Publications by authors named "Yan-Min Zhang"

59 Publications

Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation MYBPC3-E334K.

Heart Vessels 2021 Apr 8. Epub 2021 Apr 8.

Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, 127# Changle West Road, Xi'an, Shaanxi, China.

The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relatively high frequency in gnomAD (0.03% overall, with 0.3% in East Asians and 0.8% in Japanese). The main aim is to clarify the clinical importance and phenotype-genotype correlations in subjects with or without MYBPC3-E334K alone. The prevalence of MYBPC3-E334K was sequenced in 1017 HCM unrelated probands. The clinical features, morphology phenotypes, and electrical phenotypes were further analyzed according to the phenotype and genotype status in families with single-mutation MYBPC3-E334K. Nine of 1017 (0.88%) unrelated HCM probands were detected harboring MYBPC3-E334K, and three of them harbored a second variant in sarcomere protein gene. Family study and co-segregation analyses indicated that patients with single-mutation MYBPC3-E334K showed autosomal dominant mode of inheritance with incomplete penetrance. The overall disease penetrance was 52.6%, and the disease penetrance was higher in males than in females (100% in men vs 25% in women, p = 0.003). The mean age at diagnosis of males was approximately 25 years younger than females (36.57 ± 18.65 vs 62.33 ± 12.10, p = 0.062). The variant MYBPC3-E334K was classified as a likely pathogenic variant, and a second sarcomere variant did not reveal obvious cumulative effects. The patients harboring single-mutation MYBPC3-E334K had incomplete penetrance, and males demonstrated higher penetrance and early onset HCM than females. A second sarcomere variant did not reveal obvious cumulative effects.
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http://dx.doi.org/10.1007/s00380-021-01834-xDOI Listing
April 2021

Spatial learning and memory deficits induced by prenatal glucocorticoid exposure depend on hippocampal CRHR1 and CXCL5 signaling in rats.

J Neuroinflammation 2021 Apr 2;18(1):85. Epub 2021 Apr 2.

Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, 410008, China.

Background: Prenatal synthetic glucocorticoid (sGC) exposure increases the susceptibility to cognitive and affective disorders in postnatal life. We previously demonstrated that prenatal sGC exposure results in an increase in corticotropin-releasing hormone (CRH) receptor type 1 (CRHR1) expression in the hippocampus of rats, and CRHR1 is involved in synapse formation via regulation of C-X-C chemokine ligand 5 (CXCL5) in hippocampus. We sought to investigate that the roles of CRHR1 and CXCL5 in learning and memory impairment caused by prenatal sGC exposure.

Methods: Pregnant rats were administered with saline or dexamethasone (DEX) from gestational day (GD) 14 to GD21. DEX offspring at 2-day old were treated with saline and CRHR1 antagonists (antalarmin and CP154526) for 7 days. Some DEX offspring received intra-hippocampal injection of AAV9 carrying CXCL5 gene. Spatial learning and memory was assessed by Morris water maze test. Immunofluorescence analysis was applied to show synapsin I and PSD95 signals in hippocampus. Synapsin I and PSD95 protein level and CXCL5 concentration were determined by western blotting and ELISA, respectively. Organotypic hippocampal slice cultures were used to investigate the effect of DEX on CXCL5 production in vitro.

Results: Both male and female DEX offspring displayed impairment of spatial learning and memory in adulthood. Synapsin I and PSD95 signals and CXCL5 levels were decreased in DEX offspring. DEX offspring with antalarmin and CP154526 treatment showed improved spatial learning and memory. Antalarmin and CP154526 treatment increased synapsin I and PSD95 signals and CXCL5 concentration in hippocampus. Bilaterally hippocampal injection of AAV9 carrying CXCL5 gene improved the spatial learning and memory and increased CXCL5 concentration and synapsin I and PSD95 levels in hippocampus. DEX dose-dependently suppressed CXCL5 production in cultured hippocammpal slices, which was prevented by antalarmin treatment.

Conclusion: CRHR1 and CXCL5 signaling in the hippocampus are involved in spatial learning and memory deficits caused by prenatal DEX exposure. CRHR1 activation contributes to decreased CXCL5 production in hippocampus induced by prenatal DEX treatment. Our study provides a molecular basis of prenatal GC exposure programming spatial learning and memory.
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http://dx.doi.org/10.1186/s12974-021-02129-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019183PMC
April 2021

sp. nov., a halotolerant actinobacterium isolated from saline lake sediment.

Int J Syst Evol Microbiol 2020 Aug 20;70(8):4661-4667. Epub 2020 Jul 20.

College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.

A novel Gram-stain-positive bacterium, designated CFH 91151, was isolated from sediment collected from a saline lake in Yuncheng, Shanxi Province, PR China. Cells of strain CFH 91151 were rod-or v-shaped, aerobic, non-motile, non-spore-forming and halotolerant. Results of 16S rRNA gene sequence analysis revealed that strain CFH 91151 was closely related to MX5 and H17 (98.7 and 98.4% sequence similarity, respectively). The strain grew at 4-45 °C, pH 5.0-9.0 and with 0-14.0 % (w/v) NaCl. Cells were positive for catalase, nitrate was not used and HS was not produced. Major cellular fatty acids were anteiso-C (62.76 %), anteiso-C (12.09 %) and iso-C (9.46 %). The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, two unidentified phospholipids and three unidentified glycolipids. The menaquinone was MK-9 (H4). The genome size was 4.10 Mbp with a G+C content of 72.4 mol%. The average amino acid identity (ANI) and DNA-DNA hybridization (DDH) values between CFH 91151 and the other species of the genus were found to be low (ANIm <87.19 %, ANIb <84.38 % and DDH <29.30 %). Based on physiological properties, chemotaxonomic characteristics and low ANI and DDH results, strain CFH 91151 is considered to represent a novel species, for which the name sp. nov. is proposed. The type strain is CFH 91151 (=DSM 105976=KCTC 49061).
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http://dx.doi.org/10.1099/ijsem.0.004329DOI Listing
August 2020

Recent advance in the development of novel, selective and potent FGFR inhibitors.

Eur J Med Chem 2020 Jan 16;186:111884. Epub 2019 Nov 16.

Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China. Electronic address:

Mutation or abnormal expression of protein tyrosine kinases (PTKs) is one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes including FGFR1, FGFR2, FGFR3 and FGFR4. Their abnormal expression in cells is considered to be the main cause of tumorigenesis, so inhibiting FGFRs is thought to be important targets for cancer treatment. This article mainly summarizes the recent development of FGFR inhibitors in the past 5 years, and hopes to guide the future research on the design and synthesis of FGFR inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2019.111884DOI Listing
January 2020

sp. nov., isolated from a hot spring.

Int J Syst Evol Microbiol 2020 Jan;70(1):550-554

College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.

A novel Gram-staining negative, aerobic, motile by flagellum, rod-shaped bacterium, designated CFH 70021 was isolated from a hot spring soil sample collected from Tengchong, Yunnan province, PR China. Growth of CFH 70021 occurred at 15-50 °C (optimum 50 °C), pH 5.0-7.0 (optimum pH 7.0) and with 0-3.0 % (w/v) NaCl (optimum 0 %, w/v). The genome of CFH 70021 consisted of four complete circular chromosomes and five plasmids, the genomic DNA G+C content was 69.3 mol%. Comparison of the 16S rRNA gene sequences indicated that CFH 70021 represented a member of the genus and showed close relationship with the type strains of CC-HIH038 (97.8 %), IMMIB AFH-6 (97.6 %), GSF71 (97.6 %), DSM 21654 (97.4 %) and IMMIB TAR-3 (97.2 %). The polar lipids of CFH 70021 contained diphosphatidylglycerol, phosphatidylmehtylethanolamine, phosphatidylglycerol, phosphatidylcholine, two aminolipids and an unidentified phospholipid. The predominant cellular fatty acids (>10 %) included Ccyclo ω (11.4 %), C (27.6 %) and summed feature 8 (Cω7/Cω6, 40.9 %). The major isoprenoid quinone was Q-10. On the basis of the low ANIb result (<78 %) and different phenotypic and chemotaxonomic characters, we conclude that strain CFH 70021 represents a novel member of the genus , for which the name sp. nov. is proposed. The type strain is CFH 70021 (=KCTC 62259= CCTCC AB2018121).
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http://dx.doi.org/10.1099/ijsem.0.003788DOI Listing
January 2020

sp. nov., isolated from the intestine of grass carp.

Int J Syst Evol Microbiol 2020 Jan;70(1):543-549

College of Fisheries, Henan Normal University, Xinxiang, 453007, PR China.

A novel Gram-negative bacterium, designated CFH 10530, was isolated from the intestine of grass carp. The sample was collected from the aquaculture training base at the College of Fisheries, Henan Normal University, Xinxiang, PR China. Cells of strain CFH 10530 were coccoid, ovoid or short-rod-shaped, aerobic, non-spore-forming and non-motile. 16S rRNA gene sequence analysis demonstrated that strain CFH 10530 was closely related to SYSUP0003 (97.7 % sequence similarity), HN-182 (96.5 %) and DCY94 (96.1 %). The strain grew optimally at 25-28 °C, at pH 7.0 and with 0-2 % (w/v) NaCl. Cells were positive for catalase and oxidase, nitrate was reduced and HS was not produced. The isoprenoid quinone was Q-10. Major cellular fatty acids were summed feature 8, C and C3-OH. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, one unidentified aminolipid and five unidentified polar lipids. The genome size was 3 331 229 bp with a G+C content of 69.6 mol%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between CFH 10530 and the other species of the genus were found to be below the recommended levels for species delineation (ANIm <85, ANIb <80 and dDDH <24 %). Based on its physiological properties, chemotaxonomic characteristics and low ANI and dDDH results, strain CFH 10530 is considered to represent a novel species for which the name sp. nov., is proposed. The type strain is CFH 10530 (=KCTC 62919=CGMCC 1.16597).
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http://dx.doi.org/10.1099/ijsem.0.003790DOI Listing
January 2020

Novel phenotype-genotype correlations of hypertrophic cardiomyopathy caused by mutation in α-actin and myosin-binding protein genes in three unrelated Chinese families.

J Cardiol 2019 05 29;73(5):438-444. Epub 2018 Dec 29.

Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address:

Background: The correlations between genotype and phenotype in hypertrophic cardiomyopathy (HCM) have not been established. Mutation of α-actin gene (ACTC1) is a rare cause of HCM. This study aimed to explore novel genotype-phenotype correlations in HCM patients with the variants in ACTC1 and myosin-binding protein (MYBPC3) genes in three unrelated Chinese families.

Methods: Clinical, electrocardiographic, and echocardiographic examinations were performed in three Han pedigrees. Exon and boarding intron analysis of 96 cardio-disease-related genes was performed using second-generation sequencing on three probands. The candidate variants were validated in 14 available family members and 300 unrelated healthy controls by bi-directional Sanger sequencing. The pathogenicity and conservation were calculated using MutationTaster, PolyPhen-2, SIFT, and Clustal X. Pathogenicity classification of the variants was based on American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: Nine members fulfilled diagnostic criteria for HCM with clinical characteristics, electrocardiographic, and echocardiographic findings. Two candidate variants in ACTC1 p.Asp26Asn (ACTC1-D26N) and MYBPC3 p.Arg215Cys (MYBPC3-R215C) were identified in patients. Only ACTC1-D26N strongly co-segregated with the HCM phenotype. Seven patients who harbored variant ACTC-D26N only were diagnosed with non-obstructive HCM, and four of these patients exhibited a triphasic left ventricular (LV) filling pattern. Two patients carrying both ACTC1-D26N and MYBPC3-R215C variants showed a higher LV outflow tract pressure gradient. Bioinformatics analysis revealed that the two variants were deleterious and highly conserved across species. According to ACMG guidelines, ACTC1-D26N is classified as a likely pathogenic mutation. The second variation MYBPC3-R215C may function as a genetic modifier, which remains uncertain here.

Conclusions: Novel p.(Asp26Asn) mutation of ACTC1 was associated with HCM phenotype, and the penetrance is extremely high (∼81.8%) in adults. The second variation, MYBPC3-R215C may function as a genetic modifier, which remains uncertain here.
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http://dx.doi.org/10.1016/j.jjcc.2018.09.005DOI Listing
May 2019

Virtual Screening Strategy Combined Bayesian Classification Model, Molecular Docking for Acetyl-CoA Carboxylases Inhibitors.

Curr Comput Aided Drug Des 2019 ;15(3):193-205

Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, Nanjing, Jiangsu, China.

Introduction: Acetyl-CoA Carboxylases (ACC) have been an important target for the therapy of metabolic syndrome, such as obesity, hepatic steatosis, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), type 2 diabetes (T2DM), and some other diseases.

Methods: In this study, virtual screening strategy combined with Bayesian categorization modeling, molecular docking and binding site analysis with protein ligand interaction fingerprint (PLIF) was adopted to validate some potent ACC inhibitors. First, the best Bayesian model with an excellent value of Area Under Curve (AUC) value (training set AUC: 0.972, test set AUC: 0.955) was used to screen compounds of validation library. Then the compounds screened by best Bayesian model were further screened by molecule docking again.

Results: Finally, the hit compounds evaluated with four percentages (1%, 2%, 5%, 10%) were verified to reveal enrichment rates for the compounds. The combination of the ligandbased Bayesian model and structure-based virtual screening resulted in the identification of top four compounds which exhibited excellent IC 50 values against ACC in top 1% of the validation library.

Conclusion: In summary, the whole strategy is of high efficiency, and would be helpful for the discovery of ACC inhibitors and some other target inhibitors.
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http://dx.doi.org/10.2174/1573409914666181109110030DOI Listing
September 2019

Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase.

Bioorg Med Chem 2018 09 11;26(16):4735-4744. Epub 2018 Aug 11.

Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China. Electronic address:

Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.
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http://dx.doi.org/10.1016/j.bmc.2018.08.013DOI Listing
September 2018

Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family.

Cardiol Young 2018 Sep 6;28(9):1106-1114. Epub 2018 Jul 6.

1Department of Ultrasound,Xijing Hospital,Fourth Military Medical University,Xi'an,Shaanxi,China.

Background: We previously reported four heterozygous missense mutations of MYH7, KCNQ1, MYLK2, and TMEM70 in a single three-generation Chinese family with dual Long QT and hypertrophic cardiomyopathy phenotypes for the first time. However, the clinical course among the family members was various, and the potential myocardial dysfunction has not been investigated.

Objectives: The objective of this study was to investigate the echocardiographic and electrocardiographic characteristics in a genetic positive Chinese family with hypertrophic cardiomyopathy and further to explore the association between myocardial dysfunction and electric activity, and the identified mutations.

Methods: A comprehensive echocardiogram - standard two-dimensional Doppler echocardiography and three-dimensional speckle tracking echocardiography - and electrocardiogram were obtained for members in this family.

Results: As previously reported, four missense mutations - MYH7-H1717Q, KCNQ1-R190W, MYLK2-K324E, and TMEM70-I147T - were identified in this family. The MYH7-H1717Q mutation carriers had significantly increased left ventricular mass indices, elevated E/e' ratio, deteriorated global longitudinal stain, but enhanced global circumferential and radial strain compared with those in non-mutation patients (all p<0.05). The KCNQ1-R190W carriers showed significantly prolonged QTc intervals, and the MYLK2-K324E mutation carriers showed inverted T-waves (both p<0.05). However, the TMEM70-I147T mutation carriers had similar echocardiography and electrocardiographic data as non-mutation patients.

Conclusions: Three of the identified four mutations had potential pathogenic effects in this family: MYH7-H1717Q was associated with increased left ventricular thickness, elevated left ventricular filling pressure, and altered myocardial deformation; KCNQ1-R190W and MYLK2-K324E mutations were correlated with electrocardiographic abnormalities reflected in long QT phenotype and inverted T-waves, respectively.
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http://dx.doi.org/10.1017/S1047951118000860DOI Listing
September 2018

The Cardioprotective Effects of 4-O-(2″-O-acetyl-6″-O- P-coumaroyl-β-D-glucopyranosyl)-P-coumaric Acid (4-ACGC) on Chronic Heart Failure.

Iran J Pharm Res 2018 ;17(2):593-600

Department of Emergency, Liaocheng People's Hospital of Shandong Province, Liaocheng 252000, China.

The 4-ACGC isolated from BP was prepared to investigate the cardioprotective effects on attenuating chronic heart failure and . A chronic heart failure (CHF) rat model was established to investigate the cardioprotective effects of 4-ACGC. From this, several cardiac function indexes were recorded. The inflammatory markers including tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-1β (IL-1β) were evaluated by enzyme-linked immunosorbent assay (ELISA). Subsequently, serum levels of myocardial enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) were also assessed by ELISA kits. Ultimately, the cardioprotective and anti-inflammatory effects of 4-ACGC were further verified on CMECs. The results showed that the treatment of 4-ACGC significantly reduced cardiac hypertrophy and reversed the Ejection Fraction (EF), Heart Rate (HR), Fractional Shortening (FS), and Cardiac Output (CO) changes in CHF rats. The treatment of 4-ACGC could effectively inhibit the inflammatory cytokines induced by CHF. It's also showed that a reverse effect of 4-ACGC on serum increased levels of LDH and CK in CHF rats. The increased levels of IL-1β and IL-6 stimulated by TNF-α on CMECs were also decreased after treating with 4-ACGC. The present study provided experimental evidence that 4-ACGC possessed obvious cardioprotective effects on attenuating CHF. 4-ACGC could suppress the expression of inflammatory mediators and myocardial enzymes, which might be one of the mechanisms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985177PMC
January 2018

Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis and .

Front Pharmacol 2018 1;9:434. Epub 2018 May 1.

International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the and anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO's anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO's anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.
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http://dx.doi.org/10.3389/fphar.2018.00434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938359PMC
May 2018

Screening and analysis of key active constituents in Guanxinshutong capsule using mass spectrum and integrative network pharmacology.

Chin J Nat Med 2018 Apr;16(4):302-312

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address:

Guanxinshutong capsule (GXSTC) is an effective and safe traditional Chinese medicine used in the treatment of cardiovascular diseases (CVDs) for many years. However, the targets of this herbal formula and the underlying molecular mechanisms of action involved in the treatment of CVDs are still unclear. In the present study, we used a systems pharmacology approach to identify the active ingredients of GXSTC and their corresponding targets in the calcium signaling pathway with respect to the treatment of CVDs. This method integrated chromatographic techniques, prediction of absorption, distribution, metabolism, and excretion, analysis using Kyoto Encyclopedia of Genes and Genomes, network construction, and pharmacological experiments. 12 active compounds and 33 targets were found to have a role in the treatment of CVDs, and four main active ingredients, including protocatechuic acid, cryptotanshinone, eugenol, and borneol were selected to verify the effect of (GXSTC) on calcium signaling system in cardiomyocyte injury induced by hypoxia and reoxygenation. The results from the present study revealed the active components and targets of GXSTC in the treatment of CVDs, providing a new perspective to enhance the understanding of the role of the calcium signaling pathway in the therapeutic effect of GXSTC.
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http://dx.doi.org/10.1016/S1875-5364(18)30060-8DOI Listing
April 2018

CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.

FASEB J 2018 08 15;32(8):4258-4269. Epub 2018 Mar 15.

Department of Physiology, Second Military Medical University, Shanghai, China.

Pregnant women at risk of preterm labor usually receive synthetic glucocorticoids (sGCs) to promote fetal lung development. Emerging evidence indicates that antenatal sGC increases the risk of affective disorders in offspring. Data from animal studies show that such disorders can be transmitted to the second generation. However, the molecular mechanisms underlying the intergenerational effects of prenatal sGC remain largely unknown. Here we show that prenatal dexamethasone (Dex) administration in late pregnancy induced depression-like behavior in first-generation (F1) offspring, which could be transmitted to second-generation (F2) offspring with maternal dependence. Moreover, corticotropin-releasing hormone (CRH) and CRH receptor type 1 (CRHR1) expression in the hippocampus was increased in F1 Dex offspring and F2 offspring from F1 Dex female rats. Administration of a CRHR1 antagonist to newborn F1 Dex offspring alleviated depression-like behavior in these rats at adult. Furthermore, we demonstrated that increased CRHR1 expression in F1 and F2 offspring was associated with hypomethylation of CpG islands in Crhr1 promoter. Our results revealed that prenatal sGC exposure could program Crh and Crhr1 gene expression in hippocampus across 2 generations, thereby leading to depression-like behavior. Our study indicates that prenatal sGC can cause epigenetic instability, which increases the risk of disease development in the offspring's later life.-Xu, Y.-J., Sheng, H., Wu, T.-W., Bao, Q.-Y., Zheng, Y., Zhang, Y.-M., Gong, Y.-X., Lu, J.-Q., You, Z.-D., Xia, Y., Ni, X. CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.
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http://dx.doi.org/10.1096/fj.201700948RRDOI Listing
August 2018

The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy.

Cardiology 2017;138(4):228-237. Epub 2017 Sep 2.

Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Aims: We investigated the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations in a Chinese family with hypertrophic cardiomyopathy.

Methods: Clinical, electrocardiographic (ECG), echocardiographic, and cardiac magnetic resonance (CMR) examinations of members of a Chinese family were followed by exon and boarding intron analyses of 96 genes in the proband using second-generation sequencing. We confirmed the mutations by bidirectional Sanger sequencing in the members and in 300 healthy controls.

Results: We detected MYH7-V878A and CACNA1C-A1594V mutations in this family. The members with both mutations showed inverted T-waves and ST-segment depression in ECG recordings, severe left ventricular (LV) hypertrophy in echocardiography, and myocardial fibrosis in CMR; subject II-11 did not show late gadolinium enhancement. Among those with only the MYH7-V878A mutation, subject III-7 showed abnormal ECG recordings, asymmetric septal hypertrophy, and myocardial fibrosis, and subjects II-13 and III-15 showed some abnormal repolarization, borderline LV wall thickness, and normal CMR findings. Those with only the CACNA1C-A1594V mutation showed nearly normal readings in all examinations. The members with both mutations displayed more severe LV hypertrophy and elevated LV filling pressure than those with 1 or no mutation (p < 0.05).

Conclusion: Our results suggest that the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations may have a cumulative effect.
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http://dx.doi.org/10.1159/000478900DOI Listing
August 2018

Paradoxical embolism: A report of 2 cases.

Medicine (Baltimore) 2017 Jun;96(26):e7332

Department of Peripheral Vascular Disease, the First Affiliated Hospital of Xi'an Jiaotong University Section of Pediatric Cardiology, Heart Center, Northwest Women's and Children's Hospital Department of Breast Cancer, Shaanxi Provincial Tumor Hospital, Xi'an, Shaanxi, PR China.

Rationale: Paradoxical embolism (PDE) refers to direct passage of venous thrombi into the arterial circulation through an arteriovenous shunt.

Patient Concerns: Case 1 presented with initial symptoms of shock and cerebral infarction. Case 2 developed middle cerebral artery occlusion during angiography.

Diagnoses: 2 cases were diagnosed as PDE.

Interventions: They received thrombolytic therapy and anticoagulant therapy.

Outcomes: The patients had recovery.

Lessons: This report highlights the myriad clinical manifestations of PDE and underlines the importance of meticulous history taking and physical examination for early diagnosis.
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http://dx.doi.org/10.1097/MD.0000000000007332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500069PMC
June 2017

Change in iron metabolism in rats after renal ischemia/reperfusion injury.

PLoS One 2017 20;12(4):e0175945. Epub 2017 Apr 20.

Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China.

Previous studies have indicated that hepcidin, which can regulate iron efflux by binding to ferroportin-1 (FPN1) and inducing its internalization and degradation, acts as the critical factor in the regulation of iron metabolism. However, it is unknown whether hepcidin is involved in acute renal ischemia/reperfusion injury (IRI). In this study, an IRI rat model was established via right renal excision and blood interruption for 45 min in the left kidney, and iron metabolism indexes were examined to investigate the change in iron metabolism and to analyze the role of hepcidin during IRI. From 1 to 24 h after renal reperfusion, serum creatinine and blood urea nitrogen were found to be time-dependently increased with different degrees of kidney injury. Regular variations in iron metabolism indexes in the blood and kidneys were observed in renal IRI. Renal iron content, serum iron and serum ferritin increased early after reperfusion and then declined. Hepcidin expression in the liver significantly increased early after reperfusion, and its serum concentration increased beginning at 8 h after reperfusion. The splenic iron content decreased significantly in the early stage after reperfusion and then increased time-dependently with increasing reperfusion time, and the hepatic iron content showed a decrease in the early stage after reperfusion. The early decrease of the splenic iron content and hepatic iron content might indicate their contribution to the increase in serum iron in renal IRI. In addition, the duodenal iron content showed time-dependently decreased since 12 h after reperfusion in the IRI groups compared to the control group. Along with the spleen, the duodenum might contribute to the decrease in serum iron in the later stage after reperfusion. The changes in iron metabolism indexes observed in our study demonstrate an iron metabolism disorder in renal IRI, and hepcidin might be involved in maintaining iron homeostasis in renal IRI. These findings might suggest a self-protection mechanism regulating iron homeostasis in IRI and provide a new perspective on iron metabolism in attenuating renal IRI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175945PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398610PMC
September 2017

Improvement of soybean transformation via Agrobacterium tumefaciens methods involving α-aminooxyacetic acid and sonication treatments enlightened by gene expression profile analysis.

Plant Cell Rep 2016 Jun 9;35(6):1259-71. Epub 2016 Mar 9.

Institute of Food and Oil Crops, Hebei Academy of Agriculture and Forestry Sciences, Shijiazhuang, 050035, China.

Key Message: Antagonists and sonication treatment relieved the structural barriers of Agrobacterium entering into cells; hindered signal perception and transmission; alleviated defense responses and increased cell susceptibility to Agrobacterium infection. Soybean gene expression analysis was performed to elucidate the general response of soybean plant to Agrobacterium at an early stage of infection. Agrobacterium infection stimulated the PAMPs-triggered immunity (BRI1, BAK1, BZR1, FLS2 and EFR) and effector-triggered immunity (RPM1, RPS2, RPS5, RIN4, and PBS1); up-regulated the transcript factors (WRKY25, WRKY29, MEKK1P, MKK4/5P and MYC2) in MAPK pathway; strengthened the biosynthesis of flavonoid and isoflavonoid in the second metabolism; finally led to a fierce defense response of soybean to Agrobacterium infection and thereby lower transformation efficiency. To overcome it, antagonist α-aminooxyacetic acid (AOA) and sonication treatment along with Agrobacterium infection were applied. This novel method dramatically decreased the expression of genes coding for F3'H, HCT, β-glucosidase and IF7GT, etc., which are important for isoflavone biosynthesis or the interconversion of aglycones and glycon; genes coding for peroxidase, FLS2, PBS1 and transcription factor MYC2, etc., which are important components in plant-pathogen interaction; and genes coding for GPAT and α-L-fucosidase, which are important in polyesters formation in cell membrane and the degradation of fucose-containing glycoproteins and glycolipids on the external surface of cell membrane, respectively. This analysis implied that AOA and sonication treatment not only relieved the structural membrane barriers of Agrobacterium entering into cells, but also hindered the perception of 'invasion' signal on cell membrane and intercellular signal transmission, thus effectively alleviated the defense responses and increased the cell susceptibility to Agrobacterium infection. All these factors benefit the transformation process; other measures should also be further explored to improve soybean transformation.
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http://dx.doi.org/10.1007/s00299-016-1958-2DOI Listing
June 2016

Urocortin 2 But Not Urocortin 3 Promotes the Synaptic Formation in Hipppocampal Neurons via Induction of NGF Production by Astrocytes.

Endocrinology 2016 Mar 29;157(3):1200-10. Epub 2015 Dec 29.

Department of Physiology, Second Military Medical University, Shanghai 200433, China.

CRH family peptides play differential role during various physiological and pathophysiological responses, such as stress. Urocortins (UCNs) have been implicated to play complementary or contrasting actions for the effects of CRH during stress. It has been shown that activation of CRH receptor type 1 (CRHR1) results in decreased synapse formation in hippocampus. We therefore explored the effect of UCN2 and UCN3, the exclusive CRHR2 agonists, on synaptic formation in hippocampus. In hippocampal slices cultures, UCN2 but not UCN3 treatment increased the levels of presynaptic protein synapsinI and postsynaptic protein postsynaptic density 95 (PSD95), which was reversed by CRHR2 antagonist astressin 2B. In isolated hippocampal neurons, however, UCN2 decreased the numbers of synapsinI- and PSD95-labeled terminals/clusters via CRHR2. Treatment of hippocampal neurons with the media of UCN2-treated astrocytes led to an increase in synapsinI- and PSD95-labeled terminals. In neuron-astrocyte cocultures, UCN2 also enhanced the numbers and level of synapsinI- and PSD95-labeled terminals. These effects did not occur if glial cells were transfected with CRHR2 small interfering RNA. UCN2 but not UCN3 treatment induced nerve growth factor (NGF) production in astrocytes via CRHR2. The effects of the media of UCN2-treated glial cells on synapse formation in hippocampal neurons were prevented by administration of NGF receptor antagonists. Our data indicate that UCN2 promotes synapse formation in hippocampus via induction of NGF secretion from astrocytes. CRHR2 in glial cells mediates the stimulatory effects of CRH. Glia-neuron communication is critical for neuronal circuits remodeling and synaptic plasticity in response to neurohormones or neuromodulators.
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http://dx.doi.org/10.1210/en.2015-1812DOI Listing
March 2016

Expression of maize heat shock transcription factor gene ZmHsf06 enhances the thermotolerance and drought-stress tolerance of transgenic Arabidopsis.

Funct Plant Biol 2015 Nov;42(11):1080-1091

Plant Genetic Engineering Center of Hebei Province/Institute of Genetics and Physiology, Hebei Academy of Agriculture and Forestry Sciences, Shijiazhuang 050051, PR China.

Based on the information of 25 heat shock transcription factor (Hsf) homologues in maize according to a genome-wide analysis, ZmHsf06 was cloned from maize leaves and transformed into Arabidopsis thaliana (L. Heynh.) (ecotype, Col-0). Three transgenic positive lines were selected to assess the basic and acquired thermotolerance and drought-stress tolerance under stresses and for some physiological assays. The sequence analysis indicates that ZmHsf06 contained the characteristic domains of class A type plant Hsfs. The results of qRT-PCR showed that the expression levels of ZmHsf06 were elevated by heat shock and drought stress to different extents in three transgenic lines. Phenotypic observation shows that compared with the Wt (wild-type) controls, the overexpressing ZmHsf06 of Arabidopsis plants have enhanced basal and acquired thermotolerance, stronger drought-stress tolerance and growth advantages under mild heat stress conditions. These results are further confirmed by physiological and biochemical evidence that transgenic Arabidopsis plants exhibit higher seed germination rate, longer axial-root length, higher activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), higher leaf chlorophyll content, but lower relative electrical conductivity (REC), malondialdehyde (MDA) and osmotic potential (OP) than the Wt controls after heat shock and drought treatments. ZmHsf06 may be a central representative of maize Hsfs and could be useful in molecular breeding of maize or other crops for enhanced tolerances, particularly during terminal heat and drought stresses.
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http://dx.doi.org/10.1071/FP15080DOI Listing
November 2015

Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches.

Int J Mol Sci 2015 Oct 15;16(10):24451-74. Epub 2015 Oct 15.

School of Science, China Pharmaceutical University, Nanjing 211169, China.

Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-RafV600E synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q²=0.542, r²=0.989 for B-Raf; q²=0.768, r²=0.991 for KDR) and CoMSIA models (q²=0.519, r²=0.992 for B-Raf; q²=0.849, r²=0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r²pred=0.764 (CoMFA), r²pred=0.841 (CoMSIA) for B-Raf, r²pred=0.912 (CoMFA), r²pred=0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.
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http://dx.doi.org/10.3390/ijms161024451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632759PMC
October 2015

Ferulic acid inhibits H2O2-induced oxidative stress and inflammation in rat vascular smooth muscle cells via inhibition of the NADPH oxidase and NF-κB pathway.

Int Immunopharmacol 2015 Oct 30;28(2):1018-25. Epub 2015 Aug 30.

School of Medicine, Xi'an Jiaotong University, PR China. Electronic address:

Ferulic acid (FA) is a dietary phenolic acid and has a wide range of therapeutic effects, including anti-aging, antitumor activity and antihypertensive effects. The aim of present study was to evaluate the inhibitory effects of FA on cell inflammation and oxidative stress against hydrogen peroxide (H2O2)-induced injury in rat vascular smooth muscle cells (VSMCs) in vitro. VSMCs were pretreated with FA 2h before H2O2 incubation. The results suggested that FA inhibited H2O2-induced cell injury by reducing the MDA and increasing the SOD activity and GSH content. In rat VSMCs exposed to H2O2, FA increased the cell viability and restored the mitochondrial membrane depolarization. The level of ROS generation was reduced by pretreatment with FA through inhibiting the expression of NADPH oxidase and down-regulating MAPK and AKT pathways. We found that H2O2 stimulated the production of IL-6, IL-1β, TNF-α and NO, which could be reduced by pretreatment with FA through inhibiting the p-NF-κB as well as the iNOS expression. In conclusion, our results show that FA may serve as a novel drug in the treatment of these pathologies by inhibiting NADPH oxidase and NF-κB and subsequently decreasing VSMC oxidative stress and inflammation. These suggest that the inhibitory effect of FA on VSMC inflammation and oxidative stress is partially attributed to depressing NADPH and NF-κB expressions in VSMCs, decreasing the ROS production and reducing apoptosis of VSMCs.
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http://dx.doi.org/10.1016/j.intimp.2015.07.037DOI Listing
October 2015

The wheat NHX antiporter gene TaNHX2 confers salt tolerance in transgenic alfalfa by increasing the retention capacity of intracellular potassium.

Plant Mol Biol 2015 Feb 31;87(3):317-27. Epub 2014 Dec 31.

Institute of Genetics and Physiology, Hebei Academy of Agriculture and Forestry Sciences, Plant Genetic Engineering Center of Hebei Province, Shijiazhuang, 050051, China,

Previous studies have shown that TaNHX2 transgenic alfalfa (Medicago sativa L.) accumulated more K(+) and less Na(+) in leaves than did the wild-type plants. To investigate whether the increased K(+) accumulation in transgenic plants is attributed to TaNHX2 gene expression and whether the compartmentalization of Na(+) into vacuoles or the intracellular compartmentalization of potassium is the critical mechanism for TaNHX2-dependent salt tolerance in transgenic alfalfa, aerated hydroponic culture was performed under three different stress conditions: control condition (0.1 mM Na(+) and 6 mM K(+) inside culture solution), K(+)-sufficient salt stress (100 mM NaCl and 6 mM K(+)) and K(+)-insufficient salt stress (100 mM NaCl and 0.1 mM K(+)). The transgenic alfalfa plants had lower K(+) efflux through specific K(+) channels and higher K(+) absorption through high-affinity K(+) transporters than did the wild-type plants. Therefore, the transgenic plants had greater K(+) contents and [K(+)]/[Na(+)] ratios in leaf tissue and cell sap. The intracellular compartmentalization of potassium is critical for TaNHX2-induced salt tolerance in transgenic alfalfa.
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http://dx.doi.org/10.1007/s11103-014-0278-6DOI Listing
February 2015

Intravenous infusion of mesenteric lymph from severe intraperitoneal infection rats causes lung injury in healthy rats.

World J Gastroenterol 2014 Apr;20(16):4771-7

Yan-Min Zhang, Tianjin Medical University, Intensive Care Unit, Tianjin Nankai Hospital, Tianjin 300100, China.

Aim: To investigate whether mesenteric lymph from rats with severe intraperitoneal infection (SII) induces lung injury in healthy rats.

Methods: Twenty adult male specific pathogen-free Wistar rats were divided into two groups. Animals in the SII group received intraperitoneal injection of Escherichia coli (E. coli) at a dose of 0.3 mL/100 g. Control rats underwent the same procedure, but were injected with normal saline rather than E. coli. We ligated and drained the mesenteric lymphatic vessels and collected the mesenteric lymph. Mesenteric lymph collected from SII or control rats was infused intravenously into male healthy rats at a rate of 1 mL/h for 4 h. At the end of the infusion, all rats were sacrificed. Lungs were removed and examined histologically, and wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were determined. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. We performed Western blot to investigate the activation of Toll-like receptor (TLR)-4, and nuclear factor (NF)-κB p65.

Results: Compared with the control infusion group, there were obvious pathological changes in the SII group. The W/D ratio was significantly increased in the SII compared to control infusion group (5.86 ± 0.06 vs 5.37 ± 0.06, P < 0.01). MPO activity significantly increased in the SII infusion rats with a mean level of 0.86 ± 0.02 U/g compared to 0.18 ± 0.05 U/g in the control group (P < 0.01). The concentrations of TNF-α and IL-6 were significantly increased in the SII infusion group. The concentration of TNF-α was significantly increased in the SII infusion rats compared to control infusion rats (2104.46 ± 245.91 vs 1475.13 ± 137.82 pg/mL, P < 0.01). The concentration of IL-6 was significantly increased in the SII infusion rats with a mean level of 50.56 ± 2.85 pg/mL compared to 43.29 ± 2.02 pg/mL (P < 0.01). The expression levels of TLR-4 (7496.68 ± 376.43 vs 4589.02 ± 233.16, P < 0.01) and NF-κB (8722.19 ± 323.96 vs 6498.91 ± 338.76, P < 0.01) were significantly increased in the SII infusion group compared to the control infusion group. The infusion of SII lymph, but not control lymph, caused lung injury.

Conclusion: The results indicate that SII lymph is sufficient to induce acute lung injury.
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http://dx.doi.org/10.3748/wjg.v20.i16.4771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000515PMC
April 2014

Momordica cochinchinensis seed extracts suppress migration and invasion of human breast cancer ZR-75-30 cells via down-regulating MMP-2 and MMP-9.

Asian Pac J Cancer Prev 2014 ;15(3):1105-10

School of Medicine, Xi'an Jiaotong University, Xi'an, China E-mail :

Objective: Metastases and invasion are the main reasons for oncotherapy failure. Momordica cochinchinensis (Mu Bie Zi in Chinese) had been used for a variety of purposes, and shown anti-cancer action. In this article, we focused on effects on regulation of breast cancer cell ZR-75-30 metastases and invasion by extracts of Momordica cochinchinensis seeds (ESMCs).

Methods: Effect of ESMCs on ZR-75-30 human breast cancer cells proliferation were evaluated by MTT assay and on invasion and migration by wound-healing and matrigel invasion chamber assays. Expression and protease activity of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, were analyzed by Western blotting and gelatin zymography, respectively.

Results: ESMC revealed strong growth inhibitory effects on ZR-75-30 cells, and effectively inhibited ZR-75-30 cell invasion in a dose-dependent manner. Western blot and gelatin zymography analysis showed that ESMC significantly inhibited the expression and secretion of MMP-2 and MMP-9 in ZR-75-30 cells.

Conclusions: ESMC has the potential to suppress the migration and invasion of ZR-75-30 cancer cells, and it might prove to of interest in the development of novel inhibitors for breast cancer.
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http://dx.doi.org/10.7314/apjcp.2014.15.3.1105DOI Listing
November 2014

[Study on antitumor effect of wutousan].

Zhong Yao Cai 2013 Aug;36(8):1301-4

School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.

Objective: To screen the active extracts from three traditional Chinese medicines.

Methods: Five traditional Chinese medicines including Unprocessed Aconiti Radix, Aconiti Radix Cocta, Phellodendri Chinensis Cortex were extracted with 70% alcohol or water respectively. The cell proliferation effect of these extracts was tested with MTT assay in SMMC7721, MCF7, A549, Hela and SGC7901.

Results: The 70% alcohol extract of Unprocessed Aconiti Radix, Aconiti Radix Cocta, Phellodendri Chinensis Cortex displayed remarkable inhibitory effect in the A549 and Hela in a dose-dependent manner.

Conclusion: The alcohol extract of Unprocessed Aconiti Radix, Aconiti Radix Cocta, Phellodendri Chinensis Cortex and the water extraction of Phellodendri Chinensis Cortex present obviously inhibitory effect in both A549 and Hela. The combination of Aconiti Radix with Phellodendri Chinensis Cortex has synergistic inhibitory effect on Hela.
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August 2013

[Cardiac sodium channelopathy from bench to bedside].

Zhonghua Er Ke Za Zhi 2013 Nov;51(11):874-7

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November 2013

Protective effect of melatonin on bone marrow mesenchymal stem cells against hydrogen peroxide-induced apoptosis in vitro.

J Cell Biochem 2013 Oct;114(10):2346-55

Department of Histology and Embryology, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Shandong University School of Medicine, Jinan, PR China.

Bone marrow mesenchymal stem cells (MSCs) transplantation has shown great promises for treating various central nervous system (CNS) diseases. However, poor viability of transplanted MSCs in injured CNS has limited the therapeutic efficiency. Oxidative stress is one of major mechanisms underlying the pathogenesis of CNS diseases and has a negative impact on the survival of transplanted MSCs. Melatonin has recently been reported to have the antioxidant and anti-apoptotic properties in serial of cells. This study was designed to investigate the protective effect and potential mechanisms of melatonin against hydrogen peroxide (H2O2)-induced apoptosis of MSCs. MSCs were pretreated with melatonin (1, 10, and 100 nM, respectively) for 30 min, followed by exposure to 400 µM H2O2 and melatonin together for 12 h. The present study reports that melatonin pretreatment significantly attenuated H2O2-induced MSC apoptosis in a dose-dependent manner. Consistently, melatonin effectively suppressed the generation of intracellular ROS, expression ratio of Bax/Bcl-2, activation of caspase-3 and expression of phospho-P38MAPK in H2O2-induced MSCs. Luzindole, a nonselective melatonin receptor antagonist, significantly counteracted melatonin's promotion effect on cell survival, indicating that melatonin exerts its protective effect on MSCs, at least in part, through the activation of melatonin receptors. The findings suggest that melatonin may be an effectively protective agent against oxidative stress-induced MSC apoptosis.
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http://dx.doi.org/10.1002/jcb.24582DOI Listing
October 2013

Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis.

Cell Physiol Biochem 2013 17;31(4-5):693-702. Epub 2013 May 17.

Department of Neurosurgery, the Second Hospital of Hebei Medical University, Shijiazhuang, China.

Background: Cannabinoid type 2 (CB2) receptor agonists can protect myocardium against ischemia/reperfusion (I/R) injury although the underlying mechanism remains unclear. Here we report the antiapoptotic effect of CB2 receptor agonist, JWH133, during myocardial ischemia/reperfusion injury and potential underlying mechanisms.

Methods: Ischemia was performed by blocking left coronary artery of rat for 30 min. After ischemia for 30 min, the rat heart was reperfused for 120 min by loosing the ligation of blocking left coronary artery. JWH133 (20 mg/kg), a CB2 receptor selective agonist, or vehicles were injected intravenously 5 minutes before ischemia. Infarct size of myocardium was assessed by histological stain, myocardial apoptosis index (AI) was determined by TUNEL, and mitochondrial membrane potential (∆Ψm) was measured by flow cytometry. Western blots were performed to measure the cytochrome c release, cleaved caspase 3, cleaved caspase 9 and PI3K/Akt kinase phosphorylation.

Results: JWH133 significantly reduced the infarct size and AI of myocardium suffering I/R compared to vehicle-treated group. Further mechanistic study revealed that activation of CB2 receptor by JWH133 inhibited the loss of ΔΨm, reduction of the cleaved caspases-3 and -9, release of mitochondrial cytochrome c to the cytosol, and increase of phosphorylated Akt. These JWH133-mediated effects could be totally abrogated by PI3K inhibitor wortmanin or CB2 receptor antagonist AM630.

Conclusion: Our results demonstrate that activation of CB2 receptor by JWH133 prevent apoptosis during ischemia/reperfusion through inhibition of the intrinsic mitochondria-mediated apoptotic pathway and involvement of the PI3K/Akt signal pathway.
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http://dx.doi.org/10.1159/000350088DOI Listing
December 2013

[Significance of high sensitivity C-reactive protein level for predicting risk of nonalcoholic fatty liver in type 2 diabetes mellitus patients].

Zhonghua Gan Zang Bing Za Zhi 2013 Jan;21(1):57-61

Department of Gastroenterology, Affiliated Kailuan Hospital of Hebei United University, Tangshan 063000, China.

Objective: To investigate the significance of high sensitivity C-reactive protein (hsCRP) levels in serum for detecting type 2 diabetes mellitus (T2DM) patients at risk of developing nonalcoholic fatty liver (NAFLD).

Methods: Individuals with T2DM (n = 9489) were recruited from the Kailuan Company between 2006 and 2007 for the first phase of this community-based prospective cohort study. For the second phase of the study, the original cohort was recruited for follow-up (at two years from each subject's original enrollment date (baseline)). The total followed-up subjects (n = 2802; 2344 males, 458 females, 22-88 years old) were categorized into quartiles according to baseline measurements of serum hsCRP levels (less than or equal to 0.30, > 0.30-0.60, > 0.60-1.92 and > 1.92 mg/L) and used to determine the relationship between change in incidence rates of NAFLD and predictive value of baseline serum hsCRP levels by logistic regression analysis.

Results: Twenty-nine percent (n = 813) of the followed-up subjects developed NAFLD. The incidence (%) of NAFLD at the two-year follow-up had increased in conjunction with the level of serum hsCRP detected at baseline (quartile 1: 22.5%, 2: 27.3%, 3: 32.1%, and 4: 34.3%; all, P less than 0.01). It was found that the subjects in the highest quartile had an increased risk of NAFLD (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.42-2.28, P less than 0.01), as compared with those in the lowest quartile. Moreover, when the regression model was adjusted for baseline factors of age, sex, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting serum glucose, and body mass index, the risk of NAFLD remained significantly higher for the highest quartile (vs. the lowest quartile; OR = 1.49, 95% CI: 1.16-1.91, P less than 0.01).

Conclusion: Serum hsCRP levels may be predictive of development of NAFLD in individuals with type 2 diabetes mellitus. The risk of NAFLD increases in parallel with increasing levels of serum hsCRP.
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http://dx.doi.org/10.3760/cma.j.issn.1007-3418.2013.01.015DOI Listing
January 2013