scholarly journals VGLUT2/ Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain By CFA

2019 ◽  
Author(s):  
YuWen Tang ◽  
ZhiYou Peng ◽  
ShouJun Tao ◽  
Jianliang Sun ◽  
WenYuan Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Signaling Pathway ◽  
Inflammatory Pain ◽  
Glutamate Transporter ◽  
Underlying Mechanism ◽  
Control Group ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase 5 ◽  
Heat Hyperalgesia

AbstractVesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating the heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in mediating release of glutamate, contributed to the inflammatory heat. It remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in Inflammatory pain mediated by Cdk5 and the heat hyperalgesia induced by complete Freund’s adjuvant (CFA) can be reversed by roscovitine, a selective inhibitor for Cdk5 through inhibition of VGLUT2 expression. Immunohistochemistry results suggest that when compared with rats in a control group, rats in an experimental group showed significant coexpression of Cdk5/VGLUT2 in small and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA. Moreover, our study revealed that the expression of VGLUT2 protein in DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection. Additionally, p25 but not p35, a activator of Cdk5, protein was significantly increased and reduced by roscovitine. The increased expressions of VGLUT2 protein was significantly reduced by roscovitine as well. Our study showed that VGLUT2/Cdk5 signaling pathway contributed to the inflammatory pain medicated by Cdk5/p25.

scholarly journals VGLUT2/Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain by Complete Freund’s Adjuvant

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yuwen Tang ◽  
Zhiyou Peng ◽  
Shoujun Tao ◽  
Jianliang Sun ◽  
Wenyuan Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Signaling Pathway ◽  
Inflammatory Pain ◽  
Glutamate Transporter ◽  
Underlying Mechanism ◽  
Complete Freund’S Adjuvant ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant ◽  
Heat Hyperalgesia

Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund’s adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.

scholarly journals Liraglutide Promotes Osteoblastic Differentiation in MC3T3-E1 Cells by ERK5 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yue Sun ◽  
Yuzhen Liang ◽  
Zhengming Li ◽  
Ning Xia
Keyword(s):  
Signaling Pathway ◽  
Osteoblastic Differentiation ◽  
Control Group ◽  
Activity Levels ◽  
Expression Levels ◽  
Protein Levels ◽  
Proliferation And Differentiation ◽  
Glucagon Like Peptide 1 ◽  
Differentiation And Proliferation

Liraglutide is a glucagon-like peptide-1 analogue widely used in the treatment of type 2 diabetes mellitus. However, the effects of liraglutide on osteoblast proliferation and differentiation in MC3T3-E1 cells have not been fully elucidated. In the present study, the promoting effects of liraglutide were investigated in MC3T3-E1 cells. The results indicated that cell viability was affected following the treatment of the cells with different concentrations of liraglutide (0, 10, 100, and 1000 nM) at different time periods of culture (24, 48, and 72 h). Moreover, the activity levels of alkaline phosphatase and the number of mineralized nodules in MC3T3-E1 cells were significantly increased following treatment with 100 nM liraglutide. The mRNA and protein levels of Col-1, OPG, and OCN in MC3T3-E1 cells were also markedly increased following 100 nM liraglutide treatment compared with those of the control group. The expression levels of the ERK5 signaling pathway key proteins (MEK5, p-ERK5, ERK5, and NUR77) were increased following liraglutide treatment in MC3T3-E1 cells, and the gene expression levels of the ERK5 signaling pathway were also elevated. Moreover, the ERK5 inhibitor XMD8-92 significantly decreased the expression levels of p-ERK5 and NUR77 as well as the proliferation of osteoblasts. However, these changes could be rescued by liraglutide to some extent. Therefore, these results revealed that liraglutide may promote osteoblastic differentiation and proliferation in MC3T3-E1 cells via the activation of the ERK5 signaling pathway.

scholarly journals Effect of Shikonin on Spinal Cord Injury in Rats Via Regulation of HMGB1/TLR4/NF-kB Signaling Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 481-491 ◽  
Author(s):  
Yihui Bi ◽  
Yapeng Zhu ◽  
Mingkai Zhang ◽  
Keke Zhang ◽  
Xingyi Hua ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Motor Function ◽  
Tissue Repair ◽  
Underlying Mechanism ◽  
Molecular Signaling ◽  
Cord Injury

Background/Aims: Shikonin, a compound extracted from Zicao, has been demonstrated to hold anti-bacterial, anti-inflammatory, and anti-tumor activities in various diseases and it has been shown to protect human organs from injuries. However, the effect of shikonin on the recovery of spinal cord injury (SCI) remains unknown. This study was designed to estimate the potential therapeutic effect and underlying mechanism of shikonin on SCI in vivo. Methods: In the study, we used HE staining, ELISA assay, transfection assay, TUNEL assay, real time PCR and Western blot to detect the effects of shikonin on spinal cord injury in rats. Results: we showed that shikonin could promote the recovery of motor function and tissue repair after SCI treatment in rats SCI model. Moreover, we demonstrated that shikonin inhibited the spinal cord edema in SCI model of rats. According to further investigation, shikonin induced the reduction of inflammatory response through decreasing the expression levels of HMGB1, TLR4 and NF-κB after SCI injury. In addition, we also found that shikonin could suppress the apoptosis and expression of caspase-3 protein in SCI model of rats. Conclusion: Our results demonstrated that shikonin induced the recovery of tissue repair and motor function via inactivation of HMGB1/TLR4/NF-κB signaling pathway in SCI model of rats. Meanwhile, shikonin regulated the inflammation response in SCI by suppressing the HMGB1/TLR4/NF-κB signaling pathway. The described mechanism sheds novel light on molecular signaling pathway in spinal cord injury and secondary injury including inflammatory response.

scholarly journals Ginsenoside Rd Attenuates Tau Phosphorylation in Olfactory Bulb, Spinal Cord, and Telencephalon by Regulating Glycogen Synthase Kinase 3β and Cyclin-Dependent Kinase 5

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Ling Li ◽  
Tian Li ◽  
Xin Tian ◽  
Ling Zhao
Keyword(s):  
Spinal Cord ◽  
Olfactory Bulb ◽  
Transgenic Mice ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Cyclin Dependent Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Pathological Changes ◽  
Ginsenoside Rd ◽  
Cyclin Dependent Kinase 5

Objective. Ginseng is a plant of the family Acanthopanaceae. It has been used for thousands of years in China. It is known as the king of hundred herbs. It was recorded first in Shennong Baicao Jing. It has been found that ginsenoside Rd is a neuroprotective agent. This article aims to explore the protective roles of ginsenoside Rd in Alzheimer’s disease. Rd, a Chinese herb, may be a promising treatment drug for Alzheimer’s disease (AD) and is also reported to be related to several pathological changes, including the deposition of Aβ and tau hyperphosphorylation in AD as it decreases the deposition of tau hyperphosphorylation in APP transgenic mice. Methods. In this study, APP transgenic mice were pretreated with 10 mg/kg Rd for six months, and the effect of Rd on neuropathological deficits in the olfactory bulb, spinal cord, and telencephalon of APP transgenic mice was investigated. The phosphorylation levels of tau (S199/202, S396, S404, and Tau5) and the activities of the proteins glycogen synthase kinase 3β (Tyr216) and cyclin-dependent kinase 5 (P25/P35) were measured. Results. The pretreatment of Rd effectively decreased the production and deposition of hyperphosphorylated tau (S199/202, S396, and S404) protein by depressing the expression of glycogen synthase kinase 3β (GSK-3β/Tyr216) and cyclin-dependent kinase 5 (CDK5/P25). Conclusion. These findings suggest that ginsenoside Rd could improve the pathological changes of AD in the olfactory bulb, spinal cord, and telencephalon, which further demonstrated the potential therapeutic effect of Rd in early AD.

scholarly journals Relationship between plasma cyclin-dependent kinase 5 levels and local immunoglobulin levels in patients with nasal polyps

2021 ◽  
Vol 67 (3) ◽  
pp. 125-128
Author(s):  
Cui Liu ◽  
Qian Luo ◽  
Yan Tang ◽  
Gaoxin Yu ◽  
Kuai Liang ◽  
...  
Keyword(s):  
Nasal Polyp ◽  
Nasal Polyps ◽  
Plasma Cells ◽  
Control Group ◽  
Cyclin Dependent Kinase ◽  
Nasal Tumors ◽  
Polyp Tissue ◽  
The Relationship ◽  
Immunoglobulin Levels ◽  
Cyclin Dependent Kinase 5

Nasal polyps are the most common benign nasal tumors that can lead to nasal obstruction and other annoying problems for the patient. Several hypotheses have been proposed as the basic mechanism of nasal polyps. In order to investigate one of the possible causes that can be a disorder in the regulation of systemic immune responses, the present study was designed to investigate the relationship between plasma cyclin-dependent kinase 5 (CDK5) levels and local immunoglobulin levels in patients with nasal polyps. A cross-section study was used to evaluate concentrations of local immunoglobulin levels (IgE, IgM, IgA, and IgG) on blood and polyp specimens from 60 patients with nasal polyps, and 60 control groups. Western Blot Analysis was done for CDK5 in plasma cells. IgA, IgG and IgE concentrations were significantly higher in polyp tissue specimens, but not in blood, of nasal polyp patients compared to the control group. Furthermore, plasma CDK5 levels were significantly higher in nasal polyp tissue compared with control. The difference in IgA, IgE and IgG expression between nasal polyp tissue and blood, supported by increased numbers of plasma cells, suggests a local production of these local immunoglobulins in nasal polyps in response to chronic antigens. Among local immunoglobulins, only there was a significant correlation between CDK5 with IgG (positive correlation) and IgE (negative correlation). The exact explanation for the relationship between plasma CDK5 and local immunoglobulins in nasal polyps needs further studies.

scholarly journals Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

2020 ◽  
Author(s):  
Chenyu Wu ◽  
Huanwen Chen ◽  
Rong Zhuang ◽  
Yongli Wang ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Betulinic Acid ◽  
Neurological Diseases ◽  
Underlying Mechanism ◽  
Autophagy Flux ◽  
Wide Range ◽  
Cord Injury

Abstract Background：Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. Methods：Using a mouse model of SCI, survival and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, and pyroptosis; ROS- and AMPK-related signaling pathways were also examined. Results：Our results showed that BA significantly improves functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS-activity and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induces mitophagy to eliminate the accumulation of ROS and subsequently inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Conclusion: BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

scholarly journals Effects of Huanglian-Renshen-Decoction, a Fixed Mixture of Traditional Chinese Medicine, on the Improvement of Glucose Metabolism by Maintenance of Pancreatic β Cell Identity in db/db Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Fen Yuan ◽  
Dingkun Wang ◽  
Leyi Ma ◽  
Xin Qin ◽  
Jing Gong ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Caspase 3 ◽  
Serum Insulin ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Control Group ◽  
High Dose ◽  
Model Group ◽  
Cell Identity

Huanglian-Renshen-Decoction (HRD) is widely used to treat type 2 diabetes mellitus (T2DM) in China. However, the underlying mechanism is unclear. We aimed to investigate the mechanism by which HRD regulates the glucose level. Forty 7-8-week-old db/db (BSK) mice were randomly assigned to the following four groups: model, low dose HRD (LHRD), high dose HRD (HHRD), and saxagliptin (SAX). Additionally, 10 db/m mice were assigned to control group. The experimental mice were administered 3.03g/kg/d and 6.06g/kg/d of HRD in the LHRD and HHRD groups, respectively, and 10mg/kg/d saxagliptin in the SAX group for 8 weeks. The control and model groups were supplied with distilled water. After the intervention, the pancreas and blood were collected and tested. Compared with that of model group, the fasting blood glucose (FBG) was significantly decreased in all intervention groups (p < 0.05 or 0.01), whereas fasting serum insulin (FINS) was increased significantly in both HHRD and SAX groups. The immunofluorescence images showed that the mass of insulin+ cells was increased and that of glucagon+ cells was reduced obviously in experimental groups compared to those of the model group. In addition, the coexpression of insulin, glucagon, and PDX1 was decreased in HHRD group, and the level of caspase 12 in islet was decreased significantly in all intervention groups. However, little difference was found in the number and morphology of islet, and the expression of ki67, bcl2, bax, caspase 3, and cleaved-caspase 3 in the pancreas among groups. Interestingly, the cleaved-Notch1 level was increased and the Ngn3 level in islet was decreased significantly in HHRD group. The HRD showed dose-dependent effects on glucose metabolism improvement through maintenance of β cell identity via a mechanism that might involve the Notch1/Ngn3 signal pathway in db/db mice.

scholarly journals Artesunate Combined With Metformin Ameliorate on Diabetes-Induced Xerostomia by Mitigating Superior Salivatory Nucleus and Salivary Glands Injury in Type 2 Diabetic Rats via the PI3K/AKT Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Siqin Zhang ◽  
Jiarui Li ◽  
Xiaolin Nong ◽  
Yuxiang Zhan ◽  
Jiazhi Xu ◽  
...  
Keyword(s):  
Urine Volume ◽  
Underlying Mechanism ◽  
Diabetic Rats ◽  
Diabetic Group ◽  
Akt Pathway ◽  
Control Group ◽  
Sprague Dawley ◽  
Bdnf Expression ◽  
Parasympathetic Innervation

Polydipsia and xerostomia are the most common complications that seriously affect oral health in patients with diabetes. However, to date, there is no effective treatment for diabetic xerostomia. Recent studies have reported that artesunate (ART) and metformin (Met) improve salivary gland (SG) hypofunction in murine Sjögren’s syndrome. Therefore, aim of this study was to investigate the effect and underlying mechanism of artesunate (ART) alone and in combination with metformin (Met) on hyposalivation in type 2 diabetes mellitus (T2DM) rats. T2DM rats were induced using a high-fat diet and streptozotocin. SPF male Sprague–Dawley rats were divided into the following five groups: normal control group, untreated diabetic group, ART-treated diabetic group (50 mg/kg), Met-treated diabetic group (150 mg/kg), and ART/Met co-treated diabetic group (50 mg/kg ART and 150 mg/kg Met). ART and Met were intragastrically administered daily for 4 weeks. The general conditions, diabetes parameters and serum lipids were evaluated after drug treatment. Furthermore, we observed changes in the central superior salivatory nucleus (SSN) and SG, and changes in the AQP5 expression, parasympathetic innervation (AChE and BDNF expression), and PI3K/AKT pathway- (p-AKT, and p-PI3K), apoptosis- (Bax, Bcl-2, and Caspase3), and autophagy- (LC3 and P62) related markers expression in T2DM rats after treatment. Our results showed that ART or Met alone and ART/Met combination attenuated a range of diabetic symptoms, including weight loss, urine volume increase, water consumption increase, hyperglycemia, insulin resistance, glucose intolerance and dyslipidemia. More importantly, we found that these three treatments, especially ART/Met combination, mitigated hyposalivation in the T2DM rats via improving the central SSN and SGs damage in hyperglycemia. Our data also indicated that ART/Met attenuated SG damage though regulating the PI3K/Akt pathway to inhibit apoptosis and autophagy of SGs in the T2DM rats. Moreover, ART/Met preserved parasympathetic innervation (AChE and BDNF expression) in SGs to alleviate diabetes-induced hyposalivation likely through rescuing central SSN damage. Taken together, these findings might provide a novel rationale and treatment strategy for future treatment of diabetes-induced xerostomia in the clinic.

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