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Wang Z, Li X, Li Y, Sun X, Wang Y, Lu T, Zhao D, Ma X, Sun H. The insular cortex-nucleus tractus solitarius glutamatergic pathway involved in acute stress-induced gastric mucosal damage in rats. Neurobiol Stress 2025; 36:100723. [PMID: 40242326 PMCID: PMC12002970 DOI: 10.1016/j.ynstr.2025.100723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/22/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Previous studies have shown that acute stress-induced gastric mucosal damage is linked to excessive activation of parasympathetic nervous system. The Insular Cortex (IC), the higher centers of the parasympathetic nervous system, serves as both the integration site of gastric sensory information and play a crucial role in the regulation of gastric function. However, whether the IC is involved in Restraint water-immersion stress (RWIS)-induced gastric mucosal damage has not been reported. In this study, we examined the expression of neuronal c-Fos, PSD95 and SYN-1 protein expression in IC during RWIS by immunofluorescence and western blot techniques, as well as assessed IC blood oxygenation level dependant (BOLD) through functional MRI. Chemical genetics techniques specifically modulate the activity of IC glutamatergic neurons and IC-nucleus tractus solitary (NTS) glutamatergic pathway to elucidate their contributions to RWIS-induced gastric mucosal damage. The results showed that the expression of c-Fos, PSD95, and SYN-1 protein in IC increased significantly after RWIS, along with a noticeable enhancement in fMRI signal intensity. Furthermore, inhibiting IC glutamatergic neurons and the IC-NTS glutamatergic neural pathway resulted in a significant reduction in gastric mucosal damage, an increase in the expression of Occludin, Claudin-1, and PCNA in the gastric wall, while the expression of nNOS decreased and CHAT increased. These findings suggest that during RWIS, IC glutaminergic neurons are activated, promoting stress-induced gastric mucosal damage through the IC-NTS-vagal nerve pathway.
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Affiliation(s)
- Zepeng Wang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Xinyu Li
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Yuanyuan Li
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Xuehan Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Yuxue Wang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Tong Lu
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China
| | - Dongqin Zhao
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China
| | - Haiji Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan, 250014, China
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Sun H, Li C, Shi Y, Wang Y, Li J, Fan L, Yu Y, Ji X, Gao X, Hou K, Li Y. Investigating the L-Glu-NMDA receptor-H 2S-NMDA receptor pathway that regulates gastric function in rats' nucleus ambiguus. Front Pharmacol 2024; 15:1389873. [PMID: 38751777 PMCID: PMC11094298 DOI: 10.3389/fphar.2024.1389873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/15/2024] [Indexed: 05/18/2024] Open
Abstract
Background In previous investigations, we explored the regulation of gastric function by hydrogen sulfide (H2S) and L-glutamate (L-Glu) injections in the nucleus ambiguus (NA). We also determined that both H2S and L-Glu have roles to play in the physiological activities of the body, and that NA is an important nucleus for receiving visceral sensations. The purpose of this study was to explore the potential pathway link between L-Glu and H2S, resulting in the regulation of gastric function. Methods Physiological saline (PS), L-glutamate (L-Glu, 2 nmol), NaHS (2 nmol), D-2-amino-5-phopho-novalerate (D-AP5, 2 nmol) + L-Glu (2 nmol), aminooxyacetic acid (AOAA, 2 nmol) + L-Glu (2 nmol), D-AP5 (2 nmol) + NaHS (2 nmol) were injected into the NA. A balloon was inserted into the stomach to observe gastric pressure and for recording the changes of gastric smooth muscle contraction curve. The gastric fluid was collected by esophageal perfusion and for recording the change of gastric pH value. Results Injecting L-Glu in NA was found to significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01). On the other hand, injecting the PS, pre-injection N-methyl-D-aspartate (NMDA) receptor blocker D-AP5, cystathionine beta-synthase (CBS) inhibitor AOAA and re-injection L-Glu did not result in significant changes (p > 0.05). The same injection NaHS significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01), but is eliminated by injection D-AP5 (p > 0.05). Conclusion The results indicate that both exogenous L-Glu and H2S injected in NA regulate gastric motility and gastric acid secretion through NMDA receptors. This suggests that NA has an L-Glu-NMDA receptor-CBS-H2S pathway that regulates gastric function.
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Wang Z, Shen Y, Huang C, Wang Y, Zhang X, Guo F, Weng R, Ma X, Sun H. Astrocytes in the spinal cord contributed to acute stress-induced gastric damage via the gap junction protein CX43. Brain Res 2023; 1811:148395. [PMID: 37156321 DOI: 10.1016/j.brainres.2023.148395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/10/2023]
Abstract
Rat restraint water-immersion stress (RWIS) is a compound stress of high intensity and is widely used to study the pathological mechanisms of stress gastric ulcers. The spinal cord, as a part of the central nervous system, plays a dominant role in the gastrointestinal tract, but whether the spinal cord is involved in rat restraint water-immersion stress (RWIS)-induced gastric mucosal damage has not been reported. In this study, we examined the expression of spinal astrocytic glial fibrillary acidic protein (GFAP), neuronal c-Fos, connexin 43 (Cx43), and p-ERK1/2 during RWIS by immunohistochemistry and Western blotting. In addition, we intrathecally injected the astrocytic toxin L-a-aminoadipate (L-AA), gap junction blocker carbenoxolone (CBX), and ERK1/2 signaling pathway inhibitor PD98059 to explore the role of astrocytes in the spinal cord in RWIS-induced gastric mucosal damage and its possible mechanism in rats. The results showed that the expression of GFAP, c-Fos, Cx43, and p-ERK1/2 was significantly elevated in the spinal cord after RWIS. Intrathecal injection of both the astrocyte toxin L-AA and the gap junction blocker CBX significantly attenuated RWIS-induced gastric mucosal damage and decreased the activation of astrocytes and neurons induced in the spinal cord. Meanwhile, the ERK1/2 signaling pathway inhibitor PD98059 significantly inhibited gastric mucosal damage, gastric motility and RWIS-induced activation of spinal cord neurons and astrocytes. These results suggest that spinal astrocytes may regulate the RWIS-induced activation of neurons via CX43 gap junctions and play a critical role in RWIS-induced gastric mucosa damage through the ERK1/2 signaling pathway.
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Affiliation(s)
- Zepeng Wang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Yangyang Shen
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Chenxu Huang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Yuwei Wang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Xinzhou Zhang
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Feiyang Guo
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Rongxin Weng
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
| | - Haiji Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, 88# Wenhua Road, Jinan 250014, China.
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Sun H, Ding H, Shi Y, Li C, Jin H, Yang X, Chen Z, Tian P, Zhu J, Sun H. Exogenous Hydrogen Sulfide Within the Nucleus Ambiguus Inhibits Gastrointestinal Motility in Rats. Front Physiol 2020; 11:545184. [PMID: 33013478 PMCID: PMC7516268 DOI: 10.3389/fphys.2020.545184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/21/2020] [Indexed: 11/13/2022] Open
Abstract
Hydrogen sulfide (H2S) is a neuromodulator in the central nervous system. However, the physiological role of H2S in the nucleus ambiguus (NA) has rarely been reported. This research aimed to elucidate the role of H2S in the regulation of gastrointestinal motility in rats. Male Wistar rats were randomly assigned to sodium hydrosulfide (NaHS; 4 and 8 nmol) groups, physiological saline (PS) group, capsazepine (10 pmol) + NaHS (4 nmol) group, L703606 (4 nmol) + NaHS (4 nmol) group, and pyrrolidine dithiocarbamate (PDTC, 4 nmol) + NaHS (4 nmol) group. Gastrointestinal motility curves before and after the injection were recorded using a latex balloon attached with a pressure transducer, which was introduced into the pylorus through gastric fundus. The results demonstrated that NaHS (4 and 8 nmol), an exogenous H2S donor, remarkably suppressed gastrointestinal motility in the NA of rats (P < 0.01). The suppressive effect of NaHS on gastrointestinal motility could be prevented by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist, and PDTC, a NF-κB inhibitor. However, the same amount of PS did not induce significant changes in gastrointestinal motility (P > 0.05). Our findings indicate that NaHS within the NA can remarkably suppress gastrointestinal motility in rats, possibly through TRPV1 channels and NF-κB-dependent mechanism.
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Affiliation(s)
- Hongzhao Sun
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Haikun Ding
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Yuan Shi
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Chenyu Li
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Haoran Jin
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Xiaoyue Yang
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Zhaosong Chen
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Pengpeng Tian
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Jianping Zhu
- Key Laboratory of Animal Resistance, School of Life Sciences, Shandong Normal University, Jinan, China
| | - Haiji Sun
- Key Laboratory of Animal Resistance, School of Life Sciences, Shandong Normal University, Jinan, China
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Zhao DQ, Xue H, Sun HJ. Nervous mechanisms of restraint water-immersion stress-induced gastric mucosal lesion. World J Gastroenterol 2020; 26:2533-2549. [PMID: 32523309 PMCID: PMC7265141 DOI: 10.3748/wjg.v26.i20.2533] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/07/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
Stress-induced gastric mucosal lesion (SGML) is one of the most common visceral complications after trauma. Exploring the nervous mechanisms of SGML has become a research hotspot. Restraint water-immersion stress (RWIS) can induce GML and has been widely used to elucidate the nervous mechanisms of SGML. It is believed that RWIS-induced GML is mainly caused by the enhanced activity of vagal parasympathetic nerves. Many central nuclei, such as the dorsal motor nucleus of the vagus, nucleus of the solitary tract, supraoptic nucleus and paraventricular nucleus of the hypothalamus, mediodorsal nucleus of the thalamus, central nucleus of the amygdala and medial prefrontal cortex, are involved in the formation of SGML in varying degrees. Neurotransmitters/neuromodulators, such as nitric oxide, hydrogen sulfide, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, enkephalin, 5-hydroxytryptamine, acetylcholine, catecholamine, glutamate, γ-aminobutyric acid, oxytocin and arginine vasopressin, can participate in the regulation of stress. However, inconsistent and even contradictory results have been obtained regarding the actual roles of each nucleus in the nervous mechanism of RWIS-induced GML, such as the involvement of different nuclei with the time of RWIS, the different levels of involvement of the sub-regions of the same nucleus, and the diverse signalling molecules, remain to be further elucidated.
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Affiliation(s)
- Dong-Qin Zhao
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Hua Xue
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Hai-Ji Sun
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
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Zhao DQ, Gong SN, Ma YJ, Zhu JP. Medial prefrontal cortex exacerbates gastric dysfunction of rats upon restraint water‑immersion stress. Mol Med Rep 2019; 20:2303-2315. [PMID: 31322177 PMCID: PMC6691265 DOI: 10.3892/mmr.2019.10462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 06/04/2019] [Indexed: 12/11/2022] Open
Abstract
Restraint water-immersion stress (RWIS) can induce a gastric mucosal lesions within a few hours. The medial prefrontal cortex (mPFC) is involved in the RWIS process. The present study investigated the modulatory effects and molecular mechanisms of the mPFC on gastric function under an RWIS state. Male Wistar rats were divided into four groups; namely, the control, RWIS 4 h (RWIS for 4 h only), sham-operated and bilateral-lesioned (bilateral-lesioned mPFC) groups. The gastric erosion index (EI) and gastric motility (GM) were determined, and the proteomic profiles of the mPFC were assessed by isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography and tandem mass spectrometry. Additionally, iTRAQ results were verified by western blot analysis. Compared with the RWIS 4 h group and the sham-control group, the bilateral-lesioned group exhibited a significantly lower EI (P<0.01). In the bilateral-lesioned group, RWIS led to a significant decrease in EI and GM. When comparing the control and RWIS 4 h groups, 129 dysregulated proteins were identified, of which 88 were upregulated and 41 were downregulated. Gene Ontology functional analysis demonstrated that 29 dysregulated proteins, including postsynaptic density protein 95, were directly associated with axon morphology, axon growth and synaptic plasticity. Ingenuity pathway analysis revealed that the dysregulated proteins were mainly involved in neurological disease signaling pathways, including the NF-κB and ERK signaling pathways. These data indicated that the presence of the mPFC exacerbates gastric mucosal injury in awake rats during RWIS. Although the quantitative proteomic analysis elucidated the nervous system molecular targets associated with the production of gastric mucosal lesions, such as the role of PSD95. The underlying molecular mechanisms of synaptic plasticity need to be further elucidated.
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Affiliation(s)
- Dong-Qin Zhao
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Sheng-Nan Gong
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Ying-Jie Ma
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Jian-Ping Zhu
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
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Destruction of the Dorsal Motor Nucleus of the Vagus Aggravates Inflammation and Injury from Acid-Induced Acute Esophagitis in a Rat Model. Anal Cell Pathol (Amst) 2019; 2019:8243813. [PMID: 31281769 PMCID: PMC6589286 DOI: 10.1155/2019/8243813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/10/2019] [Accepted: 05/12/2019] [Indexed: 02/07/2023] Open
Abstract
Background/Aims The aim of this study is to examine the protective effect of the cholinergic anti-inflammatory pathway (CAP) in experimental esophagitis in rats. Methods A total of 40 male Sprague-Dawley (SD) rats were randomly divided into five groups as follows: control group, sham + saline group, sham + acid group, operation + saline group, and operation + acid group. Two weeks after the dorsal motor nucleus of the vagus (DMV) destruction, hydrochloric acid with pepsin was perfused into the lower part of the esophagus for 90 min. The rats were sacrificed 60 min after perfusion. The esophagus was prepared for hematoxylin and eosin (HE) staining, and the degree of inflammation and NF-κB activation in the esophagus was measured. Inflammatory cytokines (TNF-α, IL-6, IL-1β, and PGE2) in the esophagus were measured by ELISA. The brain was removed and processed for c-fos immunohistochemistry staining. The c-fos-positive neurons were counted and analyzed. Results The TNF-α, IL-1β, IL-6, and PGE2 concentrations in the esophageal tissue increased after acid perfusion. The microscopic esophagitis scores and the activation of NF-κB p65 in the esophagus were significantly higher in the operation + acid group than in the operation + saline group. c-fos-positive neurons significantly increased in rats receiving acid perfusion in the amygdala (AM), the paraventricular nucleus of the hypothalamus (PVN), the parabrachial nucleus (PBN), the nucleus of the solitary tract (NTS)/DMV, the nucleus ambiguous (NA), the reticular nucleus of the medulla (RNM), and the area postrema (AP). After DMV destruction, c-fos expression was reduced in the AM, PVN, PBN, NTS/DMV, NA, RNM, and AP, especially in the AM, PVN, NTS/DMV, RNM, and AP. Conclusions The DMV is an important nucleus of the CAP. The DMV lesion can aggravate esophageal inflammation and injury from acid-induced acute esophagitis in a rat model. The CAP has a protective effect on the acute esophagitis rat model and could be a new therapy for reflux esophagitis (RE).
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He F, Wang M, Geng X, Ai H. Effect of Electroacupuncture on the Activity of Corticotrophin-Releasing Hormone Neurons in the Hypothalamus and Amygdala in Rats Exposed to Restraint Water-Immersion Stress. Acupunct Med 2018; 36:394-400. [DOI: 10.1136/acupmed-2017-011450] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2017] [Indexed: 12/16/2022]
Abstract
Objective To investigate the effects of electroacupuncture (EA) treatment on gastric mucosal lesions and the activity of corticotrophin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus and the central nucleus of the amygdala (CNA) in a rat model of restraint water-immersion stress (RWIS). Methods 24 male Wistar rats were randomly divided into three groups: normal, RWIS, and RWIS+EA (n=8 per group). Rats in the RWIS group and RWIS+EA group received RWIS for 3 hours. For rats in the RWIS+EA group, EA was applied at ST36 in the bilateral hind legs for 30 min before RWIS. Rats in the normal group did not receive stressors or EA treatment. The gastric mucosal lesions of each rat were evaluated by the erosion index (EI) according to the methods of Guth. The activity of CRH neurons in the PVN and CNA was measured by a dual immunohistochemical test for Fos and CRH in the brain sections. Results RWIS induced serious gastric mucosal lesions. The mean gastric EI was significantly decreased in the RWIS+EA group versus the RWIS group (P=0.005). Stress induced significant activation of CRH neurons in the PVN and CNA compared with the normal group (P<0.001 for both). The mean number of Fos+CRH immunoreactive neurons in the PVN and CNA were both decreased inRWIS+EA versusRWIS groups (P<0.001 and P=0.001). Conclusions EA at ST36 can ameliorate RWIS-induced gastric mucosal lesions and suppress the Fos expression of CRH neurons in the PVN and CNA, suggesting a potentially therapeutic role for EA in stress-related gastric disorders.
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Affiliation(s)
- Feng He
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Min Wang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China
| | - Xiwen Geng
- Advanced Materials Genome Innovation Team, Advanced Materials Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, China
| | - Hongbin Ai
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China
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Sun H, Zhao P, Liu W, Li L, Ai H, Ma X. Ventromedial hypothalamic nucleus in regulation of stress-induced gastric mucosal injury in rats. Sci Rep 2018; 8:10170. [PMID: 29977067 PMCID: PMC6033936 DOI: 10.1038/s41598-018-28456-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/22/2018] [Indexed: 01/22/2023] Open
Abstract
Previous studies showed that restraint water-immersion stress (RWIS) increases the expression of Fos protein in the ventromedial hypothalamic nucleus (VMH), indicating the VMH involving in the stress-induced gastric mucosal injury (SGMI). The present study was designed to investigate its possible neuro-regulatory mechanisms in rats receiving either VMH lesions or sham surgery. The model for SGMI was developed by restraint and water (21 ± 1 °C) immersion for 2 h. Gastric mucosal injury index, gastric motility, gastric acid secretion and Fos expression in the hypothalamus and brainstem were examined on the 15th postoperative day in RWIS rats. Gastric mucosal injury in VMH-lesioned rats was obviously aggravated compared to the control. Gastric acidity under RWIS was obviously higher in VMH-lesioned rats than that in sham rats. Meantime, the VMH-lesioned rats exhibited marked increases in the amplitude of gastric motility in the VMH lesions group after RWIS. In VMH-lesioned rats, Fos expression significantly increased in the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in response to RWIS. These results indicate that VMH lesions can aggravate the stress-induced gastric mucosal injury through the VMH-dorsal vagal complex (DVC)-vagal nerve pathway.
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Affiliation(s)
- Haiji Sun
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, 250014, China.
| | - Pan Zhao
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, 250014, China
| | - Wenkai Liu
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, 250014, China
| | - Lei Li
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, 250014, China
| | - Hongbin Ai
- Key Laboratory of Animal Resistance Biology of Shandong Province, School of Life Science, Shandong Normal University, Jinan, 250014, China
| | - Xiaoli Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, China.
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Sun H, Ma X. α5-nAChR modulates nicotine-induced cell migration and invasion in A549 lung cancer cells. ACTA ACUST UNITED AC 2015. [PMID: 26205096 DOI: 10.1016/j.etp.2015.07.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cigarette smoking is the most important risk factor in the development of human lung cancer. Nicotine, the major component in tobacco, not only contributes to carcinogenesis but also promotes tumor metastasis. By binding to nicotinic acetylcholine receptors (nAChRs), nicotine induces the proliferation and migration of non-small cell lung cancer. Recently studies have indicated that α5-nAChR is highly associated with lung cancer risk and nicotine dependence. Nevertheless, it is unclear whether nicotine promotes the migration and invasion through activation of α5-nAChR in lung cancer. In the present study, A549 cell was exposed to 1μN nicotine for 8, 24 or 48h. Wound-healing assay and transwell assay were used to evaluate the capability of A549 cell migration and cell invasion, respectively. Silencing of α5-nAChR was done by siRNA. Western blotting and PCR were used to detect α5-nAChR expression. Nicotine can induce activation of α5-nAChR in association with increased migration and invasion of human lung cancer A549 cell. Treatment of cells with α5-nAChR specific siRNA blocks nicotine-stimulated activation of α5-nAChR and suppresses A549 cell migration and invasion. Reduction of α5-nAChR resulted in upregulation of E-cadherin, consistent with E-cadherin being inhibitive of cancer cell invasion. These findings suggest that nicotine-induced migration and invasion may occur in a mechanism through activation of α5-nAChR, which can contribute to metastasis or development of human lung cancer.
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Affiliation(s)
- Haiji Sun
- College of Life Science, Shandong Normal University, Jinan 250014, China
| | - Xiaoli Ma
- Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
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Zhao DQ, Ai HB. Oxytocin and vasopressin involved in restraint water-immersion stress mediated by oxytocin receptor and vasopressin 1b receptor in rat brain. PLoS One 2011; 6:e23362. [PMID: 21858088 PMCID: PMC3157380 DOI: 10.1371/journal.pone.0023362] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 07/13/2011] [Indexed: 12/31/2022] Open
Abstract
Aims Vasopressin (AVP) and oxytocin (OT) are considered to be related to gastric functions and the regulation of stress response. The present study was to study the role of vasopressinergic and oxytocinergic neurons during the restraint water-immersion stress. Methods Ten male Wistar rats were divided into two groups, control and RWIS for 1h. The brain sections were treated with a dual immunohistochemistry of Fos and oxytocin (OT) or vasopressin (AVP) or OT receptor or AVP 1b receptor (V1bR). Results (1) Fos-immunoreactive (Fos-IR) neurons dramatically increased in the hypothalamic paraventricular nucleus (PVN), the supraoptic nucleus (SON), the neucleus of solitary tract (NTS) and motor nucleus of the vagus (DMV) in the RWIS rats; (2) OT-immunoreactive (OT-IR) neurons were mainly observed in the medial magnocellular part of the PVN and the dorsal portion of the SON, while AVP-immunoreactive (AVP-IR) neurons mainly distributed in the magnocellular part of the PVN and the ventral portion of the SON. In the RWIS rats, Fos-IR neurons were indentified in 31% of OT-IR neurons and 40% of AVP-IR neurons in the PVN, while in the SON it represented 28%, 53% respectively; (3) V1bR-IR and OTR-IR neurons occupied all portions of the NTS and DMV. In the RWIS rats, more than 10% of OTR-IR and V1bR-IR neurons were activated in the DMV, while lower ratio in the NTS. Conclusion RWIS activates both oxytocinergic and vasopressinergic neurons in the PVN and SON, which may project to the NTS or DMV mediating the activity of the neurons by OTR and V1bR.
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Affiliation(s)
- Dong-Qin Zhao
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Shandong Province, People's Republic of China
| | - Hong-Bin Ai
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Shandong Province, People's Republic of China
- * E-mail:
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Lu CL, Li ZP, Zhu JP, Zhao DQ, Ai HB. Studies on functional connections between the supraoptic nucleus and the stomach in rats. J Physiol Sci 2011; 61:191-9. [PMID: 21431982 PMCID: PMC10717751 DOI: 10.1007/s12576-011-0137-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2010] [Accepted: 02/22/2011] [Indexed: 12/17/2022]
Abstract
The present study was to investigate whether there are functional connections between the hypothalamic supraoptic nucleus (SON) and the stomach, which is the case with the paraventricular nucleus. The rats were divided into four groups. Group I: the neuronal discharge was recorded extracellularly in the NTS, DMV or SON before and after cold physiological saline (4°C) was perfused into the stomach and effused from the duodenum. Group II: the rats were stimulated as for Group I and c-Fos expression in NTS, DMV and SON was examined. Group III: the control to Group II. Group IV: gastric motility was recorded continuously before and after microinjection of L: -Glu into the SON. In Group I, the discharge frequency increased in all the three nuclei, while in Group II, Fos expression in NTS, DMV and SON was, respectively, greater than that of Group III. In Group IV, microinjection of L: -Glu (5 nmol) into SON significantly inhibited gastric motility. These data suggest there are functional connections between SON and stomach.
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Affiliation(s)
- Chang-Liang Lu
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Science, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Zhao-Ping Li
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Science, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Jian-Ping Zhu
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Science, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Dong-Qin Zhao
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Science, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Hong-Bin Ai
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Science, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
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Vlasenko OV, Buzyka TV, Maiskii VA, Pilyavskii AI, Maznychenko AV. Activation of Neurons of the Medullary Centers of the Autonomic Nervous System Related to Motivated Operant Movements Realized by Rats. NEUROPHYSIOLOGY+ 2011. [DOI: 10.1007/s11062-011-9166-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Zhao DQ, Lu CL, Ai HB. The role of catecholaminergic neurons in the hypothalamus and medullary visceral zone in response to restraint water-immersion stress in rats. J Physiol Sci 2011; 61:37-45. [PMID: 21161464 PMCID: PMC10717081 DOI: 10.1007/s12576-010-0119-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2010] [Accepted: 10/28/2010] [Indexed: 12/14/2022]
Abstract
The activity of catecholaminergic neurons in the hypothalamus and the medullary visceral zone (MVZ) in rats in response to restraint water-immersion stress (RWIS) was measured by use of dual Fos and tyrosine hydroxylase (TH) immunohistochemistry. In RWIS rats Fos immunoreactive (Fos-IR) nuclei dramatically increased in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), and the ventrolateral medulla (VLM). A small number of TH-immunoreactive (TH-IR) and Fos/TH double-labeling neurons in the PVN, and their absence from the SON, were observed in both RWIS and nonstressed rats. More TH-IR neurons were observed in the MVZ of RWIS rats than in nonstressed rats. In RWIS and nonstressed rats, the percentage of Fos-IR nuclei in TH-IR neurons was 38.0 and 14.3% in the DMV, 34.4 and 9.7% in the NTS, 18.6 and 4.5% in the AP, and 45.7 and 18.9% in the VLM, respectively. In conclusion, catecholaminergic neurons in the MVZ are involved in the response to RWIS; although the PVN and SON also participate in the response to RWIS, the mechanism is not via catecholaminergic neurons.
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Affiliation(s)
- Dong-Qin Zhao
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Chang-Liang Lu
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
| | - Hong-Bin Ai
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan, 250014 Shandong People’s Republic of China
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Gallas S, Sinno MH, Boukhettala N, Coëffier M, Dourmap N, Gourcerol G, Ducrotté P, Déchelotte P, Leroi AM, Fetissov SO. Gastric electrical stimulation increases ghrelin production and inhibits catecholaminergic brainstem neurons in rats. Eur J Neurosci 2010; 33:276-84. [PMID: 21059113 DOI: 10.1111/j.1460-9568.2010.07474.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gastric electrical stimulation (GES) is a new therapeutic option for functional dyspepsia and gastroparesis. In addition to ameliorating nausea and vomiting, GES results in improved appetite which is not always associated with accelerated gastric emptying. To explore the central and peripheral factors underlying GES-associated improvement of appetite we developed a GES model in anaesthetized Wistar rats. During laparotomy, two electrodes were implanted into the stomach and high-frequency low-energy GES (14 Hz, 5 mA) was applied. The effects of 1 h GES were compared with sham stimulation. After GES, c-Fos expression was increased in the mucosal and submucosal layers of the stimulated area (174%). In the stomach, GES increased ghrelin mRNA (178%) and doubled the number of ghrelin-positive cells, resulting in elevated plasma levels of ghrelin (2.3 ± 0.2 vs. 1.6 ± 0.2 ng/mL). In the arcuate nucleus of the hypothalamus, GES increased c-Fos (277%) and agouti-related protein (AgRP) mRNA expression (135%). GES reduced the number of c-Fos-positive cells throughout the nucleus of the solitary tract (between 93 and 75% from rostral to caudal levels) including catecholaminergic neurons (81% at caudal level). Gastric emptying, plasma glucose and heart rate variability were not affected by GES. This study shows that GES may improve appetite via stimulation of main orexigenic pathways, including ghrelin production in the stomach and AgRP in the hypothalamus, as well as by reducing the activity of catecholaminergic brainstem neurons.
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Affiliation(s)
- Syrine Gallas
- Digestive System & Nutrition Laboratory (ADEN EA4311), Institute of Medical Research and Innovation, Rouen University & Hospital, IFR23, Rouen 76183, France
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Zhang YY, Zhu WX, Cao GH, Cui XY, Ai HB. c-Fos expression in the supraoptic nucleus is the most intense during different durations of restraint water-immersion stress in the rat. J Physiol Sci 2009; 59:367-75. [PMID: 19484338 PMCID: PMC10717109 DOI: 10.1007/s12576-009-0044-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 05/05/2009] [Indexed: 12/31/2022]
Abstract
Restraint water-immersion stress (RWIS) can induce anxiety, hypothermia, and severe vagally-mediated gastric dysfunction. The present work explored the effects of different durations of RWIS on neuronal activities of the forebrain by c-Fos expression in conscious rats exposed to RWIS for 0, 30, 60, 120, or 180 min. The peak of c-Fos induction was distinct for different forebrain regions. The most intense c-Fos induction was always observed in the supraoptic nucleus (SON), and then in the hypothalamic paraventricular nucleus (PVN), posterior cortical amygdaloid nucleus (PCoA), central amygdaloid nucleus (CeA), and medial prefrontal cortex (mPFC). Moreover, body temperature was reduced to the lowest degree after 60 min of RWIS, and the gastric lesions tended to gradually worsen with the prolonging of RWIS duration. These data strongly suggest that these nuclei participate in the organismal response to RWIS to different degrees, and may be involved in the hypothermia and gastric lesions induced by RWIS.
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Affiliation(s)
- Yu-Yu Zhang
- Key Laboratory of Animal Resistance of Shandong Province and College of Life Sciences, Shandong Normal University, 250014 Jinan, People’s Republic of China
| | - Wen-Xing Zhu
- Key Laboratory of Animal Resistance of Shandong Province and College of Life Sciences, Shandong Normal University, 250014 Jinan, People’s Republic of China
| | - Guo-Hong Cao
- Key Laboratory of Animal Resistance of Shandong Province and College of Life Sciences, Shandong Normal University, 250014 Jinan, People’s Republic of China
| | - Xi-Yun Cui
- Key Laboratory of Animal Resistance of Shandong Province and College of Life Sciences, Shandong Normal University, 250014 Jinan, People’s Republic of China
| | - Hong-Bin Ai
- Key Laboratory of Animal Resistance of Shandong Province and College of Life Sciences, Shandong Normal University, 250014 Jinan, People’s Republic of China
- College of Life Sciences, Shandong Normal University, Shandong Province, 250014 Jinan, People’s Republic of China
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