetheless, it induced peripheral neuropathy. It has been suggested that many cytokines may play a role in mediating neuropathic pain, but the underlying molecular mechanism is not fully understood. Recent studies have shown that neuropathic pain is closely related to the purinergic ligand-gated ion channel 7 receptor (P2X7R), one of the P2X receptors, which is richly expressed in glial cells. P2X7-p38 pathway is correlated with microglia- and satellite glial cell- (SGC-) mediated neuropathic pain. However, the association of P2X7R and p38MAPK in mediating BTZ-induced neuropathic pain remains unclear. In this study, the relationship between P2X7R activation and p38 phosphorylation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in the development and maintenance of BTZ-induced neuropathic pain was elucidated. The results showed that BTZ increased mechanical thresholds in rats, accompanied with upregulation of P2X7R expression and p38MAPK phosphorylation, indicating that P2X7R and p38MAPK are key molecules in the development and maintenance of BTZ-induced neuropathic pain. Inhibiting p38MAPK phosphorylation with SB203580 resulted in downregulation of P2X7R expression levels. Inhibition of P2X7R with Brilliant Blue G (BBG) reversed neuropathic pain might decrease through the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 via inhibiting p38MAPK phosphorylation. The P2X7R/p38MAPK signaling pathway in SGCs of DRG and microglia of SDH might be a potential pharmacological target behind this mechanism as an opportunity to relieve BTZ-induced neuropathic pain.

scholarly journals Paeoniflorin and Albiflorin Attenuate Neuropathic Pain via MAPK Pathway in Chronic Constriction Injury Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Jianyu Zhou ◽  
Linyuan Wang ◽  
Jingxia Wang ◽  
Chun Wang ◽  
Zhihui Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Mapk Pathway ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Necrosis Factor

Neuropathic pain remains as the most frequent cause of suffering and disability around the world. The isomers paeoniflorin (PF) and albiflorin (AF) are major constituents extracted from the roots ofPaeonia (P.) lactifloraPall. Neuroprotective effect of PF has been demonstrated in animal models of neuropathologies. However, only a few studies are related to the biological activities of AF and no report has been published on analgesic properties of AF about neuropathic pain to date. The aim of this study was to compare the effects of AF and PF against CCI-induced neuropathic pain in rat and explore the underlying mechanism. We had found that both PF and AF could inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway in spinal microglia and subsequent upregulated proinflammatory cytokines (interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α)). AF further displayed remarkable effects on inhibiting the activation of astrocytes, suppressing the overelevated expression of phosphorylation of c-Jun N-terminal kinases (p-JNK) in astrocytes, and decreasing the content of chemokine CXCL1 in the spinal cord. These results suggest that both PF and AF are potential therapeutic agents for neuropathic pain, which merit further investigation.

scholarly journals Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation.

1996 ◽  
Vol 16 (4) ◽  
pp. 1295-1304 ◽  
Author(s):  
J DiDonato ◽  
F Mercurio ◽  
C Rosette ◽  
J Wu-Li ◽  
H Suyang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Rapid Degradation ◽  
Extracellular Stimuli ◽  
Nf Kappab ◽  
The Relationship ◽  
Necrosis Factor

Extracellular stimuli that activate the transcription factor NF-kappaB cause rapid phosphorylation of the IkappaBalpha inhibitor, which retains NF-kappaB in the cytoplasm of nonstimulated cells. Phosphorylation of IkappaBalpha is followed by its rapid degradation, the inhibition of which prevents NF-kappaB activation. To determine the relationship between these events, we mapped the inducible phosphorylation sites of IkappaBalpha. We found that two residues, serines 32 and 36, were phosphorylated in response to either tumor necrosis factor, interleukin-1, or phorbol ester. Substitution of either serine blocks or slows down induction of IkappaBalpha degradation. Substitutions of the homologous sites in IkappaBbeta, serines 19 and 23, also prevent inducible IkappaBbeta degradation. We suggest that activation of a single IkappaB kinas e or closely related IkappaB kinases is the first cr itical step in NF-kappaB activation. Once phosphorylated, IkappaB is ubiquitinated. Unlike wild-type IkappaBalpha, the phosphorylation-defective mutants do not undergo inducible polyubiquitination. As substitution of a conserved lysine residue slows down the ubiquitination and degradation of IkappaBalpha without affecting its phosphorylation, polyubiquitination is required for inducible IkappaB degradation.

scholarly journals Changes in Cytokine Expression after Electroacupuncture in Neuropathic Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Myeoung Hoon Cha ◽  
Taick Sang Nam ◽  
Yongho Kwak ◽  
Hyejung Lee ◽  
Bae Hwan Lee
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Dorsal Root ◽  
Interleukin 1 ◽  
Cytokine Expression ◽  
Sprague Dawley ◽  
Expression Levels ◽  
Sprague Dawley Rats ◽  
Necrosis Factor

The production of proinflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α) plays a key role in chronic pain such as neuropathic pain. We investigated changes in cytokine expression in injured peripheral nerves and dorsal root ganglia (DRG) following electroacupuncture (EA) treatment. Neuropathic pain was induced by peripheral nerve injury to the left hind limb of Sprague-Dawley rats under pentobarbital anesthesia. Two weeks later, the nerve-injured rats were treated by EA for 10 minutes. The expression levels of IL-1β, IL-6, and TNF-αin peripheral nerves and DRG of neuropathic rats were significantly increased in nerve-injured rats. However, after EA, the cytokine expression levels were noticeably decreased in peripheral nerves and DRG. These results suggest that EA stimulation can reduce the levels of proinflamtory cytokines elevated after nerve injury.

scholarly journals Change of Scaling-Induced Proinflammatory Cytokine on the Clinical Efficacy of Periodontitis Treatment

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Kou-Gi Shyu ◽  
Cheuk-Sing Choy ◽  
Daniel Chung-Lang Wang ◽  
Wei-Chen Huang ◽  
Shyuan-Yow Chen ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Tumor Necrosis Factor ◽  
Proinflammatory Cytokines ◽  
Interleukin 6 ◽  
Chronic Periodontitis ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
The Relationship ◽  
Necrosis Factor

Proinflammatory cytokines are key inflammatory mediators in periodontitis. This study aimed to investigate the relationship between proinflammatory cytokines in saliva and periodontal status. To investigate the usefulness of cytokines in the therapeutic approach for periodontal disease, the relationship between stimulated cytokine changes and the periodontitis treatment outcome was investigated in this study. Saliva was obtained from 22 patients diagnosed by dentists as having chronic periodontitis. The proinflammatory cytokine (interleukin-1α(IL-1α), interleukin-1β(IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factorα(TNF-α), and tumor necrosis factorβ(TNF-β)) levels were determined using a commercially available kit. The IL-1βand IL-6 levels increased, whereas the TNF-βlevels decreased with the severity of periodontitis (4 mm pocket percentage). Poststimulation IL-1α, IL-6, and IL-8 levels were higher in patients who had an improved treatment outcome. The differences of IL-6 levels (cut point: 0.05 μg/g) yielded a sensitivity and specificity of 90.0% and 81.82%, respectively, for predicting the periodontitis treatment outcome. Among the proinflammatory cytokines, stimulated IL-6 was an excellent marker for predicting the periodontitis treatment outcome.

Plasma Level of IL-1β in Disseminated Intravascular Goagulation

1991 ◽  
Vol 65 (04) ◽  
pp. 364-368 ◽  
Author(s):  
Hideo Wada ◽  
Shigehisa Tamaki ◽  
Motoaki Tanigawa ◽  
Mikio Takagi ◽  
Yoshitaka Mori ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Plasma Level ◽  
Organ Failure ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Solid Cancer ◽  
Normal Individuals ◽  
The Relationship ◽  
Necrosis Factor

SummaryThe plasma level of interleukin-1β (IL-1β) was determined in normal individuals, patients with disseminated intravascular coagulation (DIC), patients in the pre-DIC period (within 7 days before the onset of DIC), and non-DIC patients to examine the relationship between DIC and the plasma ILlp level. The plasma IL-1β level was 0-0.085 ng/ml in normal individuals, with little difference being seen according to related age. It was significantly higher in the DIC group (0.19 ± 0.19 ng/ml) than in the pre-DIC group (0.05 ± 0.08 ng/ml) or the non-DIC group (0.09 ± 0.01 ng/ml). The plasma IL-1β level was not markedly elevated in leukemia patients, even in the DIC group, but it was significantly increased in the DIC group of solid cancer patients and was generally elevated in patients with sepsis. It was markedly elevated to 0.39 ± 0.26 ng/ml in patients with organ failure. When mononuclear cells were incubated with lipopolysaccharide, it was found that IL-1β, tumor necrosis factor, and tissue factor (TF) were released into the medium, and there was an increase of TF release from endothelial cells incubated with this medium. These results suggest that the increase in IL-Iβ reflected the activation of monocytes and may be an important factor in DIC and its associated organ failure.

Pancreatic beta-cell-selective production of tumor necrosis factor-alpha induced by interleukin-1

Diabetes ◽  
1993 ◽  
Vol 42 (7) ◽  
pp. 1026-1031 ◽  
Author(s):  
K. Yamada ◽  
N. Takane ◽  
S. Otabe ◽  
C. Inada ◽  
M. Inoue ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Beta Cell ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Pancreatic Beta Cell ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor
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