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Su Z, Miao B, Xu MQ, Yang MJ, Fei SJ, Zhang JF. Protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus on chronic visceral hypersensitivity in rats. Brain Res 2020; 1747:147048. [DOI: 10.1016/j.brainres.2020.147048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/26/2020] [Accepted: 08/06/2020] [Indexed: 02/08/2023]
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The Roles of GABA in Ischemia-Reperfusion Injury in the Central Nervous System and Peripheral Organs. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4028394. [PMID: 31814874 PMCID: PMC6878816 DOI: 10.1155/2019/4028394] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/27/2019] [Accepted: 10/18/2019] [Indexed: 12/30/2022]
Abstract
Ischemia-reperfusion (I/R) injury is a common pathological process, which may lead to dysfunctions and failures of multiple organs. A flawless medical way of endogenous therapeutic target can illuminate accurate clinical applications. γ-Aminobutyric acid (GABA) has been known as a marker in I/R injury of the central nervous system (mainly in the brain) for a long time, and it may play a vital role in the occurrence of I/R injury. It has been observed that throughout cerebral I/R, levels, syntheses, releases, metabolisms, receptors, and transmissions of GABA undergo complex pathological variations. Scientists have investigated the GABAergic enhancers for attenuating cerebral I/R injury; however, discussions on existing problems and mechanisms of available drugs were seldom carried out so far. Therefore, this review would summarize the process of pathological variations in the GABA system under cerebral I/R injury and will cover corresponding probable issues and mechanisms in using GABA-related drugs to illuminate the concern about clinical illness for accurately preventing cerebral I/R injury. In addition, the study will summarize the increasing GABA signals that can prevent I/R injuries occurring in peripheral organs, and the roles of GABA were also discussed correspondingly.
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Keshavarzi Z, Mohebbati R, Mohammadzadeh N, Alikhani V. THE PROTECTIVE ROLE OF ESTRADIOL & PROGESTERONE IN MALE RATS, FOLLOWING GASTRIC ISCHEMIA-REPERFUSION. ACTA ENDOCRINOLOGICA-BUCHAREST 2018; 14:30-35. [PMID: 31149233 DOI: 10.4183/aeb.2018.30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background and Aim Ischemia-reperfusion (I/R) injury frequently occurs in different situations. Female sex hormones have a protective function. The purpose of this study was to determine the function of female sexual hormones on the gastric damage induced by I/R in male rats. Methods Forty (40) Wistar rats were randomized into five groups: intact, ischemia- reperfusion (IR), IR + estradiol (1mg/kg), IR + progesterone (16 mg / kg) and IR + combination of estradiol (1mg / kg) and progesterone (16 mg/ kg). Before the onset of ischemia and before reperfusion all treatments were done by intraperitoneal (IP) injection. After animal anesthesia and laparotomy, celiac artery was occluded for 30 minutes and then circulation was established for 24 hours. Results expressed as mean ± SEM and P <0.05 were considered statistically significant. Results The Glutathione (GSH) concentration significantly decreased after induction of gastric IR (P<0.001). Estradiol (P<0.001) and combined estradiol and progesterone (P<0.001) significantly increased GSH levels. The myeloperoxidase (MPO) concentration significantly increased after induction of gastric IR (P<0.001). Different treatments significantly reduced MPO levels (P<0.001). The gastric acid concentration significantly increased after induction of gastric IR (P<0.001). Treatment with estradiol, progesterone (P<0.05) and combined estradiol and progesterone (P<0.01) significantly reduced gastric acid levels. Superoxide dismutase (SOD) concentration decreased after induction of gastric IR. The SOD levels were not significant. Conclusion These data suggested that female sexual steroids have a therapeutic effect on gastrointestinal ischemic disorders by reduction of MPO and gastric acid, and increasing gastric GSH & SOD levels following gastric IR.
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Affiliation(s)
- Z Keshavarzi
- North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - R Mohebbati
- Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - V Alikhani
- Mashhad University of Medical Sciences, Mashhad, Iran
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Gao L, Zhao H, Zhu T, Liu Y, Hu L, Liu Z, Huang H, Chen F, Deng Z, Chu D, Du D. The Regulatory Effects of Lateral Hypothalamus Area GABA B Receptor on Gastric Ischemia-Reperfusion Injury in Rats. Front Physiol 2017; 8:722. [PMID: 28983255 PMCID: PMC5613147 DOI: 10.3389/fphys.2017.00722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 09/06/2017] [Indexed: 12/16/2022] Open
Abstract
HIGHLIGHTS
The aim of the research was to determine the functional effects and molecular mechanisms of GABAB receptor on ischemia reperfusion-induced gastric injury in rats. The lateral hypothalamus area GABAB receptor attenuated the ischemia reperfusion-induced gastric injury by up-regulating the production of GABA, GABABR, and down-regulating P-GABABR in the brain. This work would provide a new therapeutic strategy for acute gastric injury. Gastric ischemia-reperfusion (GI-R) injury progression is largely associated with excessive activation of the greater splanchnic nerve (GSN). This study aims to investigate the protective effects of GABAB receptor (GABABR) in the lateral hypothalamic area (LHA) on GI-R injury. A model of GI-R injury was established by clamping the celiac artery for 30 min and then reperfusion for 1 h. The coordinate of FN and LHA was identified in Stereotaxic Coordinates and then the L-Glu was microinjected into FN, GABAB receptor agonist baclofen, or GABAB receptor antagonist CGP35348 was microinjected into the LHA, finally the GI-R model was prepared. The expression of GABABR, P-GABABR, NOX2, NOX4, and SOD in the LHA was detected by western blot, PCR, and RT-PCR. The expression of IL-1β, NOX2, and NXO4 in gastric mucosa was detected by western blot. We found that microinjection of L-Glu into the FN or GABAB receptor agonist (baclofen) into the LHA attenuated GI-R injury. Pretreatment with GABAB receptor antagonist CGP35348 reversed the protective effects of FN stimulation or baclofen into the LHA. Microinjection of baclofen into the LHA obviously reduced the expression of inflammatory factor IL-1β, NOX2, and NOX4 in the gastric mucosa. Conclusion: The protective effects of microinjection of GABABR agonist into LHA on GI-R injury in rats could be mediated by up-regulating the production of GABA, GABABR, and down-regulating P-GABABR in the LHA.
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Affiliation(s)
- Lin Gao
- Neurology Center, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou, China
| | - Huiru Zhao
- Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
| | - Tao Zhu
- Department of Life Science, Heze UniversityHeze, China
| | - Yeliu Liu
- Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical UniversityHuai'an, China
| | - Li Hu
- Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
| | - Zhenguo Liu
- Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
| | - Hai Huang
- Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
| | - Fuxue Chen
- Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
| | - Zhenxu Deng
- Department of Life Science, Heze UniversityHeze, China
| | - Dechang Chu
- Department of Life Science, Heze UniversityHeze, China
| | - Dongshu Du
- Neurology Center, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou, China.,Shanghai Key Laboratory of Bio-Crops, College of Life Science, Shanghai UniversityShanghai, China
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Gao L, Zhu T, Xie G, Lou X, Li S, Zhou Y, Deng Z, Chu D, Lou J, Du D. GABA(A) receptor overexpression in the lateral hypothalamic area attenuates gastric ischemia‑reperfusion injury in rats. Mol Med Rep 2014; 11:1057-62. [PMID: 25354809 DOI: 10.3892/mmr.2014.2816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 08/22/2014] [Indexed: 11/05/2022] Open
Abstract
Excessive activation of the greater splanchnic nerve (GSN) has previously been determined to contribute to the progression of gastric ischemia‑reperfusion (GI‑R) injury. The present study was designed to estimate the protective effects of GABAA receptor (GABA(A)R) overexpression in the lateral hypothalamic area (LHA) against GI‑R injury. The GI‑R injury model was induced in rats by clamping the celiac artery for 30 min and then reperfusing for 1 h. Microinjection of recombinant adenoviral vectors overexpressing GABA(A)R (Ad‑GABA(A)R) or control adenoviral vectors (Ad‑Con) into the LHA was conducted in GI‑R and normal control rats. Significant protective effects were observed on day 2 after Ad‑GABA(A)R treatment in the GI‑R injury rats. Ad‑GABA(A)R treatment reduced plasma norepinephrine levels, plasma angiotensin II levels and peripheral GSN activity, but increased the gastric mucosal blood flow, as compared with Ad‑Con treatment. These results indicate that adenoviral vector‑induced GABA(A)R overexpression in the LHA blunts GSN activity and subsequently alleviates the effects of gastric injury in GI‑R rats.
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Affiliation(s)
- Lin Gao
- Department of Neurology, The Affiliated Second Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Tao Zhu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, P.R. China
| | - Guilin Xie
- Life Science College of Northeast Agricultural University, Harbin, Heilongjiang 150030, P.R. China
| | - Xiangxin Lou
- Department of Bioengineering, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, P.R. China
| | - Shibao Li
- Department of Laboratory Medicine, Lianyungang Hospital Affiliated Bengbu Medical College, Lianyungang, Jiangsu 222006, P.R. China
| | - Yan Zhou
- Department of Laboratory Medicine, Lianyungang Hospital Affiliated Bengbu Medical College, Lianyungang, Jiangsu 222006, P.R. China
| | - Zhenxu Deng
- Department of Life Science, Heze University, Heze, Shandong 274500, P.R. China
| | - Dechang Chu
- Department of Life Science, Heze University, Heze, Shandong 274500, P.R. China
| | - Jiyu Lou
- Department of Neurology, The Affiliated Second Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Dongshu Du
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, P.R. China
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Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats. Acta Pharmacol Sin 2014; 35:185-94. [PMID: 24362327 DOI: 10.1038/aps.2013.140] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 08/28/2013] [Indexed: 12/12/2022]
Abstract
AIM To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus (PVN) on ulcerative colitis (UC) in rats and to explore the relevant mechanisms. METHODS 2,4,6-Trinitrobenzenesulfonic acid (100 mg/kg in 50% ethanol) was instilled into the colon of adult male SD rats to induce UC. A colonic damage score (CDS) was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion. RESULTS Microinjection of glutamate (3, 6 and 12 μg) into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid (0.3 μg) was microinjected into PVN or into the nucleus tractus solitarius (NTS) that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V1 receptor antagonist DPVDAV (200 ng) was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. CONCLUSION The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.
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Du DS, Zhu T, Ren ST, Xie GL, Li SB, Chu DC, Liu XT, Liu M, Ma XB, Zhou MH, Zhu DN, Deng ZX, Wang J. γ-Aminobutyric acid-mediated neurotransmission in cerebellar-hypothalamic circuit attenuates gastric mucosal injury induced by ischemia-reperfusion. Neurogastroenterol Motil 2013; 25:313-e249. [PMID: 23279161 DOI: 10.1111/nmo.12062] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Excessive greater splanchnic nerve (GSN) activation contributes to the progression of gastric ischemia-reperfusion (GI-R) injury. This study was designed to investigate the protective mechanism of cerebellar fastigial nucleus (FN) stimulation against GI-R injury. METHODS The GI-R injury model was induced in rats by clamping the celiac artery for 30 min, and then reperfusion for 30 min, 1, 3, 6, or 24 h, respectively. KEY RESULTS Microinjection of L-Glu (3, 6, 12 μg) into the FN dose-dependently attenuated GI-R injury and GSN activity. In addition, there was an enhancement of gastric mucosal blood flow in GI-R rats. Pretreatment with the glutamic acid decarboxylase antagonist into the FN, the GABAA receptor antagonist into the lateral hypothalamic area or lesion of superior cerebellar peduncle all reversed the protective effects of the FN stimulation. Furthermore, the FN stimulation reduced the TUNEL-positive gastric mucosal cell and Bax-positive gastric mucosal cell in GI-R rats. CONCLUSIONS & INFERENCES These results indicate that the protective effects of the FN stimulation against GI-R injury may be mediated by attenuation of the excessive GSN activation, gastric mucosal cell apoptosis, and Bax expression in GI-R rats.
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Affiliation(s)
- D S Du
- Department of Physiology and Pathophysiology, Shanghai Medical College of Fudan University, Shanghai, China
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Zhu JZ, Fei SJ, Zhang JF, Zhu SP, Liu ZB, Li TT, Qiao X. Muscimol microinjection into cerebellar fastigial nucleus exacerbates stress-induced gastric mucosal damage in rats. Acta Pharmacol Sin 2013; 34:205-13. [PMID: 23247592 DOI: 10.1038/aps.2012.152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM To investigate the effects of microinjection of the GABA(A) receptor agonist muscimol into cerebellar fastigial nucleus (FN) on stress-induced gastric mucosal damage and the underlying mechanism in rats. METHODS Stress-induced gastric mucosal damage was induced in adult male SD rats by restraining and immersing them in cold water for 3 h. GABA(A) receptor agonist or antagonist was microinjected into the lateral FN. The decussation of superior cerebellar peduncle (DSCP) was electrically destroyed and the lateral hypothalamic area (LHA) was chemically ablated by microinjection of kainic acid. The pathological changes in the gastric mucosa were evaluated using TUNEL staining, immunohistochemistry staining and Western blotting. RESULTS Microinjection of muscimol (1.25, 2.5, and 5.0 μg) into FN significantly exacerbated the stress-induced gastric mucosal damage in a dose-dependent manner, whereas microinjection of GABA(A) receptor antagonist bicuculline attenuated the damage. The intensifying effect of muscimol on gastric mucosal damage was abolished by electrical lesion of DSCP or chemical ablation of LHA performed 3 d before microinjection of muscimol. Microinjection of muscimol markedly increased the discharge frequency of the greater splanchnic nerve, significantly increased the gastric acid volume and acidity, and further reduced the gastric mucosal blood flow. In the gastric mucosa, further reduced proliferation cells, enhanced apoptosis, and decreased anti-oxidant levels were observed following microinjection of muscimol. CONCLUSION Cerebellar FN participates in the regulation of stress-induced gastric mucosal damage, and cerebello-hypothalamic circuits contribute to the process.
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Liu HX, Fei SJ, Ye HH, Zhang JL, Zhang YM. Effect of propofol on proliferation and apoptosis of gastric mucosal cells in gastric ischemia-reperfusion injury in mice. Shijie Huaren Xiaohua Zazhi 2012; 20:1495-1501. [DOI: 10.11569/wcjd.v20.i17.1495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the changes in proliferation and apoptosis of gastric mucosal cells in gastric ischemia-reperfusion (I/R) injury, and to clarify whether propofol has a gastric protection effect and the possible mechanisms involved.
METHODS: Seventy-two Kunming mice were randomly divided into four groups: sham operation group, I/R injury group, fat emulsion group, and propofol group. Except the sham operation group, I/R injury was induced in other groups by clamping the celiac artery for 30 min and allowing reperfusion for 1h. The mice were finally sacrificed to observe morphological changes and investigate gastric mucosal damage index (GMDI). The histological changes of the stomach were observed using light microscopy. The content of malondialdehyde (MDA) and activity of superoxide dismutas (SOD) in gastric mucosal cells were measured by colorimetry analysis. Immunohistochemistry and TdT-mediated d-UTP-biotin nick end-labeling (TUNEL) assay were used to observe PCNA expression and apoptosis in gastric mucosa, and the expression of Bax and Bcl-2 proteins was determined by Western blot.
RESULTS: Severe mucosal lesions induced by gastric I/R were considerably reduced following administration of propofol (25 mg/kg); mucosal and submueosal hyperemia, edema, and deep erosion were improved significantly. Compared to the I/R group, treatment with propofol significantly reduced gastric mucosal MDA content and cell apoptosis (33.9% ± 1.3% vs 60.8% ± 6.9%, P < 0.01), enhanced SOD activity, promoted cell proliferation (16.0% ± 1.8% vs 6.4% ± 1.2%, P < 0.01), and regulated Bax (0.453 ± 0.025 vs 0.268 ± 0.023, P < 0.01) and Bcl-2 (0.513 ± 0.014 vs 0.752 ± 0.015, P < 0.01) protein expression.
CONCLUSION: Propofol protects against gastric gastric I/R injury possibly by promoting gastric mucosal cell proliferation and inhibiting apoptosis.
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Mitochondrial dependent apoptosis: ameliorative effect of flunarizine on ischemia-reperfusion of celiac artery-induced gastric lesions in the rat. Dig Dis Sci 2011; 56:2244-51. [PMID: 21327706 DOI: 10.1007/s10620-011-1607-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 01/29/2011] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Ischemia-reperfusion is a major event for induction of cellular apoptosis. Apoptosis is due to the activation of death receptor and/or mitochondrial pathways. Mitochondrial permeability transition pore opening is the cause of apoptosis. In our present study, we tried to evaluate the role of flunarizine in ischemia and reperfusion of celiac artery-induced gastric lesion in the rat. METHODS The therapeutic potential of flunarizine was assessed by measuring the changes in gastric lesion index, biomarker (i.e., thiobarbituric acid reactive substance, reduced glutathione, superoxide dismutase, myeloperoxidase, and total calcium and protein content), and mitochondrial damage (i.e., adenosine triphosphate and deoxyribonucleic acid fragmentation content) in ischemia and reperfusion-induced gastric lesion model. RESULTS Medium and higher doses of flunarizine produced a significant (P<0.05) ameliorative effect which was observed from the assessment of all the above-mentioned parameters (i.e., increase in reduced glutathione, superoxide dismutase and decrease in thiobarbituric acid reactive substance, myeloperoxidase, and total calcium content). Similar results were also obtained from omeprazole and cyclosporine. In the pre-treated group, deoxyribonucleic acid fragmentation pattern has also indicated that a mitochondria-associated anti-apoptotic effect of flunarizine was responsible to prevent the ischemia and reperfusion of celiac artery-induced gastric lesion. CONCLUSION The gastroprotective effect of flunarizine may be produced due to its inactivation potential of mitochondrial permeability transition pore opening associated with anti-oxidative, calcium regulation along with its anti-apoptotic effect.
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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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Gao L, Fei S, Qiao W, Zhang J, Xing H, Du D. Protective effect of chemical stimulation of cerebellar fastigial nucleus on stress gastric mucosal injury in rats. Life Sci 2011; 88:871-8. [PMID: 21419784 DOI: 10.1016/j.lfs.2011.03.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 02/23/2011] [Accepted: 03/11/2011] [Indexed: 12/16/2022]
Abstract
AIMS We investigated the protective effects of chemical stimulation of cerebellar fastigial nucleus (FN) on stress gastric mucosal injury (SGMI) and its possible neuro-regulatory mechanisms in rats. MAIN METHODS Chemical stimulation, electrical stimulation, chemical ablation, electrolytic lesion, and microinjection were used to investigate the effects of FN simulation on SGMI. The model of SGMI was established by restraint and water (21±1°C)-immersion (RWI) for 3h in rats. The gastric mucosal injury index indicated the severity of gastric mucosal injuries. KEY FINDINGS We showed that microinjection of L-glutamic acid into the FN or electrical stimulation of the FN markedly attenuated SGMI. Either chemical lesion of the FN or electrical ablation of the decussation of superior cerebellar peduncle (DSCP) obviously aggravated SGMI. The protective effect of FN stimulation on SGMI was reversed after chemical ablation of the lateral hypothalamic area (LHA). The protective effect of FN was prevented by pretreatment with the glutamic acid decarboxylase antagonist, 3-MPA into the FN or GABA(A) receptor antagonist, bicuculline into the LHA. The protective effect of FN was abolished by pretreatment with sympathectomy. The discharge frequency of greater splanchnic nerve (GSN) was decreased and gastric mucosal blood flow (GMBF) was increased after chemical stimulation of FN. These results indicate that the FN participates in regulation of SGMI, and is a specific area in the CNS for exerting protective effects on the SGMI. The DSCP, LHA and peripheral sympathetic nerve may be involved in this process. SIGNIFICANCE Our findings might provide a new and improved understanding of the cerebellar function and an effective treatment strategy for stress gastric mucosal injury.
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Affiliation(s)
- Ling Gao
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical College 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China
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Zhang YM, Zhang WW, Zhang JF. JNK mediates the effects of oxytocin microinjected into the paraventricular nucleus on gastric ischemia-reperfusion in rats. Shijie Huaren Xiaohua Zazhi 2009; 17:1919-1924. [DOI: 10.11569/wcjd.v17.i19.1919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the molecular mechanism underlying the role of JNK in mediating the effects of oxytocin (OT) microinjected into the paraventricular nucleus (PVN) on gastric ischemia-reperfusion (GI-R) injury.
METHODS: Sprague-Dawley (SD) rats were randomly divided into four groups: vehicle group, OT group, atosiban group and OT plus atosiban group. GI-R injury was induced in rats by clamping the celiac artery for 30 min and then reperfusing for 1 h. A cannula was inserted into the unilateral PVN for microinjection of OT. The expression of p-JNK, Bax and Bcl-2 proteins in rat gastric mucosa was examined by Western blot and immunohistochemistry.
RESULTS: Compared with the vehicle group, microinjection of OT (600 ng) into PVN significantly decreased the expression of p-JNK and Bax proteins but increased the expression of Bcl-2 protein in gastric mucosa following GI-R (all P < 0.01). Pre-administration of atosiban (an OT receptor antagonist) into the lateral cerebral ventricle could prevent the effects of OT (F = 56.33, P < 0.01; F = 145.2, P < 0.01, F = 49.32, P < 0.01), increase the expression of p-JNK and Bax proteins, and decrease the expression of Bcl-2 protein when compared with the OT group.
CONCLUSION: Microinjection of OT into PVN attenuates GI-R injury through down-regulation of p-JNK protein, which in turn leads to a decrease in Bax expression and an increase in Bcl-2 expression.
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The role of nuclear factor-kappaB in the effect of angiotensin II in the paraventricular nucleus in protecting the gastric mucosa from ischemia-reperfusion injury in rats. J Gastroenterol 2009; 43:687-98. [PMID: 18807130 DOI: 10.1007/s00535-008-2217-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2007] [Accepted: 05/12/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND The purpose of this study was to elucidate the role of nuclear factor kappaB (NF-kappaB) in the development of gastric ischemia-reperfusion (GI-R) injury and in mediating the effects of angiotensin II (Ang II) in the paraventricular nucleus (PVN) on GI-R injury. METHODS GI-R injury was induced in rats by clamping the celiac artery for 30 min and then reperfusing for 1 h. A cannula was inserted into the unilateral PVN for microinjection of Ang II. The expressions and levels of NF-kappaB (p65), IkappaB-alpha, and phosphorylated IkappaB-alpha in rat gastric mucosa were examined by Western blotting and immunohistochemistry. A laser Doppler flowmeter was used to assess gastric blood flow (GBF). Malondialdehyde (MDA) was determined using the thiobarbituric acid (TBA) method, and superoxide dismutase (SOD) activity was determined by the xanthine/xanthine oxidase method. RESULTS Microinjection of Ang II (3, 30, and 300 ng) into the PVN dose-dependently inhibited GI-R injury. The levels and expressions of NF-kappaB (p65) and phosphospecific IkappaB-alpha protein increased 1 h after GI-R and were markedly reduced by microinjection of Ang II into the PVN. In contrast, the level and expression of IkappaB-alpha protein decreased 1 h after ischemia-reperfusion and recovered to the normal level by microinjection of Ang II into the PVN. The effects of Ang II were prevented by pretreatment with the Ang II AT1 receptor antagonist losartan (5 microg) microinjected into the lateral cerebral ventricle. Inhibition of NF-kappaB activity by pyrrolidine dithiocarbamate (PDTC, 200 mg/kg) produced similar effects in rats subjected to ischemia-reperfusion with or without microinjection of Ang II into the PVN. Administration of PDTC attenuated gastric mucosal injury and suppressed the activation of NF-kappaB (p65). Ang II microinjection into the PVN increased GBF and decreased the MDA content but did not alter SOD activity in the gastric mucosa following ischemia-reperfusion. CONCLUSIONS NF-kappaB plays a role in PVN Ang II-mediated protection against GI-R injury. These central effects of Ang II are mediated by AT1 receptors.
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Zhang YM, Zhang JF, Yan CD. Capsaicin-sensitive afferent fibers mediate the protective effect of electrical stimulation of paraventricular nucleus against gastric ischemia-reperfusion injury in rats. Shijie Huaren Xiaohua Zazhi 2008; 16:3616-3620. [DOI: 10.11569/wcjd.v16.i32.3616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role of capsaicin-sensitive afferent fibers in mediating the effect of electrical stimulation (ES) of paraventricular nucleus (PVN) against rat gastric ischemia-reperfusion (GI-R) injury.
METHODS: GI-R injury was induced in rats by clamping the celiac artery for 30 min and then reperfusing for 1 h. The methods of nuclear electric stimulation to excite the PVN and pretreatment with a high dose of capsaicin to ablate the capsaicin-sensitive afferent fibers were used to explore the role of capsaicin-sensitive afferent fibers in the regulation of PVN on GI-R injury.
RESULTS: Pretreament with a high dose of capsaicin to ablate afferent fibers partly abolished the protective effect of PVN against GI-R injury and the injury was increased by 54.85% as compared with that in the PVN stimulation group (P < 0.01); Pretreament with L-nitro-L-arginine methyl ester (L-NAME) significantly abolished the protective effect of PVN against GI-R injury and the injury was increased by 72.98% as compared with that in the PVN stimulation group (P < 0.01).
CONCLUSION: Capsaicin-sensitive afferent fibers and endogenous NO are involved in the protective effect of PVN stimulation against GI-R injury.
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Zhang YM, Wei EQ, Hu X, Xu M, Shi Y, Zhang JF. Administration of angiotensin II in the paraventricular nucleus protects gastric mucosa from ischemia-reperfusion injury. Brain Res 2008; 1212:25-34. [PMID: 18445492 DOI: 10.1016/j.brainres.2008.03.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2007] [Revised: 03/09/2008] [Accepted: 03/13/2008] [Indexed: 12/14/2022]
Abstract
Our previous study demonstrated that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) protects against gastric ischemia-reperfusion (GI-R) injury, but it is still unknown whether angiotensin II (Ang II) in the PVN plays a role in the development of GI-R. The purpose of this study was to investigate the effect of Ang II in the PVN on GI-R injury. GI-R injury was induced in rats by clamping the celiac artery for 30 min, and then reperfusing for 30 min, 1 h, 3 h, 6 h or 24 h, respectively. A cannula was inserted into the unilateral PVN for microinjection of Ang II. The extent of gastric mucosal damage was determined by gross and histological methods. We found that microinjection of pharmacological doses of Ang II (3, 30, and 300 ng) into the PVN dose-dependently inhibited GI-R injury, and that Ang II (30 ng) markedly attenuated GI-R injury at 1 h and 3 h after reperfusion. The effect of Ang II was prevented by pretreatment with the Ang II AT1 receptor antagonist losartan (5 microg) into the lateral cerebral ventricle. Furthermore, the protective effect of Ang II on GI-R injury was abolished by propranolol (1 mg/kg, i.v.) or disconnection of the nerves innervating the adrenal glands, was augmented by sympathectomy or phentolamine (1 mg/kg, i.v.), and was not affected by subdiaphragmatic vagotomy or atropine (1 mg/kg, i.v.). These results indicate that the PVN is a responsive site for central Ang II-induced protection against GI-R injury. The central effects of Ang II are mediated by AT1 receptors in the PVN, and the peripheral effects by a sympathetic-adrenal gland/beta-adrenoceptor pathway.
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Affiliation(s)
- Yong-Mei Zhang
- Department of Pharmacology, School of Medicine, Zhejiang University, 388, Yu Hang Tang Road, Hangzhou 310058, China
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Zhang W, Zhang J, Xu M, Zhang Y. Effect of oxytocin on gastric ischemia-reperfusion injury in rats. ACTA ACUST UNITED AC 2007; 1:433-7. [DOI: 10.1007/s11684-007-0085-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Zhang YM, Wei EQ, Li L, Qiao WL, Wang L, Zhang JF. Extracellular signal-regulated kinase pathways may mediate the protective effect of electrical stimulation of the paraventricular nucleus against ischaemia-reperfusion injury of the gastric mucosa. Clin Exp Pharmacol Physiol 2007; 34:742-52. [PMID: 17600551 DOI: 10.1111/j.1440-1681.2007.04652.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
1. The aim of the present study was to elucidate the role of the extracellular signal-regulated kinase (ERK) pathway in mediating the effects of electrical stimulation of the paraventricular nucleus (PVN) on apoptosis and proliferation induced by gastric ischaemia-reperfusion injury (GI/RI). 2. To investigate the effects of electrical stimulation of the hypothalamic PVN on gastric mucosal apoptosis and proliferation in response to ischaemia-reperfusion (I/R), we used a GI/RI model by clamping the coeliac artery for 30 min and then reperfusing the artery for 30 min or 1, 3 or 6 h. We used immunohistochemistry and western blotting to investigate the expression, activation and distribution of ERKs and the dynamic changes in their downstream cellular factors Bcl-2 and Bax at different times subsequent to electrical stimulation of the PVN in the I/R-injured gastric mucosa. 3. Electrical stimulation of the PVN markedly attenuated GI/RI at 30 min and 1 and 3 h after reperfusion. Electrical stimulation decreased gastric mucosal apoptosis, increased gastric mucosal proliferation and promoted the expression and activation of phosphorylated (p)-ERK1/2 30 min after reperfusion. Electrical stimulation increased the expression of Bcl-2 and decreased the expression of Bax at 30 min and 1 and 3 h after reperfusion. In contrast, inhibition of ERK1/2 activity by the specific upstream mitogen-activated protein kinase kinase inhibitor PD98059 produced similar effects at 1 h after reperfusion in rats subjected to I/R with or without electrical stimulation of the PVN. Administration of PD98059 aggravated gastric mucosal injury, increased apoptosis, decreased proliferation in gastric mucosal cells, decreased the expression and activity of p-ERK1/2 and Bcl-2 expression and increased Bax expression. 4. These results indicate that the PVN protects against GI/RI and that this protection is associated with the inhibition of cellular apoptosis and the promotion of proliferation in the gastric mucosa, probably by activating the ERK pathway.
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Affiliation(s)
- Yong-Mei Zhang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China
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Role of mitogen-activated protein kinases in the regulation of paraventricular nucleus to gastric ischemia-reperfusion injuries. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200706020-00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Li L, Zhang YM, Qiao WL, Wang L, Zhang JF. Effects of hypothalamic paraventricular nuclei on apoptosis and proliferation of gastric mucosal cells induced by ischemia/reperfusion in rats. World J Gastroenterol 2007; 13:874-81. [PMID: 17352016 PMCID: PMC4065922 DOI: 10.3748/wjg.v13.i6.874] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei (PVN) on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion (I/R) injury.
METHODS: For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals’ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 min, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times.
RESULTS: The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, 1 h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation.
CONCLUSION: Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.
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Affiliation(s)
- Li Li
- Department of Pathophysiology, Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China
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Qiao WL, Wang L, Zhang YM, Zhang JF, Wang GM. Extracellular signal-regulated kinase 1- and 2-mediated gastric mucosal injury and repair in gastric ischemia-reperfusion of rats. J Gastroenterol 2006; 41:1158-68. [PMID: 17287895 DOI: 10.1007/s00535-006-1902-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2006] [Accepted: 08/27/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The current study was undertaken to investigate the time course of gastric ischemia-reperfusion (GI-R)-induced gastric mucosal injury and repair and whether extracellular signal-regulated kinase 1/2 (ERK1/2) were involved in GI-R-induced gastric mucosal injury and repair. METHODS Immunohistochemistry and Western blot analyses were used. RESULTS Gastric mucosal injury induced by ischemia alone was mild. However, the injury worsened after reperfusion, reaching a maximum at 1 h, and was accompanied by increased apoptotic cells and decreased proliferative cells. Then, the gastric mucosal cells began to repair the injury by enhanced proliferation, which peaked at 24 h after reperfusion, and by 72 h the damaged gastric mucosa was mostly repaired. The ERK1/2 (nonactivated ERK1/2) protein expression level and distribution profile showed no significant changes during the entire reperfusion phase, but the p-ERK1/2 (activated ERK1/2) level changed dramatically. The p-ERK1/2 protein level was decreased at 0.5 h after reperfusion began, and then gradually increased, peaking after 3 h of reperfusion; these changes in p-ERK1/2 occurred simultaneously in the cytoplasm and nucleus. On the other hand, inhibition of the activation of ERK1/2, induced by PD98059, a specific ERK1/2 upstream inhibitor, aggravated the gastric mucosal injury, and apoptosis was increased and proliferation was reduced in the gastric mucosal cells after the same duration of reperfusion. CONCLUSIONS Serious gastric mucosal damage involving apoptotic cells occurred rapidly at an early stage of reperfusion and was closely related to the suppression of ERK1/2 activation. The activated ERK1/2 signaling transduction pathway played an important role. Activated ERK1/2 participated in the regulation of gastric mucosal injury and repair induced by GI-R, and might be mediated by the inhibition of apoptosis and the promotion of proliferation in gastric mucosal cells.
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Affiliation(s)
- Wei-Li Qiao
- Department of Physiology and Neurobiology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, China
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Abstract
AIM: To develop a method of quantifying the pathological changes gastric ulcer in the experimental mice.
METHODS: The experimental mice were fed with alcohol to establish the model of gastric ulcer. The area of the ulcer was quantified by weight and picture integration. Then the ratio of ulcer area to total stomach area (ulcer area ratio, UAR) was calculated to assess the degrees of the ulcers on the stomach wall. Furthermore, the methods of weighing, picture integration, marking, and grading were compared.
RESULTS: The mark indexes and the UAR by weight and picture integration were significantly different between different grading groups (Grade 4 vs Grade 2 vs Grade 1: 84.0±27.8 vs 19.6±8.1 vs 4.0±1.0, P<0.05; 40.74±0.26% vs 4.22±0.01%vs 1.03±0.01%, P<0.05; 31.57 ±0.16% vs 4.36±0.02% vs 2.43±0.02%, P<0.05) respectively, but the petechiae have no significant difference (P>0.05). Except in one mouse, the differences of UAR between by weight and picture integration in other five mice were 0.69, 4.89, 7.41, 1.26 and 2.76 respectively, which showed UAR had no marked difference between the two methods. In comparison of model I with model II, there were no obvious differences in the mark indexes, grading indexes and the numbers of petechiae while the UARs between by weight and picture integration were significantly different (6.14±0.08%vs 27.64±0.31%, P<0.05; 6.56±0.07% vs 21.22±0.21%, P<0.05).
CONCLUSION: The degrees of the gastric ulcer can be accessed by weight, picture integration, marking and grading. Weighing is better for measuring the ulcer over the fourth grade while picture integration can be used in all the degrees. The sensitivity and accuracy of picture integration and weighing are higher than those of traditional marking and grading.
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