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Featured researches published by Nai-Nu Lin.


Free Radical Biology and Medicine | 1996

In vivo evidence of hydroxyl radical formation induced by elevation of extracellular glutamate after cerebral ischemia in the cortex of anesthetized rats

Chung-Shi Yang; Nai-Nu Lin; Pi-Ju Tsai; Lin Liu; Jon-Son Kuo

The in vivo interrelation between excitotoxicity and oxidative stress following cerebral ischemia in the cortex of anesthetized rats was investigated. Cerebral ischemia was induced by ligation of the bilateral common carotid arteries and the unilateral middle cerebral artery. Microdialysis perfusion with on-line high-performance liquid chromatography was used to monitor the hydroxyl radical levels. Extracellular hydroxyl radical levels were quantitated as the increased formation of 2.3 and 2.5 dihydroxybenzoic acid (DHBA), the hydroxylative products of salicylic acid contained in the microdialysis perfusion solutions. Elevated cortex extracellular glutamate content, resulting from the cerebral ischemia, caused an increase in the formation of hydroxyl radicals. Exogenous perfusion of authentic glutamate solutions through implanted microdialysis probes also resulted in increased hydroxyl radical formation in the cortex. The 2.3 and 2.5 DHBA levels remained elevated for an entire 80-min ischemic period. These results suggest that, after cerebral ischemia, increased oxidative stress did occur in anesthetized rats, and the oxidative stress may result from increased excitotoxicity.


Free Radical Biology and Medicine | 1995

Elevated extracellular glutamate levels increased the formation of hydroxyl radical in the striatum of anesthetized rat

Chung-Shi Yang; Pi-Ju Tsai; Nai-Nu Lin; Lin Liu; Jon-Son Kuo

Results from various in vitro experiments have indicated that excitotoxicity and oxidative stress are two interrelated major mechanisms in causing neuronal damage in brain disorders such as cerebral ischemia/reperfusion. Thus, we have conducted experiments to investigate whether in the striatum of anesthetized rats the elevated brain extracellular concentrations of glutamate could increase the formation of hydroxyl radical. Elevation of glutamate levels and trapping of hydroxyl radical were accomplished by perfusing Ringer solutions containing both glutamate and salicylic acid through microdialysis probes implanted in rat striatum. The formation of hydroxyl radical was quantitated as the increased amounts of 2,3 and 2,5 dihydroxybenzoic acid (DHBA) which were the hydroxylative products of salicylic acid. Eluted microdialysates were directly injected onto high performance liquid chromatography (HPLC) with electrochemical detector via an on-line automatic injector. This method was authenticated by in vitro studies employing Fenton-type hydroxyl radicals generation system. Our results indicated that elevated glutamate concentrations (15 mM, 1.5 mM, and 150 microM glutamate in perfusing solutions) would significantly increased both the concentrations of 2,3 and 2,5 DHBA. In conclusion, we have obtained direct evidence showing that the elevated glutamate concentrations in brain extracellular space would increase the formation of hydroxyl radical, and these results implied that oxidative stress occurring in brain disorders might be induced by excitotoxicity.


Neuroscience Letters | 2000

Effects of naloxone on lactate, pyruvate metabolism and antioxidant enzyme activity in rat cerebral ischemia/reperfusion

Chun-Jung Chen; Fu-Chou Cheng; Su-Lan Liao; Wen-Yin Chen; Nai-Nu Lin; Jon-Son Kuo

Whether naloxone may modulate energy metabolism and endogenous antioxidant enzyme activities in ischemic cortex was studied. Cerebral ischemia/reperfusion (I/R) was produced by occluding two common carotid arteries and the right middle cerebral artery for 90 min followed by reperfusion in anesthetized Sprague-Dawley rats. Both pre-treatment (0.03 or 0.3 mg) and post-treatment (0.3 mg) of naloxone by intracerebroventricular infusion significantly reduced cortical infarct volumes. Pre-treatment with 0.03 mg reduced ischemia-induced suppression of extracellular pyruvate level and enhancement of lactate/pyruvate ratio as well as cerebral I/R-induced increases of endogenous catalase, glutathione peroxidase, and manganese superoxide dismutase activities. In conclusion, neuroprotective effects of naloxone in terms of reducing brain infarction involve attenuation of the disturbance of cellular functions following cerebral I/R via restoration of mitochondrial activities or energy metabolism.


Journal of Chromatography B: Biomedical Sciences and Applications | 1994

Determination of extracellular glutathione in rat brain by microdialysis and high-performance liquid chromatography with fluorescence detection

Chung-Shi Yang; Su-Tze Chou; Nai-Nu Lin; Lin Liu; Pi-Ju Tsai; Jon-Son Kuo; Jeng-Shiow Lai

A method for the continuous monitoring of extracellular glutathione (GSH) concentrations in rat brain has been developed. This method involved the in vivo sampling of brain extracellular fluid by microdialysis perfusion and the subsequent analysis by high-performance liquid chromatography (HPLC) with fluorescence detection. Perfusates from the microdialysis probes were directly derivatized with methanolic monobromobimane which acted as the fluorescence tag. Separation of the derivatized perfusate was achieved on narrow-bore reversed-phase C18 columns. Recoveries of GSH from the microdialysis probes ranged from 1.5% to 4%. The basal extracellular GSH concentration in rat (Sprague-Dawley) brain cortex was found to be 2.10 +/- 1.78 microM (mean +/- S.D.) (results of 18 rats). Fluorescence detection and separation on narrow-bore columns provided adequate sensitivity for accurate determination of brain extracellular GSH concentrations in rats. With this method, the extracellular GSH concentrations in the cerebral cortex were found to be significantly elevated upon the onset of cerebral ischemia induced by the ligation of bilateral common carotid arteries.


Journal of Cardiovascular Electrophysiology | 2005

Increased Extracellular Collagen Matrix in Myocardial Sleeves of Pulmonary Veins: An Additional Mechanism Facilitating Repetitive Rapid Activities in Chronic Pacing‐Induced Sustained Atrial Fibrillation

Yung-Tsung Chiu; Tsu-Juey Wu M.D.; Hao‐Ji Wei; Ching-Chang Cheng; Nai-Nu Lin; Ying‐Tsung Chen; Chih-Tai Ting

Introduction: Cell uncoupling due to fibrosis or increased extracellular collagen matrix (ECM) affects the formation of ectopic focal activity. Whether or not the increase of ECM also exists in the pulmonary veins (PVs) with rapid atrial pacing is unknown. We sought to test the hypothesis that in chronic atrial pacing dogs with sustained atrial fibrillation (AF), the amount of ECM was increased in both atria and the PVs.


Journal of Chromatography B: Biomedical Sciences and Applications | 1996

In vivo, continuous and automatic monitoring of extracellular ascorbic acid by microdialysis and on-line liquid chromatography

Pi-Ju Tsai; Jen-Pey Wu; Nai-Nu Lin; Jon-Son Kuo; Chung-Shi Yang

A system for in vivo, automatic, continuous monitoring of organ extracellular ascorbic acid in anesthetized rat is described. This system involves microdialysis perfusion and a LC system equipped with an electrochemical detector. Microdialysate, eluted from a microdialysis probe implanted in the brain cortex or in the left ventricular myocardium of anesthetized rats was collected in the sample loop of an on-line injector for direct injection onto the LC system. This automated method provides a shortened sample processing time. This system was utilized to investigate the effect of cerebral ischemia on cortex extracellular ascorbic acid and the effect of myocardial ischemia on left ventricular myocardium extracellular ascorbic acid in anesthetized rats. Basal ascorbic acid concentrations in the cortex and left ventricular myocardium ranged from 9.7 to 15.4 microM (mean +/- S.D., 12.7 +/- 2.5 microM from the results of eight rats) and from 9.3 to 36.0 microM (mean +/- S.D., 24.3 +/- 8.9 microM from the results of twelve rats), respectively. Cerebral ischemia significantly elevated ascorbic acid levels in the cortex extracellular space, while myocardial ischemia did not significantly alter ascorbic acid levels in the left ventricular myocardium extracellular space.


Neuroscience Letters | 1998

Elevated extracellular glutamate concentrations increased malondialdehyde production in anesthetized rat brain cortex

Chung-Shi Yang; Pi-Ju Tsai; Nai-Nu Lin; Jon-Son Kuo

Oxidative stress is believed to be involved in the damaging mechanism of excitotoxic insult. Thus, we investigated the effect of elevated extracellular glutamate levels on malondialdehyde production, a common index of lipid peroxidation, in anesthetized rat brain cortex. Elevation of extracellular glutamate levels was achieved either by exogenously perfusing glutamate solutions, or by perfusing L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a competitive inhibitor of glutamate uptake transporter, through an implanted microdialysis probe. Malondialdehyde levels in the microdialysates, which were reacted with thiobarbituric acid, were analyzed by a high performance liquid chromatography system equipped with a fluorescence detector. Perfusion of glutamate (1.5 and 15 mM) resulted in dose-dependent increases in extracellular malondialdehyde production (as high as a 6-fold increase in malondialdehyde production following perfusion of 15 mM glutamate solution). PDC (3.14 and 31.4 mM), not only significantly increased the extracellular glutamate levels in a dose-dependent manner, but also dramatically increased malondialdehyde production (as high as 20-fold increase). These results suggest that excitotoxicity induces oxidative stress in anesthetized rat brain cortex, as evidenced by the glutamate-induced increase in malondialdehyde production.


Neuroscience Letters | 1999

Dorsal facial area of cat medulla; 5-HT2 action on glutamate release in regulating common carotid blood flow

Jon-Son Kuo; Hsing-Tan Li; Nai-Nu Lin; Chung-Shi Yang; Fu-Chou Cheng

Serotonin (5-HT) may inhibit glutamate release in the dorsal facial area (DFA) of the medulla and decrease common carotid arterial (CCA) blood flow. We attempted to clarify which subtype(s) of 5-HT receptor was involved. A microdialysis probe was inserted in DFA. The concentration of glutamate in dialysates were determined by chromatography. Glutamate concentration was dose-dependently decreased by perfusion of 5-HT or DOI, a 5-HT2 agonist, but not by 5-CT, a 5-HT1 agonist. The 5-HT-induced decrease in glutamate was reversed by co-perfusion of ketanserin, a 5-HT2 antagonist, but not by propranolol, a 5-HT1 antagonist. CCA blood flow was decreased when 5-HT or DOI was perfused, and was reversed by co-perfusing ketanserin. In conclusion, 5-HT may inhibit glutamate release via 5-HT2 receptor in DFA, resulting in the reduction of CCA blood flow.


BioMed Research International | 2011

Bronchiolitis obliterans organizing pneumonia in Swine associated with porcine circovirus type 2 infection.

Ching-Chang Cheng; Yen-Feng Lee; Nai-Nu Lin; Chieh-Liang Wu; Kwong-Chung Tung; Yung-Tsung Chiu

Bronchiolitis obliterans organizing pneumonia (BOOP) is a chronic respiratory disease. Although the pathogenesis of BOOP is still incompletely understood, BOOP is responsive to steroids and has a good prognosis. In our five pigs with chronic postweaning multisystemic wasting syndrome (PMWS), typical BOOP lesions were revealed. All five porcine lungs showed typical intraluminal plugs, and porcine circovirus type 2 (PCV2) was identified. They also exhibited similar pathologic findings such as proliferation of type II pneumocytes and myofibroblasts (MFBs), extracellular collagen matrix (ECM) deposition, and fragmentation of elastic fibers. MFBs migration correlative molecules, for instance, gelatinase A, B and osteopontin, appeared strongly in the progressing marginal area of polypoid intraluminal plugs of fibrotic lesion. These molecules colocalized with the active MFBs. Both gelatinase activity and intercellular level of active MFBs were significantly increased (P < .05). Porcine chronic bronchopneumonia leads to BOOP and it is associated with PCV2 persistent infection. Swine BOOP demonstrates similar cellular constituents with human BOOP. Perhaps their molecular mechanisms of pathogenesis operate in a similar way. Thus we infer that the swine BOOP can be considered as a potential animal model for human BOOP associated with natural viral infection. Moreover, it is more convenient to obtain samples.


Autonomic Neuroscience: Basic and Clinical | 2002

Glutamatergic and serotonergic mechanisms in the dorsal facial area for common carotid artery blood flow control in the cat

Chi-Li Gong; Nai-Nu Lin; Jon-Son Kuo

This study explored which subtyes of glutamate receptors in the dorsal facial area are involved in the interaction between glutamatergic and serotonergic actions in controlling common carotid arterial blood flow. Microinjection of glutamate (25-100 nmol), N-methyl-D-aspartate (NMDA; 1-4 nmol), or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA; 0.5-2 nmol) into the dorsal facial area dose-dependently increased common carotid arterial blood flow. The potency order was AMPA>NMDA>glutamate. The glutamate-induced increase in common carotid arterial blood flow was reduced by pretreatment with either D-2-amino-5-phosphonopentanoate (D-AP5; 2.5-5.0 nmol), or glutamate diethylester (25-50 nmol). The common carotid arterial blood flow was increased by ketanserin (1.0 nmol) and decreased by (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (1.0 nmol). Both effects were attenuated by pretreatment with either D-AP5 or glutamate diethylester. We conclude that activation of both NMDA and AMPA receptors in dorsal facial area is responsible for the increase in common carotid arterial blood flow, and AMPA receptor may play a greater role. Such response may be suppressed by 5-HT2 action.

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Yung-Tsung Chiu

National Chung Hsing University

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Ching-Chang Cheng

National Chung Hsing University

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Kwong-Chung Tung

National Chung Hsing University

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Yen-Feng Lee

National Chung Hsing University

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Yun-Ching Fu

National Yang-Ming University

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