scholarly journals Opening KATP Channels Induces Inflammatory Tolerance and Prevents Chronic Pain

2021 ◽  
Author(s):  
Cheng Qian ◽  
Yixin Fan ◽  
Lu-Lu Ji ◽  
Li Wan ◽  
Rumeng Jia ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Postoperative Pain ◽  
Signaling Pathway ◽  
Mechanical Allodynia ◽  
Katp Channels ◽  
Cytokine Signaling ◽  
Microglia Cell ◽  
Channel Opener ◽  
Channel Opening

Abstract Background: Current treatments for chronic pain are not satisfactory, prompting a frantic search for new therapeutics and new therapeutic targets. Our previous study indicates KATP channel opener has analgesic effect, but the mechanism has not been elucidated. We speculated that KATP channel opener may increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Methods: The plantar incision (PI) surgery-induced postoperative pain was performed to establish chronic pain model. Growth arrest–specific 6 (Gas6)-/- and Axl-/- mice were used for signaling research. The microglia cell line BV-2 was cultured for in vitro experiments.Results: KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice, associated with the up-regulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 dependent on Gas6/Axl signaling pathway in microglia. Opening KATP channels inhibits incision-induced mechanical allodynia by activating Gas6/Axl-SOCS3 signaling pathway. Opening KATP channels induces inflammatory tolerance to relieve neuroinflammation and postoperative pain.Conclusions: We demonstrated that KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relief chronic pain. We explored a new target for anti-inflammatory and analgesia by regulating the innate immune system, and provide a theoretical basis for clinical preemptive analgesia.

scholarly journals SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

2020 ◽  
Author(s):  
Bhavnita Soni ◽  
Shailza Singh
Keyword(s):  
Signaling Pathway ◽  
Cellular Response ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Macrophage Phenotype ◽  
Regulatory Circuit ◽  
Stat Pathway

AbstractMacrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine

2018 ◽  
Vol 16 (45) ◽  
pp. 8695-8699 ◽  
Author(s):  
Christian Bock ◽  
Kristin Beirow ◽  
Abdrrahman S. Surur ◽  
Lukas Schulig ◽  
Anja Bodtke ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Oxidation Products ◽  
Potassium Channel Opener ◽  
Channel Opener ◽  
Channel Opening

Benign by design: active sulfide-analogues of potassium channel opener flupirtine do not form reactive oxidation products in vitro.

scholarly journals Long Noncoding RNA Expression Profile in BV2 Microglial Cells Exposed to Lipopolysaccharide

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Yajuan Li ◽  
Qingmin Li ◽  
Cunjuan Wang ◽  
Shengde Li ◽  
Lingzhi Yu
Keyword(s):  
Neuropathic Pain ◽  
Signaling Pathway ◽  
Noncoding Rna ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Microglial Cells ◽  
Receptor Signaling ◽  
Microglia Cell ◽  
Receptor Signaling Pathway

Neuropathic pain, which is one of the most common forms of chronic pain, seriously increases healthcare costs and impairs patients’ quality of life with an incidence of 7–10% worldwide. Microglia cell activation plays a key role in the progression of neuropathic pain. Better understanding of novel molecules modulating microglia cell activation and these underlying functions will extremely benefit the exploration of new treatment. Recent studies suggested long noncoding RNAs may be involved in neuropathic pain. However, its underlying functions and mechanisms in microglia cell activation remain unclear. To identify the differentially expressed lncRNAs and predict their functions in the progression of microglia cell activation, GSE103156 was analyzed using integrated bioinformatics methods. The expression levels of selected lncRNAs and mRNAs were determined by real-time PCR. In the present study, a total of 56 lncRNAs and 298 mRNAs were significantly differentially expressed. The differentially expressed mRNAs were mainly enriched in NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway. The top 10 hub genes were Tnf, Il6, Stat1, Cxcl10, Il1b, Tlr2, Irf1, Ccl2, Irf7, and Ccl5 in the PPI network. Our results showed that Gm8989, Gm8979, and AV051173 may be involved in the progression of microglia cell activation. Taken together, our findings suggest that lots of lncRNAs may be involved in BV2 microglia cell activation in vitro. The findings may provide relevant information for the development of promising targets for the microglial cells activation of neuropathic pain in vivo in the future.

scholarly journals Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Zhongzhong Tu ◽  
Mengxian Xu ◽  
Jian Zhang ◽  
Ye Feng ◽  
Zhuo Hao ◽  
...  
Keyword(s):  
Viral Replication ◽  
Signaling Pathway ◽  
Rabies Virus ◽  
Antiviral Effect ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3′ untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3. IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3′ UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo. Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

2019 ◽  
Vol 44 (1) ◽  
pp. 111-117 ◽  
Author(s):  
Jeffrey S Kroin ◽  
Vaskar Das ◽  
Mario Moric ◽  
Asokumar Buvanendran
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Postoperative Pain ◽  
Mechanical Allodynia ◽  
Pain Syndrome ◽  
Saline Control ◽  
Pain Model ◽  
Time Period ◽  
Pain Models ◽  
Neuropathic Pain Model

Background and objectivesKetamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.MethodsMice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia.ResultsIn all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1–24hours compared with saline (F=121.6, p<0.0001), and three daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F=33.4, p=0.0002). In the CRPS1 model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F=116.1, p<0.0001). In the postoperative pain model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F=60.6, p<0.0001).ConclusionsThis study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.

scholarly journals The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

2020 ◽  
Author(s):  
Yaping Yue ◽  
Na Wang ◽  
Yanming Lau ◽  
Yiran Fu ◽  
Hao Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Pain Behaviors ◽  
Transient Receptor

Abstract Background: Activation of purinergic receptor P2X ligand-gated ion channel 3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential ankyrin 1 (TRPA1) by their specific ligands is a major mechanism contributing to magnified pain responses. The relationship between these nonselective cation channels and proteinase-activated receptor 2 (PAR2) activation mediated pain is still to be clarified.Methods: In this study, both in vitro model of dorsal root ganglion (DRG) neurons with PAR2 agonist SL-NH2 challenge and SL-NH2-induced pain rat model were used to approach these questions. The expression of P2X3, TRPV1, and TRPA1 in DRG neurons was investigated by quantitative real-time RT-PCR, Western blot, and immunofluorescence. The involvement of the PLCβ3/PKCε signaling pathway was also determined. The behavior test for mechanical allodynia and thermal hyperalgesia was performed. Results: SL-NH2 induced upregulation of P2X3, TRPV1, and TRPA1 through phosphorylation of phospholipase Cβ3 (PLCβ3) and protein kinase Cε (PKCε) signaling pathway in DRG neurons in vitro and in vivo. SL-NH2 also elevated the proportion of P2X3-, TRPV1-, and TRPA1-expressing neurons. The upregulation of P2X3, TRPV1, and TRPA1 and phosphorylation of PLCβ3 and PKCε in DRG neurons was paralleled with mechanical allodynia and thermal hyperalgesia behaviors in rats. Conclusions: The data of the present study imply that SL-NH2 as a noxious stimulus activates PAR2 which induces TRPV1, TRPA1, and P2X3 upregulation through PLCβ3/PKCε signaling pathway, thereby decreasing activation thresholds and increasing excitability, resulting in sustained nociceptive activity in DRG neurons, and then causing mechanical allodynia and thermal hyperalgesia behaviors. These data expanded our knowledge about PAR2-mediated pain sensitivity and its relationship with TRPV1, TRPA1, and P2X3 and provided new opportunities on management of pain behaviors.

scholarly journals Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway

2020 ◽  
Author(s):  
Juan Li ◽  
Li Zhang ◽  
Qian Li ◽  
Xing Yang ◽  
Peng Teng ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Postoperative Pain ◽  
Signaling Pathway ◽  
Gelatin Zymography ◽  
Clinical Problem ◽  
Pain Model ◽  
Mechanical Threshold ◽  
Plantar Incision ◽  
First Time

Abstract Background: Postoperative pain is a serious clinical problem with a poorly understood mechanism and lack of effective treatment. Considering hydrogen (H 2 ) could reduce neuroinflammation, we hypothesizes that hydrogen may alleviate postoperative pain and investigate the mechanism. Methods: Mice were used to establish postoperative pain model via performing a plantar incision surgery. Mechanical allodynia was measured using the Von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry and immunofluorescence staining. The animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitor to investigate the effects of H 2 on microglia. Results: Plantar incision surgery significantly decreased the mechanical threshold, and increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and ASK1 inhibitor NQDI-1 attenuated postoperative pain. H 2 treatment increased Trx1 expression, decreased ASK1, p38 and JNK phosphorylation, MMP-9 activity, pro-IL-1β maturation and IBA-1 expression in the spinal cord of postoperative pain mice, and ameliorated postoperative pain. In vitro, H 2 increased Trx1 expression and reduced MMP-9 activity induced by LPS in BV-2 cells. Additionally, H 2 also reduced ASK1, p38 and JNK phosphorylation, and IBA-1 expression induced by LPS, which were abolished by Trx1 inhibitor PX12 in BV-2 cells. Conclusions: For the first time the results confirm that H 2 can work as a therapeutic agent for ameliorating postoperative pain through Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the targeting molecules to relieve postoperative pain.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

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