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1.
Article in English | WPRIM | ID: wpr-971088

ABSTRACT

OBJECTIVE@#To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats.@*METHODS@#Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and SIRT2-knockout ( SIRT2 -/-) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed.@*RESULTS@#Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all P<0.01). Compared with the wild-type rats, SIRT2 -/- rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all P<0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all P<0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all P<0.01).@*CONCLUSIONS@#The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out SIRT2 gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.


Subject(s)
Animals , Rats , Amygdala/metabolism , Autistic Disorder/metabolism , Behavior, Animal , Disease Models, Animal , Glutamates/metabolism , Glutaminase/metabolism , Sirtuin 2/metabolism , Social Behavior
2.
Article in English | WPRIM | ID: wpr-1010549

ABSTRACT

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.


Subject(s)
Animals , Male , Rats , Acrylamides/pharmacology , Apoptosis/drug effects , Cryopreservation , Disaccharides/pharmacology , Electrolytes/pharmacology , Glutamates/pharmacology , Glutathione/pharmacology , Heart/physiology , Heart Transplantation/methods , Hepatocyte Growth Factor/antagonists & inhibitors , Histidine/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mannitol/pharmacology , Oxidative Stress/drug effects , Phenylenediamines/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Rats, Sprague-Dawley , Signal Transduction/drug effects , YAP-Signaling Proteins
3.
Zhongguo dangdai erke zazhi ; Zhongguo dangdai erke zazhi;(12): 594-600, 2019.
Article in Chinese | WPRIM | ID: wpr-775139

ABSTRACT

OBJECTIVE@#To study the effect of hyperoxic exposure on the dynamic expression of heme oxygenase-1 (HO-1) and glutamate-L-cysteine ligase catalytic subunit (GCLC) in the lung tissue of preterm neonatal rats.@*METHODS@#Cesarean section was performed for rats on day 21 of gestation to obtain 80 preterm rats, which were randomly divided into air group and hyperoxia group after one day of feeding. The rats in the air group were housed in room air under atmospheric pressure, and those in the hyperoxia group were placed in an atmospheric oxygen tank (oxygen concentration 85%-95%) in the same room. Eight rats each were selected from each group on days 1, 4, 7, 10, and 14, and lung tissue samples were collected. Hematoxylin and eosin staining was used to observe the pathological changes of lung tissue at different time points after air or hyperoxic exposure. Western blot and RT-qPCR were used to measure the protein and mRNA expression of HO-1 and GCLC in the lung tissue of preterm rats at different time points after air or hyperoxic exposure.@*RESULTS@#Compared with the air group, the hyperoxia group had a significant reduction in the body weight (P<0.05). Compared with the air group, the hyperoxia group had structural disorder, widening of alveolar septa, a reduction in the number of alveoli, and simplification of the alveoli on the pathological section of lung tissue. Compared with the air group, the hyperoxia group had significantly lower relative mRNA expression of HO-1 in the lung tissue on day 7 and significantly higher expression on days 10 and 14 (P<0.05). Compared with the air group, the hyperoxia group had significantly lower mRNA expression of GCLC in the lung tissue on days 1, 4, and 7 and significantly higher expression on day 10 (P<0.05). Compared with the air group, the hyperoxia group had significantly higher protein expression of HO-1 in the lung tissue on all days, and the protein expression of GCLC had same results as HO-1, except on day 1 (P<0.05).@*CONCLUSIONS@#Hyperoxia exposure may lead to growth retardation and lung developmental retardation in preterm rats. Changes in the protein and mRNA expression of HO-1 and GCLC in the lung tissue of preterm rats may be associated with the pathogenesis of hyperoxia-induced lung injury in preterm rats.


Subject(s)
Animals , Female , Humans , Infant, Newborn , Pregnancy , Rats , Animals, Newborn , Catalytic Domain , Cesarean Section , Cysteine , Glutamates , Heme Oxygenase-1 , Hyperoxia , Lung , Rats, Sprague-Dawley
4.
Article in English | WPRIM | ID: wpr-765337

ABSTRACT

OBJECTIVE: Globus pallidus interna (GPi) is acknowledged as an essential treatment for advanced Parkinson’s disease (PD). Nonetheless, the neurotransmitter study about its results is undiscovered. The goal of this research was to examine influences of entopeduncular nucleus (EPN) stimulation, identical to human GPi, in no-lesioned (NL) rat and 6-hydroxydopamine (6-HD)-lesioned rat on glutamate change in the striatum. METHODS: Extracellular glutamate level changes in striatum of NL category, NL with deep brain stimulation (DBS) category, 6-HD category, and 6-HD with DBS category were examined using microdialysis and high-pressure liquid chromatography. Tyrosine hydroxylase (TH) immunoreactivities in substantia nigra and striatum of the four categories were also analyzed. RESULTS: Extracellular glutamate levels in the striatum of NL with DBS category and 6-HD with DBS category were significantly increased by EPN stimulation compared to those in the NL category and 6-HD category. EPN stimulation had no significant effect on the expression of TH in NL or 6-HD category. CONCLUSION: Clinical results of GPi DBS are not only limited to direct inhibitory outflow to thalamus. They also include extensive alteration within basal ganglia.


Subject(s)
Animals , Humans , Rats , Basal Ganglia , Chromatography, Liquid , Deep Brain Stimulation , Entopeduncular Nucleus , Globus Pallidus , Glutamates , Glutamic Acid , Microdialysis , Neurotransmitter Agents , Oxidopamine , Parkinson Disease , Substantia Nigra , Thalamus , Tyrosine 3-Monooxygenase
5.
Article in English | WPRIM | ID: wpr-788766

ABSTRACT

OBJECTIVE: Globus pallidus interna (GPi) is acknowledged as an essential treatment for advanced Parkinson’s disease (PD). Nonetheless, the neurotransmitter study about its results is undiscovered. The goal of this research was to examine influences of entopeduncular nucleus (EPN) stimulation, identical to human GPi, in no-lesioned (NL) rat and 6-hydroxydopamine (6-HD)-lesioned rat on glutamate change in the striatum.METHODS: Extracellular glutamate level changes in striatum of NL category, NL with deep brain stimulation (DBS) category, 6-HD category, and 6-HD with DBS category were examined using microdialysis and high-pressure liquid chromatography. Tyrosine hydroxylase (TH) immunoreactivities in substantia nigra and striatum of the four categories were also analyzed.RESULTS: Extracellular glutamate levels in the striatum of NL with DBS category and 6-HD with DBS category were significantly increased by EPN stimulation compared to those in the NL category and 6-HD category. EPN stimulation had no significant effect on the expression of TH in NL or 6-HD category.CONCLUSION: Clinical results of GPi DBS are not only limited to direct inhibitory outflow to thalamus. They also include extensive alteration within basal ganglia.


Subject(s)
Animals , Humans , Rats , Basal Ganglia , Chromatography, Liquid , Deep Brain Stimulation , Entopeduncular Nucleus , Globus Pallidus , Glutamates , Glutamic Acid , Microdialysis , Neurotransmitter Agents , Oxidopamine , Parkinson Disease , Substantia Nigra , Thalamus , Tyrosine 3-Monooxygenase
6.
Article in English | WPRIM | ID: wpr-716302

ABSTRACT

OBJECTIVE: Alteration in glutamatergic neurotransmission and dopaminergic dysfunction has been implicated in both the initiation and expression of addiction related behaviors. This pilot study was aimed to investigate the serum levels of glutamate and dopamine in adults with internet gaming disorder (IGD). METHODS: We measured serum levels of glutamate and dopamine in male participants with IGD (n=26) and age-matched healthy controls (n=25). Clinical interviews were performed to identify IGD and to rule out psychiatric comorbidities. Serum levels of glutamate and dopamine were examined by enzyme immunoassays using ELISA Kits. RESULTS: Serum levels of glutamate were lower among IGD than control (IGD: 24.184±12.303 μg/ml; control: 33.676±12.413μg/ml; t=2.742, p=0.008), while levels of dopamine did not differ between. Serum glutamate and dopamine levels did not correlate with gaming hours and exposure to game in the IGD group. But serum glutamate levels were positively correlated with the dopamine levels (r=0.360, p=0.013). CONCLUSION: Our results suggest that altered glutamatergic neurotransmission may contribute to the pathophysiology of IGD.


Subject(s)
Adult , Humans , Male , Comorbidity , Dopamine , Enzyme-Linked Immunosorbent Assay , Glutamates , Glutamic Acid , Immunoenzyme Techniques , Immunoglobulin D , Internet , Pilot Projects , Synaptic Transmission
7.
Sheng Li Xue Bao ; (6): 148-156, 2016.
Article in Chinese | WPRIM | ID: wpr-331672

ABSTRACT

The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.


Subject(s)
Animals , Rats , Amino Acid Transport System X-AG , Animals, Newborn , Cognition , Cognition Disorders , Disease Models, Animal , Glutamates , Hippocampus , Hypoxia , Inflammation , Learning , Memory , Memory Disorders , Minocycline , Phosphorylation , Transforming Growth Factor beta1 , Tumor Necrosis Factor-alpha , tau Proteins
8.
Chinese Journal of Biotechnology ; (12): 1745-1749, 2016.
Article in Chinese | WPRIM | ID: wpr-243683

ABSTRACT

Recombinant strains expressing enzymes for ATP regeneration and L-theanine production were constructed and used for the synthesis of L-theanine. The ppk gene encoding polyphosphate kinase (PPK) from Rhodobacter sphaeroides and gmas gene encoding γ-glutamylmethylamide synthetase (GMAS) from Methylovorus mays were synthesized, and two recombinant plasmids, pETDuet-ppk+gmas and pET21a-ppk+gmas were constructed for co-expression of PPK and GMAS in Escherichia coli BL21(DE3). SDS-PAGE analysis showed that PPK and GMAS were overexpressed in soluble form in both recombinant strains. GMAS-PPK obtained from the recombinant strain containing pET21a-ppk+gmas was more efficient to synthesize L-theanine. After 24 h at 37 ℃ and pH at 7.0, 86.0% yield of L-theanine was achieved with catalytic amount of ATP. This study extends the application of enzymatic ATP regeneration system. In addition, it provides an efficient method for the biosynthesis of L-theanine.


Subject(s)
Carbon-Nitrogen Ligases , Genetics , Electrophoresis, Polyacrylamide Gel , Escherichia coli , Genetics , Glutamates , Ligases , Phosphotransferases (Phosphate Group Acceptor) , Genetics
9.
Anatomy & Cell Biology ; : 95-103, 2015.
Article in English | WPRIM | ID: wpr-23347

ABSTRACT

We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury.


Subject(s)
Brain Diseases , Calpain , Carrier Proteins , Cell Death , Cell Survival , Down-Regulation , Flow Cytometry , Glutamates , Glutamic Acid , L-Lactate Dehydrogenase , N-Methylaspartate , Neurons , Neuroprotective Agents , Protein Tyrosine Phosphatases , Receptors, N-Methyl-D-Aspartate , Uncaria
10.
Ai zheng ; Ai zheng;(12): 94-98, 2015.
Article in English | WPRIM | ID: wpr-349627

ABSTRACT

Toxic epidermal necrolysis (TEN) is a rare acute life-threatening mucocutaneous disorder that is mostly drug-related (80%-95%). It is clinically characterized as a widespread sloughing of the skin and mucosa. AP regimen (pemetrexed plus cisplatin) has been the preferred first-line chemotherapy for metastatic non-squamous non-small cell lung cancer (NSCLC). Gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has already been recommended as a first-line treatment in EGFR-mutant metastatic NSCLC. We report rare presentation of TEN involving adverse effects of AP and gefitinib combination treatment in a 42-year-old woman diagnosed with metastatic NSCLC harboring an EGFR mutation. On the 21st day after administration of the first cycle of AP regimen and the 8th day after the initiation of gefitinib treatment, she developed an acne-like rash, oral ulcer, and conjunctivitis, which later became blisters and ultimately denuded. The characteristic clinical courses were decisive for the diagnosis of TEN. Treatment with systemic steroids and immunoglobulin as well as supportive treatment led to an improvement of her general condition and a remarkable recovery.


Subject(s)
Adult , Female , Humans , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Pathology , Cisplatin , Glutamates , Guanine , Lung Neoplasms , Drug Therapy , Pathology , Neoplasm Metastasis , Pemetrexed , Quinazolines , Stevens-Johnson Syndrome
11.
Psicofarmacologia (B. Aires) ; 14(85): 21-30, apr.2014. ilus
Article in Spanish | LILACS | ID: lil-777902

ABSTRACT

Un objetivo clave de las investigaciones actuales es el estudio de las redes de señalización intracelular vinculadas a la plasticidad sináptica, así como a la supervivencia y a la muerte neuronal. Haremos una revisión bibliográfica acerca de la neurotransmisión glutamatérgica, en especial de los receptores NMDA, de las variantes en la composición de sus subunidades, y de su localización sináptica o extrasináptica que nos acerca a la comprensión de los mecanismos paradigmáticos de plasticidad sináptica como la potenciación de largo plazo (LTP) y la depresión de largo plazo (LTD), relacionados con la memoria y el aprendizaje, así como con las enfermedades neurodegenerativas generadas por la excitotoxicidad. También analizaremos las diferencias y roles opuestos del factor neurotrófico derivado del cerebro (BDNF) y del pro-BDNF en la supervivencia neuronal y la apoptosis. Y en una aplicación clínica de estos conceptos, revisaremos su influencia en el desarrollo de la enfermedad de Huntington...


A key goal of current research is to study the intracellular signaling networks associated with synaptic plasticity and survival and neuronal death. We will do a bibliographic review on glutamatergic neurotransmission, especially NMDA receptors, the variations in the composition of its subunits, and its synaptic or extrasynaptic localization, bringing us closer to understanding the paradigmatic mechanisms of LTP and LTD, related with memory and learning, as well as neurodegenerative diseases generated by excitotoxicity. We will also analyze the differences and opposing roles of BDNF and pro-BDNF in neuronal survival and apoptosis. And by clinically applying these concepts, we shall review its influece in the development of Huntington's disease...


Subject(s)
Humans , Huntington Disease/pathology , Glutamates/deficiency , Learning , Memory , Nerve Degeneration , Neuronal Plasticity , Receptors, Glutamate , Receptors, N-Methyl-D-Aspartate , Synaptic Transmission
12.
Indian J Hum Genet ; 2014 Jan-Mar ;20 (1): 20-31
Article in English | IMSEAR | ID: sea-156629

ABSTRACT

Recent advances in the study of alcoholism have thrown light on the involvement of various neurotransmitters in the phenomenon of alcohol addiction. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could be either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which have been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts alike in the field of neurotransmitters in alcoholism.


Subject(s)
Alcoholism/genetics , Dopamine , Glutamates , Humans , Neurobiology/methods , Neurotransmitter Agents/genetics , Serotonin
13.
J. bras. med ; 102(1)jan.-fev. 2014.
Article in Portuguese | LILACS | ID: lil-712208

ABSTRACT

A síndrome de fadiga crônica (SFC) é uma condição clínica que, apesar de muito prevalente, tem tratamento controverso. A suplementação com substratos como glutamina e vitaminas pode atuar como adjuvante terapêutico. Os autores descrevem um medicamento que pode atender essa finalidade, composto por glutamina 200mg, glutamato de cálcio 250mg, cloridrato de piridoxina 20mg e fosfato de ditetraetilamônio 6mg. São descritas também as ações de cada um dos componentes, e como podem auxiliar na terapêutica da SFC e em períodos de convalescença em diversas condições.


The chronic fatigue syndrome (CFS) is a clinical condition which, although highly prevalent, treatment is controversial and supplementation of substrates such as glutamine and vitamins can act as therapeutic adjuvant. A drug composition that can serve this purpose, the composition is glutamine 200mg, 250mg calcium glutamate, 20mg pyridoxine hydrochloride and phosphate ditetraetilammonium 6mg is described. Also described the actions of each component and how they can assist in the treatment of CFS and in periods of convalescence from various other conditions described.


Subject(s)
Humans , Male , Female , Fatigue Syndrome, Chronic/diet therapy , Fatigue Syndrome, Chronic/therapy , Convalescence , Dietary Vitamins , Glutamates/therapeutic use , Glutamine/therapeutic use , Minerals/therapeutic use , Pyridoxine/therapeutic use , Dietary Supplements , Tetraethylammonium/therapeutic use
14.
Chinese Journal of Hematology ; (12): 46-49, 2014.
Article in Chinese | WPRIM | ID: wpr-295721

ABSTRACT

<p><b>OBJECTIVE</b>To explore the efficacy and safety of pemetrexed in the treatment of relapsed primary central nervous system lymphoma (PCNSL).</p><p><b>METHODS</b>Seven cases with relapsed PCNSL admitted in our hospital between August 2012 and August 2013 were retrospectively reviewed.</p><p><b>RESULTS</b>Of the 7 relapsed cases, ectopic recurrence occurred in 3, in situ recurrence in 3 and leptomeningeal metastasis in 1. Patients with relapsed PCNSL were administered with high-dose pemetrexed (900 mg/m²) once for every 3 weeks and supplemented with folic acid and vitamin B₁₂. Complete remission was obtained in 2 patients, partial remission in 3 patients and progressive disease in 2. The overall response rate was 71.4% (5/7). The main adverse reactions were myelosuppression and gastrointestinal reaction.</p><p><b>CONCLUSION</b>Treatment of relapsed PCNSL is difficult, and its prognosis is very poor. Pemetrexed therapy is a meaningful trial.</p>


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Central Nervous System Neoplasms , Drug Therapy , Pathology , Glutamates , Therapeutic Uses , Guanine , Therapeutic Uses , Lymphoma, Large B-Cell, Diffuse , Drug Therapy , Pathology , Neoplasm Recurrence, Local , Pemetrexed , Prognosis , Retrospective Studies
15.
Sheng Li Xue Bao ; (6): 449-456, 2014.
Article in Chinese | WPRIM | ID: wpr-297472

ABSTRACT

This study was aimed to investigate the mechanisms underlying the modulation effect of Mas-related gene (Mrg) C receptors (MrgC) on morphine tolerance. Saline, morphine (20 μg), morphine plus bovine adrenal medulla 8-22 (BAM8-22, 1 nmol) or (Tyr(6))-2-MSH-6-12 (MSH, 5 nmol) were administered intrathecally in rats for 6 days. Pain-related molecules in the spinal cord and dorsal root ganglion (DRG) were examined using Western blot, immunocytochemistry and RT-PCR techniques. The results showed that intrathecal administration of the selective MrgC receptor agonists (BAM8-22 or MSH) remarkably attenuated or abolished chronic morphine-evoked reduction in glutamate transporters (GLAST, GLT-1 and EAAC1) in the spinal cord and increase in neuronal nitric oxide synthase (nNOS) in the spinal cord as well as DRG. In addition, MrgC receptor-like immunoreactivity (IR) was detected in superficial laminae of the spinal cord. Chronic morphine induced significant increases in MrgC receptor-IR in the spinal cord and MrgC receptor mRNA levels in DRG. These results suggest that the modulation of pro-nociceptive mediators in the spinal cord and DRG underlies the inhibition of morphine tolerance by MrgC receptor activation.


Subject(s)
Animals , Rats , Amino Acid Transport System X-AG , Metabolism , Drug Tolerance , Ganglia, Spinal , Metabolism , Glutamates , Morphine , Pharmacology , Nitric Oxide Synthase Type I , Metabolism , Pain , Pain Measurement , Peptide Fragments , Pharmacology , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled , Metabolism , Spinal Cord , Metabolism
16.
Zhonghua zhong liu za zhi ; (12): 29-33, 2014.
Article in Chinese | WPRIM | ID: wpr-329004

ABSTRACT

<p><b>OBJECTIVE</b>To evaluate the impact of histology on efficacy of pemetrexed in Chinese non-small cell lung cancer (NSCLC) patients. This report summarized the results of two clinical trials of pemetrexed in Chinese patients with advanced NSCLC in 2nd line setting and maintenance setting after 1st line (JMID study and Chinese subgroup from JMEN study) treatment.</p><p><b>METHODS</b>For the Chinese JMID study (second-line), Chinese patients with locally advanced or metastatic (stage IIIA, IIIB or IV) NSCLC who had prior chemotherapy were enrolled. The study was designed to investigate the noninferiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) to docetaxel (75 mg/m(2), day 1 of each 21-day cycle) in terms of overall survival (OS). For the global JMEN study (maintenance), patients initially diagnosed with IIIB or IV NSCLC, those who had not progressed after completing at least four cycles of platinum-based chemotherapy were enrolled to test for the superiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) over placebo with progression free survival (PFS) as primary endpoint.</p><p><b>RESULTS</b>In JMID study, the OS was similar between the pemetrexed group (Pem group) and docetaxel group (Doc group). Retrospective histological subtype analysis showed survival benefits (both OS and PFS) numerically of non-squamous patients over squamous patients in the Pem group (OS: HR 0.74, 95% CI 0.45-1.21, P = 0.2267, median 11.7 vs. 9.7 months; PFS: HR 0.77, 95% CI 0.44-1.34, P = 0.3585, median 3.0 vs. 1.7 months). In the Chinese subgroup of JMEN study, the median PFS in the Pem group for squamous and nonsquamous patients was 4.2 and 1.5 months for squamous patients, the median OS in the Pem group for squamous and nonsquamous patients was 22.5 and 6.2 months for squamous patients. In JMEN China subgroup analysis, the HR on histology was not analyzed due to the small sample size. In terms of safety profile, drug-related grade 3 or 4 hematological toxicities (leukocytopenia and neutropenia) events occurring after second-line treatment were significantly lower in the Pem group than in the Doc group (both P < 0.001). Similarly in patients receiving pemetrexed maintenance after first-line treatment, incidences of toxicity events were low.</p><p><b>CONCLUSIONS</b>Consistent with global results, in Chinese NSCLC patients, histology has an impact on the efficacy of pemetrexed, in which non-squamous histology predicts a positive outcome for patients treated with pemetrexed. In terms of overall safety, pemetrexed is better than docetaxel with a lower incidence of adverse events and anticipates manageable safety profile in NSCLC patients. Based on consistent Chinese data from the two studies, pemetrexed is recommended as a standard chemotherapy regime in both second-line and maintenance setting after first-line treatment for Chinese non-squamous NSCLC patients.</p>


Subject(s)
Humans , Antineoplastic Agents , Therapeutic Uses , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Pathology , China , Disease-Free Survival , Glutamates , Therapeutic Uses , Guanine , Therapeutic Uses , Lung Neoplasms , Drug Therapy , Pathology , Pemetrexed , Treatment Outcome
17.
Chin. med. j ; Chin. med. j;(24): 1545-1549, 2014.
Article in English | WPRIM | ID: wpr-322232

ABSTRACT

<p><b>BACKGROUND</b>Tumor cells can reduce the number of dendritic cells (DCs) in the tumor environment and cause DC dysfunction through autocrine or paracrine pathways. We sought to measure cyclooxygenase-2 (COX-2) expression in bombesin-inhibited DCs treated with theanine in vitro and to explore the protection and activation effects of theanine on DCs.</p><p><b>METHODS</b>Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting were used to analyze the effects of theanine on COX-2 expression and interleukin (IL)-12/IL-10 secretion of bombesin-treated DCs.</p><p><b>RESULTS</b>DCs acquired an impaired phenotype as a result of bombesin treatment. Theanine increased the expression of mature DC surface molecules. The number of cell apoptosis with the treatment of bombesin and theanine significantly decreased, accounting for 15.9%, compared with 26.1% of cell apoptosis with bombesin. COX-2 expression in bombesin-treated DCs was inhibited by theanine in a dose-dependent manner. Theanine promoted DC secretion of IL-12. IL-12 levels reached (137.4 ± 4.9) pg/ml with theanine at 200 µmol/L. However, theanine inhibited the secretion of IL-10 in a dose-dependent manner. IL-10 levels were only (58.4 ± 6.9) pg/ml with theanine at 200 µmol/L.</p><p><b>CONCLUSION</b>Theanine inhibits the transcription and translation of COX-2 and regulates the balance of IL-10/IL-12 secretion in bombesin-inhibited DCs, leading to the recovery of a state of activation in DCs.</p>


Subject(s)
Humans , Bombesin , Pharmacology , Cells, Cultured , Cyclooxygenase 2 , Metabolism , Dendritic Cells , Metabolism , Enzyme-Linked Immunosorbent Assay , Glutamates , Pharmacology , Interleukin-10 , Metabolism , Interleukin-12 , Metabolism
18.
Article in English | WPRIM | ID: wpr-149906

ABSTRACT

The presence of epidermal growth factor receptor (EGFR) mutation is a prognostic and predictive marker for EGFR-tyrosine kinase inhibitor (TKI) therapy. However, inevitably, relapse occurs due to the development of acquired resistance, such as T790M mutation. We report a case of repeated responses to EGFR-TKIs in a never-smoked woman with adenocarcinoma. After six cycles of gemcitabine and cisplatin, the patient was treated by gefitinib for 4 months until progression. Following the six cycles of third-line pemetrexed, gefitinib retreatment was initiated and continued with a partial response for 6 months. After progression, she was recruited for an irreversible EGFR inhibitor trial, and the time to progression was 11 months. Although EGFR direct sequencing on the initial diagnostic specimen revealed a wild-type, we performed a rebiopsy from the progressed subcarinal node at the end of the trial. The result of peptide nucleic acid clamping showed L858R/L861Q.


Subject(s)
Female , Humans , Adenocarcinoma , Cisplatin , Constriction , Deoxycytidine , Epidermal Growth Factor , Glutamates , Guanine , Lung , Lung Neoplasms , Phosphotransferases , Quinazolines , ErbB Receptors , Recurrence , Retreatment , Pemetrexed
19.
Article in English | WPRIM | ID: wpr-148471

ABSTRACT

Most patients with tyrosine kinase inhibitor (TKI)-sensitive non-small cell lung cancer (NSCLC) eventually develop acquired resistance to TKIs. Factors that affect TKI-sensitive patient survival after progression during TKI treatment remain unknown. We attempted to identify factors that affected post-progression survival. We retrospectively reviewed 81 advanced NSCLC patients with disease progression following tumor response and durable (> or = 6 months) disease stabilization with first-line or second-line gefitinib. Post-progression survival (PPS) and characteristics were investigated and compared in patients who did (n = 16) and did not (n = 65) resume TKIs. Most patients were female never-smokers with adenocarcinoma. Median overall PPS was 10.3 months (95% confidence interval [CI], 7.458-13.142). Age, gender, smoking history, histology, Eastern Cooperative Oncology Group performance status at gefitinib initiation, initial stage, and platinum-based chemotherapy after gefitinib were not significant predictors of PPS. Pemetrexed use after gefitinib significantly improved PPS (18.5 vs 8.6 months; hazard ratio [HR], 0.45; P = 0.008). Gefitinib reuse tended to lengthen PPS but was insignificant in multivariate analysis (27.4 vs 8.8 months; HR, 0.53; P = 0.095). NSCLC patients assumed to have clinically acquired resistance to TKIs had relatively long PPS. TKIs reuse or pemetrexed use after progression with gefitinib may improve PPS.


Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Disease-Free Survival , Drug Resistance, Neoplasm , Glutamates/therapeutic use , Guanine/analogs & derivatives , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Retrospective Studies , Survival , Treatment Outcome
20.
Article in English | WPRIM | ID: wpr-213728

ABSTRACT

Pemetrexed is approved as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) with cisplatin and as a single agent for second-line treatment or for patients who show no disease progression after four cycles of platinum-based doublet induction chemotherapy as maintenance therapy. Pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis. Here, we report on a rare case of pemetrexed-induced pneumonitis in a patient with NSCLC.


Subject(s)
Humans , Adenocarcinoma , Carcinoma, Non-Small-Cell Lung , Cisplatin , Disease Progression , Glutamates , Guanine , Induction Chemotherapy , Lung Diseases, Interstitial , Pneumonia , Pemetrexed
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