The role of pannexin 1 in chemotherapy-induced peripheral neuropathy (CIPN).

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 6-6
Author(s):  
Adam Sterman ◽  
Regina Hanstein ◽  
David C. Spray
Keyword(s):  
Pain Therapy ◽  
Field Tests ◽  
Behavioral Changes ◽  
Satellite Glial Cells ◽  
Pannexin 1 ◽  
Tactile Threshold ◽  
Dose Limiting Toxicity ◽  
Specific Deletion ◽  
Von Frey Filaments

6 Background: CIPN is a debilitating side effect and dose limiting toxicity of anticancer drug therapies. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk between sensory neurons and satellite glial cells (SGCs), specifically ATP mediated SGC-neuron signaling. We therefore investigated CIPN in mice with neuron- or glia-specific deletion of the ATP-releasing channel Pannexin 1 (Panx 1). Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections two days apart. Controls received saline (sal). We used C57Bl6 wildtype and transgenic mice with neuron- or glia-specific Panx1 deletion (NFHcre or GFAPcre:Panx1F/F) and littermate controls (Panx1F/F), 7-11 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 3 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Overall mouse condition was assessed using Open Field Tests. Results: C57Bl6 mice developed transient tactile hypersensitivity after oxa injection, which was most prominent at day 9 and ceased at day 21. Oxa-injected mice had lower tactile thresholds (at 9 days: sal 5.5±0.3g vs. oxa 2.7±0.4g, p < 0.001) and higher response rates to filaments compared to sal-injected controls (p < 0.05), but revealed no changes in any other behavior. Mice with glia-specific Panx1 deletion did not display significant tactile hypersensitivity at any time after oxa (tactile threshold at 9 days: sal 5.5±0.3g vs. oxa 5.8±0.2g), whereas oxa induced tactile hypersensitivity did occur in mice with neuron-specific Panx1 deletion (at 9 days: sal 6±0g vs. oxa 1.3±0g, p < 0.0001) and Panx1F/F littermates (at 9 days: sal 6.0±0g vs. oxa 1.3±0.1g, p < 0.0001). Conclusions: We found that oxaliplatin induces transient CIPN, but no other behavioral changes in wildtype mice. Deletion of the ATP-releasing channel Panx1 in glia, but not in neurons, prevented CIPN development. This points to a new molecule (Panx1) and a new cell type (glia) as potential novel targets for pain therapy.

The effect of connexin 36 deletion on chemotherapy-induced peripheral neuropathy (CIPN).

2016 ◽  
Vol 34 (26_suppl) ◽  
pp. 1-1
Author(s):  
Adam Sterman ◽  
Regina Hanstein ◽  
David C. Spray
Keyword(s):  
Gap Junction ◽  
Sensory Neurons ◽  
Chemotherapeutic Agents ◽  
Satellite Glial Cells ◽  
Connexin 36 ◽  
Junction Protein ◽  
Tactile Threshold ◽  
Gap Junction Protein ◽  
Novel Target ◽  
Von Frey Filaments

1 Background: CIPN is a debilitating side effect and dose limiting toxicity of many chemotherapeutic agents. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk among the glia that surround sensory neurons (Satellite Glial Cells, SGC’s) and between sensory neurons and their adjacent SGCs via gap junctions. Since Connexin 36 (Cx36) is the main neuronal gap junction protein, we investigated CIPN in mice with deletion of Cx36. Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections 2 days apart. Controls received saline (sal). We used transgenic mice, which were either heterozygous for Cx36 or complete Cx36 knockouts (Cx36 Het or Cx36 KO), and littermate controls (Cx36 wildtype), 6-14 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 4 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Results: Oxa-injected wildtype mice had higher response rates to filaments compared to sal-injected controls (p < 0.05), and lower tactile thresholds (at 9 days: sal 6.0±0.0g vs. oxa 1.9±0.5g, p < 0.0001), indicating hypersensitivity. Compared with wildtype, mice lacking Cx36 (Cx36 KO) displayed significantly less tactile hypersensitivity after oxa (tactile threshold at 9 days: WT 1.9±0.5g vs. KO 4.0±0.4g, p < 0.01), whereas oxa induced tactile hypersensitivity occurred in a similar fashion in Cx36 Het mice (tactile threshold at 9 days: WT 1.9±0.5g vs. Het 1.5±0.1g). At 9 days, there were fewer responses to filaments in oxa-injected Cx36 KO mice compared to oxa-injected wildtype mice (p < 0.05), but not in oxa-injected Cx36 Het mice. Conclusions: We found that oxaliplatin induces transient CIPN, represented by tactile hypersensitivity, in wildtype mice. Deletion of the gap junction protein Cx36, as displayed in the Cx36 KO mice, resulted in significantly less CIPN. This is the first report that a neuronal gap junction protein may modulate pain sensitivity, and points to a new molecule (Cx36) as a potential novel target for CIPN therapy.

scholarly journals PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and modulating the intestinal microbiota

2021 ◽  
Author(s):  
Lumin Wei ◽  
Rongjing Zhang ◽  
Jinzhao Zhang ◽  
Juanjuan Li ◽  
Deping Kong ◽  
...  
Keyword(s):  
Experimental Colitis ◽  
Regulatory Subunit ◽  
Protective Effects ◽  
Intestinal Epithelial ◽  
Catalytic Subunits ◽  
Regulatory Subunits ◽  
Pka Regulatory Subunit ◽  
Cross Fostering ◽  
Specific Deletion

AbstractProtein kinase A (PKA) plays an important role in regulating inflammation via its catalytic subunits. Recently, PKA regulatory subunits have been reported to directly modulate some signaling pathways and alleviate inflammation. However, the role of PKA regulatory subunits in colonic inflammation remains unclear. Therefore, we conducted this study to investigate the role of the PKA regulatory subunit PRKAR2A in colitis. We observed that PRKAR2A deficiency protected mice from dextran sulfate sodium (DSS)-induced experimental colitis. Our experiments revealed that the intestinal epithelial cell-specific deletion of Prkar2a contributed to this protection. Mechanistically, the loss of PRKAR2A in Prkar2a−/− mice resulted in an increased IFN-stimulated gene (ISG) expression and altered gut microbiota. Inhibition of ISGs partially reversed the protective effects against DSS-induced colitis in Prkar2a−/− mice. Antibiotic treatment and cross-fostering experiments demonstrated that the protection against DSS-induced colitis in Prkar2a−/− mice was largely dependent on the gut microflora. Altogether, our work demonstrates a previously unidentified function of PRKAR2A in promoting DSS-induced colitis.

scholarly journals The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

2021 ◽  
Author(s):  
Hongsheng Wang ◽  
Wanpeng Cui ◽  
Wenbing Chen ◽  
Fang Liu ◽  
Zhaoqi Dong ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Coping With Stress ◽  
Chemical Genetic ◽  
Chronic Social Defeat Stress ◽  
Ventral Tegmental ◽  
Laterodorsal Tegmentum ◽  
Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

scholarly journals Pain therapy to reduce perioperative complications

2019 ◽  
Vol 4 (4) ◽  
pp. 158-166
Author(s):  
Stephan M. Freys ◽  
Esther Pogatzki-Zahn
Keyword(s):  
Postoperative Pain ◽  
Postoperative Complications ◽  
Adverse Events ◽  
Acute Pain ◽  
Surgical Procedure ◽  
Pain Therapy ◽  
Recovery Period ◽  
Acute Pain Therapy

AbstractThe incidence rates of adverse events secondary to any operation are a well-known problem in any surgical field. One outstanding example of such adverse events is postoperative pain. Thus, the incidence of acute postoperative pain following any surgical procedure and its treatment are central issues for every surgeon. In the times of Enhanced Recovery After Surgery (ERAS) programs, acute pain therapy became an increasingly well investigated and accepted aspect in almost all surgical subspecialties. However, if it comes to the reduction of postoperative complications, in the actual context of postoperative pain, surgeons tend to focus on the operative process rather than on the perioperative procedures. Undoubtedly, postoperative pain became an important factor with regard to the quality of surgical care: both, the extent and the quality of the surgical procedure and the extent and the quality of the analgesic technique are decisive issues for a successful pain management. There is growing evidence that supports the role of acute pain therapy in reducing postoperative morbidity, and it has been demonstrated that high pain scores postoperatively may contribute to a complicated postoperative course. This overview comprises the current knowledge on the role of acute pain therapy with regard to the occurrence of postoperative complications. Most of the knowledge is derived from studies that primarily focus on the type and quality of postoperative pain therapy in relation to specific surgical procedures and only secondary on complications. As far as existent, data that report on the recovery period after surgery, on the rehabilitation status, on perioperative morbidity, on the development of chronic pain after surgery, and on possible solutions of the latter problem with the institution of transitional pain services will be presented.

scholarly journals Eosinophil-specific deletion of IκBα in mice reveals a critical role of NF-κB–induced Bcl-xL for inhibition of apoptosis

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3896-3904 ◽  
Author(s):  
Christian Schwartz ◽  
Ralf Willebrand ◽  
Silke Huber ◽  
Rudolf A. Rupec ◽  
Davina Wu ◽  
...  
Keyword(s):  
Helminth Infection ◽  
Critical Role ◽  
Gm Csf ◽  
Eosinophil Survival ◽  
Key Points ◽  
Specific Deletion ◽  
Specific Inhibitors

Key Points IL-3, IL-5, and GM-CSF promote eosinophil survival by NF-κB–induced upregulation of Bcl-xL, which can be blocked by specific inhibitors. Specific and constitutive deletion of the inhibitor of NF-κB (IκBα) in eosinophils in vivo reduced apoptosis during helminth infection.

scholarly journals Cures That (Make You) Work

2021 ◽  
Vol 229 (3) ◽  
pp. 171-177 ◽  
Author(s):  
Jana S. Aengenheister ◽  
Renée Urban ◽  
Georg Halbeisen
Keyword(s):  
Clinical Application ◽  
Social Perception ◽  
Social Role ◽  
Health Benefits ◽  
Behavioral Changes ◽  
Total N ◽  
Health Related Behaviors ◽  
Headache Treatment ◽  
Health Related

Abstract. Successful treatment not only depends on adhering to taking medication and attending therapy but also on behavioral changes. In two experiments (total N = 256), we investigated the hypothesis that the perceived social role of a treatment as partner (co-producer of a health-benefits) or servant (sole provider of health benefits) could promote or prevent intentions to engage in health-related behaviors. Specifically, we used headache treatment as an everyday example and found that participants were more inclined to engage in headache-reducing behaviors when painkillers were described as partners as compared to servants. Implications of these findings for the importance of anthropomorphic social perception in the clinical application are discussed.

scholarly journals Aplikasi Teori Behavioristik dan Konstruktifistik dalam Kegiatan Pembelajaran di Sekolah Tinggi Ilmu Tarbiyah Raden Wijaya Mojokerto

2017 ◽  
Vol 6 (2) ◽  
pp. 33
Author(s):  
Akhmad Pandu Setiawan
Keyword(s):  
Learning Theory ◽  
Positive Reinforcement ◽  
Cognitive Learning ◽  
Behavioral Changes ◽  
Negative Evaluation ◽  
Learning Approaches ◽  
The Road ◽  
And Behavior ◽  
Desirable Behavior

Behaviorism learning theory is oriented towards results that can be measured and observed. Repetition and training used so that the desired behavior can become a habit. The expected results of the implementation of this behavioristic theory is the formation of a desired behavior. The desirable behavior gets positive reinforcement and behavior that is not appropriate awarded the negative. Evaluation or assessment based on observed behavior. In theory this learned professor was not much give a lecture, but the brief instruction is followed by examples by themselves or through simulation. The purpose of this paper is to describe the application of the theory Behavioristic and konstruktifistik in learning activities at the School of Raden Wijaya Tarbiyah Mojokerto. Behavioristic learning theory emphasizes the changes in behavior as well as a result of the interaction between stimulus and response. Learning is a process of behavioral changes as a result of the interaction between stimulus and response. A person is considered to have learned if he could show changes in behavior. Although learning theory tigkah behavior began to be abandoned century, but collaborate on this theory with cognitive learning theory and the theory of other learning is essential for creating a learning approach that is appropriate and effective, because basically there is no single theory of learning that is truly suited to creating a learning approaches and effective fit. especially with constructivism learning model. The role of the faculty in constructivist learning very demanding mastery of a broad and in-depth about the material taught. A broad and deep knowledge allow a lecturer accept different views and ideas of students and also makes it possible to indicate whether or not the idea of ​​the road. Mastery of the material allows a professor to understand all kinds of roads and the model to arrive at a solution to the problem without fixed on one model.

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