Publications by authors named "Lingshan Gou"

27 Publications

  • Page 1 of 1

Clinical value for the detection of fetal chromosomal deletions/duplications by noninvasive prenatal testing in clinical practice.

Mol Genet Genomic Med 2021 May 5:e1687. Epub 2021 May 5.

Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, China.

Objective: This study was to report the experiences on the clinical value of noninvasive prenatal testing (NIPT) for the screening of fetal chromosomal deletions/duplications.

Methods: We performed a retrospective analysis of a cohort of 20,439 pregnancies undergoing NIPT from March 2017 to September 2020 at a single center. Patients with positive NIPT results for fetal chromosomal deletions or duplications had options of invasive diagnostic testing or no further testing. The data were complied from all cases with positive NIPT results for chromosomal deletions/duplications. The positive predictive value (PPV) was calculated from tabulated data.

Results: In this cohort, positive NIPT results for fetal chromosomal deletions/duplications were found in 60 pregnant women. Of the positive samples, further invasive testing was performed in 39 cases, in which 9 cases were found to be true positive. The overall PPV for chromosomal deletions/duplications was 23.1%. In addition, fetal structural anomaly was found by ultrasound examination in three cases, in which the chromosomal deletions/duplications of three cases were not verified. Moreover, an unexpected pathogenic 8p23.3 deletion was identified by invasive testing in 1 fetus with a false positive NIPT screen for 3q27.3q29 duplication.

Conclusions: In summary, positive NIPT results of chromosomal deletions/duplications were not uncommon in clinical practice, whereas the PPV for the testing was low. Hence, potential risks and high percentage of false positives for these abnormal NIPT results might be informed to pregnant women before the choice made of invasive testing.
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http://dx.doi.org/10.1002/mgg3.1687DOI Listing
May 2021

Declining Levels of Specialized Synaptic Surface Proteins in nNOS-Expressing Interneurons in Mice Treated Prenatally with Valproic Acid.

Neurochem Res 2021 Jul 19;46(7):1794-1800. Epub 2021 Apr 19.

Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, China.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorder characterized by impaired social interaction, and repetitive or restricted interests and behaviors. Membrane proteins are a significant part of the proteins in cell and play key functions in synaptic transmission. We have recently shown that neuronal nitric oxide synthase (nNOS) expression was reduced in the basolateral amygdala (BLA) of mice following postnatal valproic acid (VPA) exposure. In the current study, we utilized a label-free proteomics approach to identify and quantify surface protein expression in nNOS-positive interneurons between VPA-treated and control mice. Western blot was used to confirm the expression of selected membrane proteins. Our proteomics data revealed differentially expressed surface proteins in nNOS interneurons, e.g. Narp, AMPA-type glutamate (AMPA) receptor subunit GluA4 and Protein kinase C gamma (PKCγ), which were validated by Western blotting in mice treated with VPA. This work will pave the way for further elucidation of the mechanisms of these differentially membrane proteins in nNOS interneurons-medicated ASD.
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http://dx.doi.org/10.1007/s11064-021-03326-wDOI Listing
July 2021

Troxerutin Improves Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.

J Agric Food Chem 2021 Mar 23;69(9):2729-2744. Epub 2021 Feb 23.

Department of Cell Biology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221009, Jiangsu, China.

Screening potential compounds for improving ulcerative colitis (UC) from clinical medication is an effective strategy for drug repurposing. We applied bioinformatics and network pharmacology to the drug screening process in this study, which helped us to screen out troxerutin that could improve UC. Troxerutin belongs to flavonoids and is used clinically as an anticoagulant and thrombolytic agent. This study found a new pharmacological activity of troxerutin, that is, it had a significant improvement effect on UC in mice. Experimental results of and levels showed that troxerutin could effectively reduce the level of oxidative stress that caused damages in intestinal epithelial cells and colonic tissue, maintain the distribution and expression of tight junction-related proteins, and protect the barrier function of colon tissue. In addition to the oxidative stress, severe inflammatory response is also an important pathological factor that aggravates UC. However, troxerutin could reduce the infiltration of inflammatory cells in the colon tissue and decrease the expression of inflammation-related proteins and proinflammatory cytokines. Due to its antioxidant and anti-inflammatory effects, troxerutin inhibited the process of cell apoptosis in the colon tissue and relieved the degree of colonic fibrosis. Bioinformatics analysis showed that the ameliorating effect of troxerutin on UC was probably related to its network regulation of signaling pathways. In summary, we discovered a new pharmacological activity of the flavonoid troxerutin against UC, which is conducive to the expansion and application of flavonoids in the treatment of human diseases.
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http://dx.doi.org/10.1021/acs.jafc.0c06755DOI Listing
March 2021

Clinical utilization of chromosomal microarray analysis for the genetic analysis in subgroups of pregnancy loss.

J Matern Fetal Neonatal Med 2020 Nov 23:1-8. Epub 2020 Nov 23.

Center for Genetic Medicine, Maternity and Child Health Care Hospital, Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China.

Objective: The underlying etiologies of pregnancy loss are heterogeneous and in many cases unexplained. This study was to explore the genetic causes of early and late pregnancy loss using chromosomal microarray analysis (CMA).

Methods: A cohort of 222 specimens of conceptions underwent genetic analysis using Affymetrix CytoScan 750 K arrays, which includes both SNP markers and copy number markers.

Results: Of the 222-products of conception (POC), the overall detection rate for clinical significantly chromosomal anomalies was 40.54%, including 53 autosomal aneuploidy (23.87%), 16 sex chromosome aneuploidy (7.21%), 5 mutiple aneuploidy (2.25%), 4 triploidy (1.80%), and 12 pathogenic copy number variants (pCNVs) (5.41%). In addition, variants of uncertain significance and loss of heterozygosity were detected in 9 samples and 2 samples, respectively. The detection rates for total chromosomal abnormalities, autosomal aneuploidy, sex chromosome aneuploidy, multiple aneuploidy, and triploidy in specimens of early pregnancy loss was higher than that of late pregnancy loss, while had lower detection rate of pCNVs. Moreover, the detection rate in POC of mothers younger than 35 years was lower than that of advanced maternal age. The detection rate was 40.57% in POC of mothers with adverse pregnancy histories, in which was comparable with that of mothers without adverse pregnancy histories.

Conclusions: CMA yielded a superior detection rate in early pregnancy loss than that of late pregnancy loss. Moreover, the incidence of chromosome abnormality in cases with advanced maternal age was higher than that of cases with younger maternal age, while adverse pregnancy history seemed not to be the factors affecting the detection rate for chromosomal abnormality in pregnancy loss.
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http://dx.doi.org/10.1080/14767058.2020.1849126DOI Listing
November 2020

Clinical management of pregnancies with positive screening results for rare autosomal aneuploidies at a single center.

J Int Med Res 2020 Nov;48(11):300060520966877

Center for Genetic Medicine, Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China.

Objective: To review our experiences on clinical management of pregnancies with positive noninvasive prenatal testing (NIPT) results for rare autosomal aneuploidies (RAAs) at a single center.

Methods: We performed a retrospective study and reviewed data from 18,016 pregnancies undergoing NIPT at a single center in China from March 2017 to February 2020. Depending on the patient's choice, women with positive screening results for RAAs underwent chromosomal microarray analysis for invasive prenatal diagnosis.

Results: Thirty-three positive cases for RAAs were identified, with a positive screening rate of 0.18%. The most common RAA was trisomy 7 (33.3%), while trisomies for other chromosomes were less frequent. Monosomies involving chromosomes 16, 14, and 22 were observed. Twenty-eight cases of RAAs underwent invasive diagnosis. Abnormal pregnancy outcomes were observed in four cases, including true fetal mosaicism (n=1), partial uniparental disomy (n=1), miscarriage (n=1), and structural anomalies on ultrasound (n=1).

Conclusions: RAAs at NIPT might be associated with fetal uniparental disomy, mosaic aneuploidy, and poor pregnancy outcomes, but most positive cases have normal pregnancy outcomes. For RAAs, genetic counseling on the potential risks of abnormal NIPT results, as well as on benefits and limitations of invasive prenatal diagnosis, might help guide clinical management.
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http://dx.doi.org/10.1177/0300060520966877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658522PMC
November 2020

Neuronal Nitric Oxide Synthase Knockdown Within Basolateral Amygdala Induces Autistic-Related Phenotypes and Decreases Excitatory Synaptic Transmission in Mice.

Front Neurosci 2020 31;14:886. Epub 2020 Aug 31.

People's Hospital Affiliated to Henan University of Chinese Medicine, Zhengzhou, China.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviors. We have recently shown that neuronal nitric oxide synthase (nNOS) expression was reduced in the basolateral amygdala of mice after postnatal valproic acid exposure. However, the specific role of nNOS downregulation in mice remains to be elucidated. Herein, we investigated the behavioral alternations of naive mice with a recombinant adeno-associated virus (rAAV)-mediated knockdown of nNOS in a comprehensive test battery, including the social interaction, marble burying, self-grooming, and open field tests. Further, the electrophysiological and surface expression changes induced by nNOS deficiency of the basolateral amygdala in these animals were examined. Our results show that nNOS knockdown displayed typical symptoms of ASD-like behaviors, such as reduced social interaction and communication, elevated stereotypes, and anxiety in mice. Surprisingly, we found that nNOS knockdown exhibited greatly reduced excitatory synaptic transmission concomitant with the lower surface expression of GluN2B-containing N-methyl-D-aspartate receptors and postsynaptic density protein 95 in mice. These findings support a notion that dysregulation of nNOS might contribute to ASD-associated phenotypes, with disease pathogenesis most likely resulting from deficits in excitatory synaptic transmission.
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http://dx.doi.org/10.3389/fnins.2020.00886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488195PMC
August 2020

Bilateral Hearing Loss and Unilateral Cochlear Ossification in a Patient With Chronic Myelogenous Leukemia.

Ear Nose Throat J 2021 Jun 24;100(3_suppl):301S-303S. Epub 2020 Sep 24.

Department of Otolaryngology, Longgang E.N.T. Hospital, Longgang, Shenzhen, Guangdong, China.

Bilateral sensorineural deafness and unilateral cochlear ossification have rarely been described in patients with chronic myeloid leukemia (CML). A 21-year-old man presented to a hospital with right-sided sudden hearing loss and tinnitus. He was diagnosed with CML. Five days later, sudden hearing loss appeared in the other ear. Abnormality of the right-sided inner ear structure was revealed by preoperative magnetic resonance imaging; honeycomb-like cochlear ossification was observed during cochlear implant surgery in the right ear. The patient's auditory performance exhibited significant improvement after bilateral cochlear implantation in our hospital. Hematological disorders must be considered in patients with sensorineural hearing loss. Cochlear implantation is feasible in patients with CML who exhibit sensorineural deafness, but cochlear ossification should be carefully evaluated by means of preoperative imaging examinations.
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http://dx.doi.org/10.1177/0145561320961073DOI Listing
June 2021

RalA exerts an inhibitory effect on IL-1β/IL-18 secretion by blocking NLRP3 inflammasome activation in levornidazole-treated human THP-1 macrophages.

Int Immunopharmacol 2020 Nov 28;88:106898. Epub 2020 Aug 28.

Department of Cell Biology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221009, Jiangsu, China. Electronic address:

The NLRP3 inflammasome is an important mediator of inflammatory responses and its regulation is an active area of research. RalA is a Ras-like GTPase, which play pivotal roles in the biology of cells. So far, there have been very few studies on RalA regulating inflammatory responses. Bioinformatics analysis predicted that RalA might participate in the regulatory network of NLRP3 inflammasome, which has been confirmed in THP-1 macrophages. After virtual screening of compounds, it was found that levonidazole selected from our virtual small molecule compound library has the potential to bind to RalA. Of note, the interaction of RalA/levornidazole was verified by Surface Plasmon Resonance-Biacore T200, LC/MS analysis and Western blotting analysis. Molecular dynamics simulations revealed that the conformational changes of RalA might be regulated by levornidazole. Additionally, IL-1β/IL-18 secretion from ATP + LPS stimulated THP-1-derived macrophages was RalA-dependently suppressed by levornidazole, suggesting that RalA might have an inhibitory effect on NLRP3 inflammasome activation. The results of co-immunoprecipitation and RalA depletion experiments showed that levornidazole could induce RalA to block the assembly of NLRP3/ASC/pro-caspase-1 complex, thereby reducing the levels of cleaved-caspase-1 and IL-1β/IL-18 secretion. Our study has suggested an anti-inflammatory function of RalA and identified its targeting chemical compound. Overall, this study clarifies a novel pharmacological mechanism by which RalA/levornidazole inhibits NLRP3 inflammasome activation and IL-1β/IL-18 secretion.
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http://dx.doi.org/10.1016/j.intimp.2020.106898DOI Listing
November 2020

Inhibition of acetyl-CoA carboxylase by PP-7a exerts beneficial effects on metabolic dysregulation in a mouse model of diet-induced obesity.

Exp Ther Med 2020 Jul 29;20(1):521-529. Epub 2020 Apr 29.

Jiangsu Province Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.

Acetyl-coenzyme A carboxylase (ACC) is a critical regulator of fatty acid metabolism and represents a promising therapeutic target for metabolic diseases, including obesity, type 2 diabetes and non-alcoholic fatty liver disease. Recently, a novel ACC inhibitor, PP-7a, was developed by our group by utilizing a structure-based drug design. In the present study, the pharmacological effects of PP-7a on the metabolic dysregulation in mice with high-fat diet (HFD)-induced obesity and the underlying mechanisms were investigated. The inhibitory effect on ACC activities was confirmed by assessing the level of malonyl-CoA, a product synthesized by the catalyzation of ACC. Following 16 weeks of being fed an HFD, the mice were administered PP-7a (15, 45 or 75 mg/kg) for 4 weeks. The effects of PP-7a on weight gain, glucose intolerance, hepatic lipid accumulation and the increase of serum triglyceride (TG), total cholesterol (TC) and free fatty acids (FFA) in mice were assessed. CP-640186 was used as a positive control drug and administered in the same manner as PP-7a. Chronic administration of PP-7a lowered the malonyl-CoA levels in liver and heart tissues of mice in the HFD group. In addition, HFD-induced weight gain and glucose intolerance were improved by PP-7a treatment in the mice fed the HFD. Furthermore, PP-7a suppressed hepatic lipid accumulation and the increase in TG, TC and FFA levels. Taken together, these results suggest that ACC inhibition by PP-7a may have a beneficial effect on metabolic dysregulation in obese mice.
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http://dx.doi.org/10.3892/etm.2020.8700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296295PMC
July 2020

Roseotoxin B alleviates cholestatic liver fibrosis through inhibiting PDGF-B/PDGFR-β pathway in hepatic stellate cells.

Cell Death Dis 2020 06 15;11(6):458. Epub 2020 Jun 15.

Department of Cell Biology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221009, Jiangsu, China.

Identifying effective anti-fibrotic therapies is a major clinical need that remains unmet. In the present study, roseotoxin B was shown to possess an improving effect on cholestatic liver fibrosis in bile duct-ligated mice, as proved by histochemical and immunohistochemical staining, hepatic biochemical parameters, and TUNEL apoptotic cell detection in tissue sections. Using cellular thermal shift assay, computational molecular docking, microscale thermophoresis technology, and surface plasmon resonance biosensor, we confirmed that PDGFR-β was a direct target of roseotoxin B in fibrotic livers. Of note, human tissue microarrays detected pathologically high expression of p-PDGFR-β in liver samples of ~80% of patients with liver fibrosis and cirrhosis. PDGF-B/PDGFR-β pathway promotes transdifferentiation and excessive proliferation of hepatic stellate cells (HSCs), which is a very crucial driver for liver fibrosis. Meaningfully, roseotoxin B blocked the formation of PDGF-BB/PDGFR-ββ complex by targeting the D2 domain of PDGFR-β, thereby inhibiting the PDGF-B/PDGFR-β pathway in HSCs. In summary, our study provided roseotoxin B as a unique candidate agent for the treatment of liver fibrosis.
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http://dx.doi.org/10.1038/s41419-020-2575-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296008PMC
June 2020

Endothelial TFEB (Transcription Factor EB) Restrains IKK (IκB Kinase)-p65 Pathway to Attenuate Vascular Inflammation in Diabetic db/db Mice.

Arterioscler Thromb Vasc Biol 2019 04;39(4):719-730

From the Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences (W.S., C.-L.Z., L.G., L.H., Y.-Y.G., Q.D., L.Z., L.W., X.Y.T., J.-Y.L., Y.H.).

Objective- TFEB (transcription factor EB) was recently reported to be induced by atheroprotective laminar flow and play an anti-atherosclerotic role by inhibiting inflammation in endothelial cells (ECs). This study aims to investigate whether TFEB regulates endothelial inflammation in diabetic db/db mice and the molecular mechanisms involved. Approach and Results- Endothelial denudation shows that TFEB is mainly expressed in ECs in mouse aortas. Western blotting shows TFEB total protein level decreases whereas the p-TFEB S142 (phosphorylated form of TFEB) increases in db/db mouse aortas, suggesting a decreased TFEB activity. Adenoviral TFEB overexpression reduces endothelial inflammation as evidenced by decreased expression of vascular inflammatory markers in db/db mouse aortas, and reduced expression of a wide range of adhesion molecules and chemokines in human umbilical vein ECs. Monocyte attachment assay shows TFEB suppresses monocyte adhesion to human umbilical vein ECs. RNA sequencing of TFEB-overexpressed human umbilical vein ECs suggested TFEB inhibits NF-κB (nuclear factor-kappa B) signaling. Indeed, luciferase assay shows TFEB suppresses NF-κB transcriptional activity. Mechanistically, TFEB suppresses IKK (IκB kinase) activity to protect IκB-α from degradation, leading to reduced p65 nuclear translocation. Inhibition of IKK by PS-1145 abolished TFEB silencing-induced inflammation in human umbilical vein ECs. Lastly, we identified KLF2 (Krüppel-like factor 2) upregulates TFEB expression and promoter activity. Laminar flow experiment showed that KLF2 is required for TFEB induction by laminar flow and TFEB is an anti-inflammatory effector downstream of laminar flow-KLF2 signaling in ECs. Conclusions- These findings suggest that TFEB exerts anti-inflammatory effects in diabetic mice and such function in ECs is achieved by inhibiting IKK activity and increasing IκBα level to suppress NF-κB activity. KLF2 mediates TFEB upregulation in response to laminar flow.
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http://dx.doi.org/10.1161/ATVBAHA.119.312316DOI Listing
April 2019

Application of karyotype analysis combined with BACs-on-Beads for prenatal diagnosis.

Exp Ther Med 2018 Oct 6;16(4):2895-2900. Epub 2018 Aug 6.

Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, Jiangsu 221009, P.R. China.

This study explored the clinical application of karyotype analysis combined with BACs-on-Beads (BoBs) technology in prenatal diagnosis. A total of 558 pregnant women who were admitted to Xuzhou Maternity and Child Health Care Hospital from July 2015 to June 2017 were enrolled in this study. All the subjects underwent amniocentesis. BoBs assay was performed for subjects in the observation group, and karyotype analysis was performed for subjects in the control group. The main technical indicators of subjects in the two groups were summarized, and cases of chromosome abnormalities were further evaluated. Clinical follow-up of their pregnancy and neonatal birth was undertaken. Finally, the chromosomal manifestations of these patients were compared with those of normal male and normal female, as well as common chromosomal abnormalities. All 558 pregnant women underwent amniocentesis again. Karyotype analysis combined with BoBs assay of amniotic fluid was performed. Cases of chromosomal abnormalities detected were: 75 cases of trisomy 21, 20 cases of trisomy 18, 1 case of trisomy 13, 27 cases of sex chromosomal abnormalities, 12 cases of balanced chromosome translocation, and 2 cases of chromosome microdeletion. The results indicated that karyotype analysis combined with BoBs technology for prenatal diagnosis was easy to perform, and provided quick results with high accuracy. The two testing methods were complementary to each other, which significantly improved the diagnostic rate of chromosomal abnormalities thus reducing birth defects and guiding continued pregnancy of high-risk pregnant women.
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http://dx.doi.org/10.3892/etm.2018.6574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125840PMC
October 2018

Decreased Number and Expression of nNOS-Positive Interneurons in Basolateral Amygdala in Two Mouse Models of Autism.

Front Cell Neurosci 2018 13;12:251. Epub 2018 Aug 13.

Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, China.

The basolateral amygdala (BLA) controls socio-emotional behaviors and is involved in the etiology of autism. We have recently shown that virtually every neuronal nitric oxide synthase (nNOS) positive cell is a GABAergic inhibitory interneuron in the mouse BLA. Here, stereology was used to quantify the number of nNOS-expressing interneurons in valproic acid (VPA)-exposed C57BL/6J (B6) and BTBR TItpr3/J (BTBR) mice models of autism. Additionally, the protein and mRNA levels of nNOS in the BLA were quantitatively assessed by western blot and qRT-PCR analysis, respectively. Our results showed the decreased number of nNOS interneurons in the BLA of animal models relative to autism. Consistently, nNOS was significantly reduced in the VPA-exposed and BTBR mice at both protein and mRNA levels. Together, these preliminary findings suggest that down-regulation of nNOS may be an attractive target for the pharmacological intervention in autism.
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http://dx.doi.org/10.3389/fncel.2018.00251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099087PMC
August 2018

Non-invasive prenatal testing in detecting sex chromosome aneuploidy: A large-scale study in Xuzhou area of China.

Clin Chim Acta 2018 Jun 12;481:139-141. Epub 2018 Mar 12.

Center for Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, Jiangsu, China. Electronic address:

Background: Cell-free fetal DNA are widely used in the prenatal genetic testing during recent years. In the present study, we tried to investigate the clinical practical feasibility of non-invasive prenatal testing (NIPT) for prenatal sex chromosome aneuploidy (SCA) analysis among pregnancies in Xuzhou area of China.

Methods: Among a cohort of 8384 pregnancies, maternal plasma samples from our prenatal diagnosis center was subject to the analysis for SCA using NIPT detection. The cases with positive screening results by NIPT detection were validated on karyotyping analysis.

Results: From 8384 clinical pregnancies, 64 cases exhibited abnormal results detected by NIPT, in which 34 cases were false positive verified by amniotic fluid puncture and chromosome karyotyping analysis. Twelve positive Turner syndrome (monosomy X) cases in NIPT was confirmed to be sex chromosome abnormal by karyotyping analysis, in which included 9 cases of monosomy X, 1 case of mosaic (45X/47XXX), and 2 cases of mosaic with 45X/45XY karyotype. Of those 9 cases with 47XXX, 5 cases were found to be true positive. Among the ten cases of Klinefelter's syndrome (47XXY) indicated by NIPT, 6 cases (60%) were true positive. Lastly, NIPT indicated 47XYY in 9 cases. Karyotyping analysis found six cases were 47XYY, and one case was mosaic (46XY/47XYY).

Conclusion: Our findings showed that the true positive rate for monosomy X was lower by NIPT detection, while prediction of other SCA was relatively accurate. Therefore, NIPT could be a potential method for SCA screening, while this technique needed to be further investigated.
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http://dx.doi.org/10.1016/j.cca.2018.03.007DOI Listing
June 2018

Inhibition of miR-92a Suppresses Oxidative Stress and Improves Endothelial Function by Upregulating Heme Oxygenase-1 in db/db Mice.

Antioxid Redox Signal 2018 02 7;28(5):358-370. Epub 2017 Aug 7.

1 Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences , Hong Kong, China .

Aims: Inhibition of microRNA-92a (miR-92a) is reported to suppress endothelial inflammation and delay atherogenesis. We hypothesize that miR-92a inhibition protects endothelial function through suppressing oxidative stress in diabetic db/db mice.

Results: In this study, we found elevated expression of miR-92a in aortic endothelium from db/db mice and in renal arteries from diabetic subjects. Endothelial cells (ECs) exposed to advanced glycation end products (AGEs) and oxidized low-density lipoprotein express higher level of miR-92a. Overexpression of miR-92a impairs endothelium-dependent relaxations (EDRs) in C57BL/6 mouse aortas. Overexpression of miR-92a suppresses expression of heme oxygenase-1 (HO-1), a critical cytoprotective enzyme, whereas inhibition of miR-92a increases HO-1 expression in human umbilical vein ECs (HUVECs) and db/db mouse aortas. Importantly, miR-92a inhibition by Ad-anti-miR-92a improved EDRs and reduced reactive oxygen species (ROS) production in db/db mouse aortas. HO-1 inhibition by SnMP or HO-1 knockdown by shHO-1 reversed the suppressive effect of miR-92a inhibition on ROS production induced by AGE treatment in C57BL/6 mouse aortas. In addition, SnMP reversed miR-92a inhibition-induced improvement of EDRs in AGE-treated C57BL/6 mouse aortas and in db/db mouse aortas.

Innovation: Expression of miR-92a is increased in diabetic aortic endothelium and inhibition of miR-92a exerts vasoprotective effect in diabetic mice through HO-1 upregulation in ECs.

Conclusion: MiR-92a expression is elevated in diabetic ECs. MiR-92a overexpression impairs endothelial function and suppresses HO-1 expression in ECs. Inhibition of miR-92a attenuates oxidative stress and improves endothelial function through enhancing HO-1 expression and activity in db/db mouse aortas. Antioxid. Redox Signal. 28, 358-370.
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http://dx.doi.org/10.1089/ars.2017.7005DOI Listing
February 2018

Bone Morphogenic Protein 4-Smad-Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function.

Arterioscler Thromb Vasc Biol 2016 Mar 14;36(3):553-60. Epub 2016 Jan 14.

From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China.

Objective: Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus.

Approach And Results: We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4. BMP4-impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from db/db mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFRα.

Conclusions: The present study provides novel evidences to show that PDGF-AA impairs endothelium-dependent vasodilation and PDGF-AA mediates BMP4-induced adverse effect on endothelial cell function through SMAD1/5- and SMAD4-dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction in diabetic mice.
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http://dx.doi.org/10.1161/ATVBAHA.115.306302DOI Listing
March 2016

Protective role of luteolin against cognitive dysfunction induced by chronic cerebral hypoperfusion in rats.

Pharmacol Biochem Behav 2014 Nov 16;126:122-30. Epub 2014 Sep 16.

School of Pharmacy, Xuzhou Medical College, Xuzhou, 221004 Jiangsu Province, PR China. Electronic address:

Chronic cerebral hypoperfusion, a mild ischemic condition, is associated with the cognitive deficits of Alzheimer's disease (AD). Luteolin, a polyphenolic compound found in foods of plant origin, belonging to the flavone subclass of flavonoids, has been shown to possess antioxidant, anti-inflammatory and antitumorigenic properties. In the present study, the effects of luteolin on chronic cerebral hypoperfusion-associated neurocognitive pathologies were investigated by using rats with permanent bilateral common carotid artery occlusion, a rat model of chronic cerebral hypoperfusion. As expected, we found that luteolin could attenuate cognitive dysfunction in chronic cerebral hypoperfused rats, as assessed using Morris water maze tests. Daily oral administration of luteolin (50, 100 and 200mg/kg) significantly scavenged oxygen free radicals, enhanced antioxidant potential, decreased the lipid peroxide production and suppressed inflammatory reaction in the cerebral cortex and hippocampus induced by chronic cerebral hypoperfusion. Meanwhile, the results indicated that cerebral hypoperfusion activated nuclear factor-κB (NF-κB), increased the expression of β-site amyloid precursor protein cleaving enzyme (BACE1), as well as elevated amyloid beta (Aβ) levels in the cortex and hippocampus. However, long-term administration of luteolin significantly down-regulated the expression of NF-κB and BACE1, accompanied by diminishing the deposition of Aβ. Our results suggest a potential therapeutic use of luteolin for cerebral hypoperfusion associated cognitive dysfunction in AD.
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http://dx.doi.org/10.1016/j.pbb.2014.09.005DOI Listing
November 2014

Beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral ischemia-reperfusion injury in rats.

Can J Physiol Pharmacol 2013 Jul 15;91(7):562-9. Epub 2013 Apr 15.

Xuzhou Medical College, Department of Pharmacology, School of Pharmacy, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou 221002, China.

Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and anti-inflammatory properties.
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http://dx.doi.org/10.1139/cjpp-2012-0309DOI Listing
July 2013

Luteolin attenuates diabetes-associated cognitive decline in rats.

Brain Res Bull 2013 May 13;94:23-9. Epub 2013 Feb 13.

Department of Pharmacy, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, Jiangsu 221002, China.

Diabetes mellitus can cause dysfunction of the central nervous system called "diabetic encephalopathy". Although various oral drugs are used to treat diabetes, they do not prevent the development of diabetes-associated cognitive decline in rats, and novel strategies for the prevention and treatment are urgently needed. Luteolin, a flavonoid isolated from Cirsium japonicum, has antioxidant, anti-inflammatory and neuroprotective activities. However, no report is available on influence of luteolin on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze test. Nissl's staining, choline esterase (ChE) activity as marker of cholinergic function and oxidative stress were assessed in the cerebral cortex and hippocampus to evaluate the neuropathological changes and the effects of luteolin on diabetic rats. The results showed that streptozotocin-induced diabetes produced obvious neuron damage and cognitive dysfunction coupling with markedly increased oxidative stress and ChE activity in the brain. In contrast, chronic treatment with luteolin (50 and 100mg/kg) improved neuronal injury and cognitive performance by attenuating oxidative stress and ChE activity in diabetic rats. In conclusion, the present study suggested that oral supplementation of luteolin might be a potential therapeutic strategy for the treatment and/or prevention of diabetic encephalopathy.
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http://dx.doi.org/10.1016/j.brainresbull.2013.02.001DOI Listing
May 2013

Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice.

Brain Res 2013 Mar 5;1503:24-32. Epub 2013 Feb 5.

Department of Pharmacy, Xuzhou Medical College, Jiangsu, China.

The present work was aimed to study the protective effect of l-theanine on chronic restraint stress (CRS)-induced cognitive impairments in mice. The stress was produced by restraining the animals in well-ventilated polypropylene tubes (3.2 cm in diameter ×10.5 cm in length) for 8h once daily for 21 consecutive days. L-theanine (2 and 4 mg/kg) was administered 30 min before the animals subjected to acute immobilized stress. At week 4, mice were subjected to Morris water maze and step-through tests to measure the cognitive function followed by oxidative parameters and corticosterone as well as catecholamines (norepinephrine and dopamine) subsequently. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters and catecholamine levels in the hippocampus and the cerebral cortex as well as corticosterone and catecholamine levels in the serum. However, not only did l-theanine treatment exhibit a reversal of the cognitive impairments and oxidative damage induced by CRS, but also reversed the abnormal level of corticosterone in the serum as well as the abnormal levels of catecholamines in the brain and the serum. This study indicated the protective effect of l-theanine against CRS-induced cognitive impairments in mice.
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http://dx.doi.org/10.1016/j.brainres.2013.01.048DOI Listing
March 2013

L-citrulline protects against glycerol-induced acute renal failure in rats.

Ren Fail 2013 31;35(3):367-73. Epub 2013 Jan 31.

Department of Pharmacy, Xuzhou Medical College, Xuzhou, China.

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.
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http://dx.doi.org/10.3109/0886022X.2012.760408DOI Listing
December 2013

Antidepressant-like effects of tea polyphenols on mouse model of chronic unpredictable mild stress.

Pharmacol Biochem Behav 2013 Mar 2;104:27-32. Epub 2013 Jan 2.

School of Pharmacy, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, PR China.

Tea polyphenols (TPs), which are the natural compounds extracted from tea leaves, possess a number of beneficial properties, such as reducing the risks of cancer and heart diseases, alleviating cognitive impairments and showing antidepressant-like activity in the forced swim test (FST) and tail suspension test (TST). The present study was designed to investigate the protective effect of TPs on the chronic unpredictable mild stress (CUMS)-induced depression model in mice and to elucidate the related underlying mechanisms. With the daily exposure to stressor for 5 consecutive weeks, TPs were administered in mice at a daily dose of 25 mg/kg or 50 mg/kg by gavage for 3 consecutive weeks from the 3rd week. Our results showed that CUMS significantly decreased the levels of serum serotonin (5-HT) and norepinephrine (NE) in the hippocampus, the prefrontal cortex and serum, and the activities of superoxide dismutase (SOD) and catalase (CAT), with an increase in lipid peroxidation level as well as a reduction in glutathione (GSH) level and an elevation in the production of malondialdehyde (MDA) in the hippocampus and the prefrontal cortex. CUMS also reduced open-field activity, sucrose consumption, as well as increased immobility duration in FST and TST. TPs administration could effectively reverse the alterations in the concentrations of 5-HT and NE, elevate the activities of SOD and CAT as well as the level of GSH, reduce the MDA level and inhibit lipid peroxidation. Moreover, TPs could effectively reverse alterations in immobility duration, sucrose consumption and open-field activity. In conclusion, TPs administration has exhibited significant antidepressant-like effects in mice with CUMS-induced depression. The antidepressant activity of TPs might be related to the alteration of monoaminergic responses and antioxidant defenses.
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http://dx.doi.org/10.1016/j.pbb.2012.12.024DOI Listing
March 2013

Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice.

Pharmacol Biochem Behav 2013 Jan 28;103(3):474-80. Epub 2012 Sep 28.

Department of Pharmacology, School of Pharmacy, Xuzhou Medical College, Xuzhou 221004, China.

The present study was aimed to investigate the effects of nizofenone administration on the chronic restraint stress-induced cognitive impairments in mice. Adult male mice were randomized into five groups: control group, nizofenone control group, chronic restraint stress group, and nizofenone treatment groups (3.0mg/kg and 9.0mg/kg). The changes of cognitive performances were examined by Morris water maze (MWM), open field and step-through tests. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters, acetylcholinesterase activity and catecholamines levels in the hippocampus and the prefrontal cortex. These changes could be reversed by nizofenone treatment. Moreover, CRS group showed higher corticosterone levels and lower catecholamines levels in the serum, which were reversed in the nizofenone treatment groups. Collectively, the present results suggested the potential of nizofenone in attenuating the CRS-induced cognitive impairments.
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http://dx.doi.org/10.1016/j.pbb.2012.09.009DOI Listing
January 2013

Protective effect of l-citrulline against ethanol-induced gastric ulcer in rats.

Environ Toxicol Pharmacol 2012 Sep 11;34(2):280-287. Epub 2012 May 11.

Department of Pharmacy, Xuzhou Medical College, Jiangsu, China. Electronic address:

We examined the protective effect of l-citrulline on ethanol-induced gastric ulcer in rats. Administration of l-citrulline at doses of 300, 600 and 900mg/kg body weight prior to ethanol ingestion protected the stomach from ulceration. The gastric lesions were significantly attenuated by all doses of l-citrulline as compared to the ethanol group. Pre-treatment with l-citrulline prevented the oxidative damage and the decrease of nitric oxide content as well as the increase of the myeloperoxidase activity. Consequently, significant changes observed included the attenuation in the elevation in total nitric oxide synthase activity and inducible nitric oxide synthase activity as well as the decrease in constitutive nitric oxide synthase activity in the gastric mucosa induced by ethanol. Analysis of serum cytokines of ethanol-induced rats showed a moderate decrease in interleukin-10 with considerable increase of interleukin-6 while l-citrulline inhibited the acute alteration of cytokines. These results suggested the gastroprotective effect of l-citrulline.
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http://dx.doi.org/10.1016/j.etap.2012.04.009DOI Listing
September 2012

A preliminary study on protective effect of L-citrulline against ischemia-reperfusion induced gastric mucosal lesions in rat.

Indian J Pharmacol 2012 Jan;44(1):31-5

School of Pharmacy, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, Jiangsu, China.

Objectives: This study was designed to investigate the gastroprotective effect of L-citrulline against gastric ischemia-reperfusion injury.

Materials And Methods: Sodium pentobarbital-anesthetized rats underwent occlusion of the celiac artery for 30 min, followed by 60 min of reperfusion. Sixty minutes before ischemia, L-citrulline at doses of 300, 600, 900 mg/kg was administered intragastrically. Based on this animal model of gastric ischemia-reperfusion injury, the gastroprotective effect of L-citrulline was assessed by determining and comparing the ulcerative index and the estimation of myeloperoxidase (MPO) activity and malondialdehyde (MDA) level in the gastric mucosal tissues. Moreover, the expression of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) protein was also determined.

Results: Intragastric administration of L-citrulline (600 and 900 mg/kg) 60 min before ischemia significantly ameliorated the gastric mucosal damage and inhibited the increase in MPO and MDA contents. Also, the increase in expression of iNOS protein was also prevented by L-citrulline. The expression of nNOS and eNOS was not affected significantly by I/R or L-citrulline.

Conclusion: The results suggest that L-citrulline, administered exogenously, exhibits gastric protection by inhibition of neutrophil infiltration in rats, which may be related in prevention of the increase in iNOS activity.
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http://dx.doi.org/10.4103/0253-7613.91863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271535PMC
January 2012

Protective effect of L-citrulline against acute gastric mucosal lesions induced by ischemia-reperfusion in rats.

Can J Physiol Pharmacol 2011 May 27;89(5):317-27. Epub 2011 May 27.

Xuzhou Medical College, School of Pharmacy, Xuzhou Medical College, Jiangsu, PR China.

The present study investigated the protective effect of L-citrulline on gastric mucosal injury induced by ischemia-reperfusion (IR) in rats. Under anesthesia, the celiac artery was clamped for 30 min, and then the clamp was removed for 60 min reperfusion. Sixty minutes before ischemia, L-citrulline was administered intragastrically at doses of 300, 600, and 900 mg/kg. After the experiment, the stomachs were removed for biochemical and histological examinations. Pretreatment with L-citrulline (300, 600, and 900 mg/kg) significantly ameliorated the gastric damage caused by IR. Moreover, L-citrulline prevented the production of lipid peroxidation and inhibited the increase of myeloperoxidase activity. The elevation in total nitric oxide synthase (NOS) activity, inducible NOS activity, and inducible NOS protein expression as well as the decrease in constitutive NOS activity and gastric mucus level in the gastric mucosa induced by IR were significantly prevented. However, the protective effect mediated by L-citrulline was significantly antagonized by coadministration of L-nitroarginine methyl ester (10 mg/kg, s.c.). These results suggest that part of the mechanism of gastric protection by L-citrulline might be through inhibiting neutrophil infiltration and preserving gastric mucus synthesis and secretion in rats, functions that are closely related to the maintenance of constitutive NOS activity.
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http://dx.doi.org/10.1139/y11-027DOI Listing
May 2011

Antidepressant-like effects of L-theanine in the forced swim and tail suspension tests in mice.

Phytother Res 2011 Nov 21;25(11):1636-9. Epub 2011 Mar 21.

School of Pharmacy, Xuzhou Medical College, 84 West Huai'hai Road, Xuzhou, Jiangsu 221002, China.

L-theanine (γ-glutamylethylamide), an amino acid component of green tea, has been shown to reduce mental and physical stress, and to improve memory function. In this study, the antidepressant effect of L-theanine was investigated in mice using the forced swim test, tail suspension test, open-field test and reserpine test. L-theanine produced an antidepressant-like effect, since the administration of L-theanine at doses of 1, 4 and 20 mg/kg for 10 successive days significantly reduced the immobility time in both the forced swim test and tail suspension test, compared with the control group, without accompanying changes in ambulation in the open-field test. Moreover, L-theanine significantly antagonized reserpine-induced ptosis and hypothermia. Taken together, these results indicate that L-theanine possessed an antidepressant-like effect in mice, which may be mediated by the central monoaminergic neurotransmitter system.
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http://dx.doi.org/10.1002/ptr.3456DOI Listing
November 2011