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1.
Fish Shellfish Immunol ; 144: 109247, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38006905

ABSTRACT

Mandarin fish (Siniperca chuatsi) is a valuable freshwater fish species widely cultured in China. Its aquaculture production is challenged by bacterial septicaemia, which is one of the most common bacterial diseases. Antimicrobial peptides (AMPs) play a critical role in the innate immune system of fish, exhibiting defensive and inhibitory effects against a wide range of pathogens. This study aimed to identify the antimicrobial peptide genes in mandarin fish using transcriptomes data obtained from 17 tissue in our laboratory. Through nucleotide sequence alignment and protein structural domain analysis, 15 antimicrobial peptide genes (moronecidin, pleurocidin, lysozyme g, thymosin ß12, hepcidin, leap 2, ß-defensin, galectin 8, galectin 9, apoB, apoD, apoE, apoF, apoM, and nk-lysin) were identified, of which 9 antimicrobial peptide genes were identified for the first time. In addition, 15 AMPs were subjected to sequence characterization and protein structure analysis. After injection with Aeromonas hydrophila, the number of red blood cells, hemoglobin concentration, and platelet counts in mandarin fish showed a decreasing trend, indicating partial hemolysis. The expression change patterns of 15 AMP genes in the intestine after A. hydrophila infection were examined by using qRT-PCR. The results revealed, marked up-regulation (approximately 116.04) of the hepcidin gene, down-regulation of the piscidin family genes expression. Moreover, most AMP genes were responded in the early stages after A. hydrophila challenge. This study provides fundamental information for investigating the role of the different antimicrobial peptide genes in mandarin fish in defense against A. hydrophila infection.


Subject(s)
Fish Diseases , Perciformes , Animals , Transcriptome , Hepcidins/genetics , Hepcidins/metabolism , Aeromonas hydrophila/genetics , Antimicrobial Peptides , Fishes/genetics , Fish Proteins/chemistry , Galectins/genetics
2.
Mol Med Rep ; 26(3)2022 Sep.
Article in English | MEDLINE | ID: mdl-35894137

ABSTRACT

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell migration assay data shown in Fig. 2D were strikingly similar to data that had appeared in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 16: 5055­5061, 2017; DOI: 10.3892/mmr.2017.7167].

3.
Front Endocrinol (Lausanne) ; 12: 649863, 2021.
Article in English | MEDLINE | ID: mdl-34177799

ABSTRACT

Immune checkpoint inhibitors (ICIs) are a group of drugs employed in the treatment of various types of malignant tumors and improve the therapeutic effect. ICIs blocks negative co-stimulatory molecules, such as programmed cell death gene-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), reactivating the recognition and killing effect of the immune system on tumors. However, the reactivation of the immune system can also lead to the death of normal organs, tissues, and cells, eventually leading to immune-related adverse events (IRAEs). IRAEs involve various organs and tissues and also cause thyroid dysfunction. This article reviews the epidemiology, clinical manifestations, possible pathogenesis, and management of ICIs-related thyroid dysfunction.


Subject(s)
Immune Checkpoint Inhibitors/metabolism , Thyroid Diseases/diagnosis , Thyroid Diseases/immunology , Thyroid Diseases/therapy , Aged , Aged, 80 and over , B7-H1 Antigen/metabolism , CTLA-4 Antigen/metabolism , Disease Progression , Female , Genetic Predisposition to Disease , HLA Antigens/biosynthesis , Homeostasis , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune System , Immunotherapy/methods , Ligands , Male , Middle Aged , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocytes/cytology , Thyroid Diseases/epidemiology , Thyroid Gland/physiopathology
4.
Aging (Albany NY) ; 12(19): 19520-19538, 2020 Oct 11.
Article in English | MEDLINE | ID: mdl-33040050

ABSTRACT

Cognitive dysfunction caused by chronic cerebral hypoperfusion is a common underlying cause of many cognition-related neurodegenerative diseases. The mechanisms of cognitive dysfunction caused by CCH are not clear. Long non-coding RNA is involved in synaptic plasticity and cognitive function, but whether lncRNA is involved in cognitive dysfunction caused by CCH has not yet been reported. In the present study, we identified the altered lncRNAs and mRNAs by deep RNA sequencing. A total of 128 mRNAs and 91 lncRNAs were up-regulated, and 108 mRNAs and 98 lncRNAs were down-regulated. Real-time reverse transcription-polymerase chain reaction verified the reliability of the lncRNA and mRNA sequencing. Gene Ontology and KEGG pathway analyses showed that differentially-expressed mRNAs were related to peptide antigen binding, the extracellular space, the monocarboxylic acid transport, and tryptophan metabolism. The co-expression analysis showed that 161 differentially expressed lncRNAs were correlated with DE mRNAs. By predicting the miRNA in which both DE lncRNAs and DE mRNAs bind together, we constructed a competitive endogenous RNA network. In this lncRNAs-miRNAs-mRNAs network, 559 lncRNA-miRNA-mRNA targeted pairs were identified, including 83 lncRNAs, 67 miRNAs, and 108 mRNAs. Through GO and KEGG pathway analysis, we further analyzed and predicted the regulatory function and potential mechanism of ceRNA network regulation. Our results are helpful for understanding the pathogenesis of cognitive dysfunction caused by CCH and provide direction for further research.

5.
J Cell Mol Med ; 24(19): 11221-11229, 2020 10.
Article in English | MEDLINE | ID: mdl-32846020

ABSTRACT

Acute lung injury (ALI) induced by sepsis is characterized by an inflammatory process related to the up-regulation of inflammatory cytokines and chemokines. In the present study, we explored the role of circC3P1 in sepsis-induced ALI in vitro and in vivo. The caecal ligation and puncture (CLP)-induced sepsis model was established through CLP surgery. Forty adult male C57BL/6 mice were randomly assigned into sham, CLP, CLP + vector and CLP + circC3P1 (each n = 10). Primary murine pulmonary microvascular endothelial cells (MPVECs) were transfected with circC3P1 or empty vector 24 hours prior to LPS treatment via Lipofectamine 2000. The expressions of circC3P1, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß were evaluated after 6-h LPS treatment. Cell apoptosis was evaluated via flow cytometry. The CLP group demonstrated pulmonary morphological abnormalities, increased concentrations of TNF-α, IL-6 and IL-1ß in the lung tissue, compared with the sham group. MPVECs treated with LPS significantly elevated TNF-α, IL-6 and IL-1ß levels and increased cell apoptosis than that in the control group. The circC3P1 overexpression in sepsis-induced ALI mice attenuated pulmonary injury, inflammation and apoptosis. Besides, circC3P1 revealed anti-inflammatory and anti-apoptotic effect in MPVEC-treated LPS. CircC3P1 overexpression reduced cell apoptosis and pro-inflammatory cytokines levels via down-regulating miR-21. CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in ALI induced by sepsis through modulating miR-21, indicating that circC3P1 is a promising therapeutic biomarker for sepsis-induced ALI.


Subject(s)
Acute Lung Injury/genetics , Acute Lung Injury/pathology , Apoptosis , Cytokines/biosynthesis , Inflammation Mediators/metabolism , MicroRNAs/metabolism , RNA, Circular/metabolism , Sepsis/complications , Acute Lung Injury/etiology , Animals , Apoptosis/genetics , Cecum/pathology , Down-Regulation/genetics , Endothelial Cells/pathology , Ligation , Lipopolysaccharides , Lung/blood supply , Lung/pathology , Male , Mice, Inbred C57BL , MicroRNAs/genetics , Microvessels/pathology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Punctures , RNA, Circular/genetics , Sepsis/genetics
6.
Neural Plast ; 2019: 2158285, 2019.
Article in English | MEDLINE | ID: mdl-30923551

ABSTRACT

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.


Subject(s)
Brain Ischemia/complications , Cognitive Dysfunction/drug therapy , Diterpenes/therapeutic use , Neuronal Plasticity/drug effects , Phenanthrenes/therapeutic use , Spatial Learning/drug effects , Animals , Brain Ischemia/psychology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/psychology , Dendritic Spines/drug effects , Dendritic Spines/physiology , Diterpenes/pharmacology , Hippocampus/drug effects , Hippocampus/physiology , Male , Neuronal Plasticity/physiology , Phenanthrenes/pharmacology , Rats , Rats, Sprague-Dawley , Spatial Learning/physiology
7.
J Alzheimers Dis ; 66(4): 1559-1576, 2018.
Article in English | MEDLINE | ID: mdl-30452417

ABSTRACT

Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.


Subject(s)
Brain Ischemia/metabolism , Glucagon-Like Peptide-2 Receptor/metabolism , Hippocampus/metabolism , Spatial Learning/physiology , Spatial Memory/physiology , Animals , Brain Ischemia/physiopathology , Dendritic Spines/metabolism , Disease Models, Animal , Male , Neuronal Plasticity/physiology , Neurons/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Up-Regulation
8.
Neurochem Res ; 43(4): 806-820, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29392519

ABSTRACT

Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti-oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long-term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-α and IL-1ß, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Luteolin/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/metabolism , Luteolin/pharmacology , Male , Maze Learning/drug effects , Maze Learning/physiology , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
9.
Curr Neurovasc Res ; 14(4): 385-396, 2017.
Article in English | MEDLINE | ID: mdl-29090669

ABSTRACT

BACKGROUND: Chronic Cerebral Hypoperfusion (CCH) is an important vascular risk factor for vascular-related dementia cognitive impairment and there are no effective measures for the prevention and treatment of cognitive deficit by CCH and the underlying mechanisms are still poorly understood. Methyl cytidine-phosphate-guanosine (CpG) binding protein 2 (MeCP2), regulated by microRNA 132 (miR-132), is as a transcriptional repressor in high concentrations in the brain, which regulates the expression of synaptic proteins and neuroplasticity, and may be involved in the cognitive deficit after CCH. But no relevant studies have been reported. The aim of this study is to investigate the status of MeCP2 expression after CCH and explore whether MeCP2 changes is associated with cognitive deficits after CCH. METHODS: We investigated MeCP2 expression after CCH using Western blotting, quantitative Real- Time Polymerase Chain Reaction (qRT-PCR) analysis and immunofluorescence technique in a rat model of permanent bilateral common carotid artery occlusion (2VO) to mimic CCH. We determined the effect of MeCP2 expression on cognitive deficits and neuroplasticity after CCH through lenti-virus stereotaxic injection, the Morris water maze and electrophysiology. RESULTS: CCH contributed to the down-regulation of MeCP2 and mecp2 expressions in the hippocampus and cortex. miR-132 up-regulated by 2VO was distinctly negatively correlated with MeCP2 down-regulation by miR-132 inhibitors. MeCP2 over-expression improved learning and memory impairment, as well as neuroplasticity after 2VO. Brain-Derived Neurotrophic Factor (BDNF) and the activities of its downstream pathways moleculars, tropomyosin receptor kinase B (TrkB) and the cAMP Response Element Binding Protein (CREB) were down-regulated by 2VO and rescued by MeCP2 over-expression. CONCLUSION: Our study found that miR-132 may participate in the down-regulation of MeCP2 after CCH and MeCP2 down-regulation was possibly involved in the cognitive deficit through regulation of BDNF and its downstream pathways after 2VO. Our findings expounded the underlying mechanisms of cognition deficit after CCH, which contributes to understanding the mechanisms of vascular dementia.


Subject(s)
Cerebrovascular Circulation/physiology , Cerebrovascular Disorders/metabolism , Cognitive Dysfunction/metabolism , Down-Regulation/physiology , Methyl-CpG-Binding Protein 2/metabolism , MicroRNAs/biosynthesis , Animals , Cerebrovascular Disorders/complications , Chronic Disease , Cognitive Dysfunction/etiology , Male , Maze Learning/physiology , Methyl-CpG-Binding Protein 2/antagonists & inhibitors , Rats , Rats, Sprague-Dawley
10.
Mol Med Rep ; 16(4): 5055-5061, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28791400

ABSTRACT

Gastric cancer is the fourth most common malignancy and the third leading cause of cancer­associated deaths worldwide. It has previously been demonstrated that microRNAs (miRNAs) are actively involved in the pathogenesis of gastric cancer. Therefore, miRNAs have been proposed as promising therapeutic targets in gastric cancer patients. MiR­744 is aberrantly expressed in different types of human cancer. However, the expression pattern and biological roles of miR­744 in gastric cancer remain unknown. The present study demonstrated that miR­744 expression was low in gastric cancer tissues and cell lines. Low expression levels of miR­744 was significantly correlated with lymph node metastasis, invasive depth and TNM staging in gastric cancer patients. The restoration of miR­744 expression inhibited cell proliferation and invasion in vitro. Bioinformatic prediction, luciferase reporter assay, reverse transcription­quantitative polymerase chain reaction and western blot analysis verified that brain­derived neurotrophic factor (BDNF) is a direct target of miR­744 in gastric cancer cells. Furthermore, BDNF was upregulated in gastric cancer tissues and inversely correlated with miR­744 expression. Furthermore, enforced BDNF expression reversed the tumor­suppressing effects of miR­744 on the proliferation and invasion of gastric cancer cells, indicating that BDNF is a functional mediator of miR­744 in gastric cancer. The present study suggests that miR­744 is a potential prognostic biomarker and treatment target in gastric cancer patients.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , MicroRNAs/genetics , RNA Interference , Stomach Neoplasms/genetics , 3' Untranslated Regions , Adult , Aged , Cell Line, Tumor , Cell Movement , Cell Proliferation , Computational Biology/methods , Female , Gene Expression , Genes, Reporter , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Stomach Neoplasms/pathology
11.
Psychiatry Res ; 246: 284-292, 2016 Dec 30.
Article in English | MEDLINE | ID: mdl-27741481

ABSTRACT

Chronic cerebral hypoperfusion (CCH) induces cognitive deficits. Although CCH can be improved, cognitive impairment is not improved accordingly. To date, many studies have focused on investigating the pathophysiological mechanisms of CCH; however, the treatment of the induced cognitive impairment remains ineffective. Thus, the mechanisms underlying cognitive impairment after CCH and potential agents for treating this impairment need to be explored further. Oxiracetam is a nootropic drug that improves clinical outcomes for some central nervous system (CNS) disorders. Whether it can improve cognitive impairment after CCH is unknown. In this study, we used behavioural methods, electrophysiology, biochemistry, histopathological staining and transmission electron microscope to investigate rat's cognitive impairment by CCH, and found that Oxiracetam could improve CCH-induced cognitive impairment and prevent deficits of neural plasticity, white matter lesions, and synaptic ultrastructure. These results suggest that Oxiracetam may be effective as a potential agent against CCH-induced cognitive impairment.


Subject(s)
Cerebrovascular Disorders/complications , Cognitive Dysfunction/drug therapy , Nootropic Agents/pharmacology , Pyrrolidines/pharmacology , Animals , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Disease Models, Animal , Male , Nootropic Agents/administration & dosage , Pyrrolidines/administration & dosage , Rats , Rats, Sprague-Dawley
12.
BMC Complement Altern Med ; 15: 137, 2015 Apr 29.
Article in English | MEDLINE | ID: mdl-25925762

ABSTRACT

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population aged over 65 years old. Mitochondrial defects and oxidative stress actively participate in degeneration of dopaminergic (DA) neurons in PD. Paeonolum, a main component isolated from Moutan cortex, has potent antioxidant ability. Here, we have examined the effects of paeonolum against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. METHODS: The overall viability and neurodegeneration of DA neurons was assessed in ETvmat2:green fluorescent protein (GFP) transgenic zebrafish, in which most monoaminergic neurons are labeled by GFP. Damage to PC12 cells was measured using a cell viability assay and assessment of nuclear morphology. Intracellular reactive oxygen species (ROS) and the level of total GSH were assessed. The mitochondrial cell death pathway including mitochondrial membrane potential, cytochrome C release and caspase-3 activity were also examined in PC12 cells. RESULTS: Paeonolum protected against MPP(+)-induced DA neurodegeneration and locomotor dysfunction in zebrafish in a concentration-dependent manner. Similar neuroprotection was replicated in the PC12 cellular model of MPP(+) toxicity. Paeonolum attenuated MPP(+)-induced intracellular ROS accumulation and restored the level of total GSH in PC12 cells. Furthermore, paeonolum significantly inhibited the mitochondrial cell death pathway induced by MPP(+). CONCLUSIONS: Collectively, the present study demonstrates that paeonolum protects zebrafish and PC12 cells against MPP(+)-induced neurotoxicity.


Subject(s)
Antioxidants/therapeutic use , Dopaminergic Neurons/drug effects , Neuroprotective Agents/therapeutic use , Paeonia/chemistry , Parkinson Disease/prevention & control , Phytotherapy , Plant Extracts/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Caspase 3/metabolism , Cell Death/drug effects , Cytochromes c/metabolism , Dopamine/metabolism , Dopaminergic Neurons/metabolism , Humans , MPTP Poisoning/metabolism , MPTP Poisoning/prevention & control , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Neuroprotective Agents/pharmacology , Neurotoxins/adverse effects , Oxidative Stress/drug effects , PC12 Cells , Parkinson Disease/metabolism , Plant Extracts/pharmacology , Rats , Reactive Oxygen Species/metabolism , Zebrafish
13.
Mar Drugs ; 12(6): 3307-22, 2014 May 30.
Article in English | MEDLINE | ID: mdl-24886868

ABSTRACT

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1-36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37-42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.


Subject(s)
Anticonvulsants/pharmacology , Epilepsy/drug therapy , Phenyl Ethers/pharmacology , Pyrans/pharmacology , Animals , Anticonvulsants/chemistry , Anticonvulsants/isolation & purification , Behavior, Animal/drug effects , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacology , Disease Models, Animal , Fungi/chemistry , High-Throughput Screening Assays/methods , Larva , Motor Activity/drug effects , Oceans and Seas , Pentylenetetrazole , Phenyl Ethers/chemistry , Phenyl Ethers/isolation & purification , Proto-Oncogene Proteins c-fos/genetics , Pyrans/chemistry , Pyrans/isolation & purification , RNA, Messenger/metabolism , Structure-Activity Relationship , Zebrafish
14.
Mar Drugs ; 12(5): 2790-801, 2014 May 12.
Article in English | MEDLINE | ID: mdl-24824025

ABSTRACT

Angiogenesis is the formation of blood vessels from pre-existing vasculature. Excessive or uncontrolled angiogenesis is a major contributor to many pathological conditions whereas inhibition of aberrant angiogenesis is beneficial to patients with pathological angiogenesis. Catunaregin is a core of novel marine compound isolated from mangrove associate. The potential anti-angiogenesis of catunaregin was investigated in human umbilical vein endothelial cells (HUVECs) and zebrafish. HUVECs were treated with different concentrations of catunaregin in the presence or absence of VEGF. The angiogenic phenotypes including cell invasion cell migration and tube formation were evaluated following catunaregin treatment in HUVECs. The possible involvement of AKT, eNOS and ERK1/2 in catunaregin-induced anti-angiogenesis was explored using Western blotting. The anti-angiogenesis of catunaregin was further tested in the zebrafish embryo neovascularization and caudal fin regeneration assays. We found that catunaregin dose-dependently inhibited angiogenesis in both HUVECs and zebrafish embryo neovascularization and zebrafish caudal fin regeneration assays. In addition, catunaregin significantly decreased the phosphorylation of Akt and eNOS, but not the phosphorylation of ERK1/2. The present work demonstrates that catunaregin exerts the anti-angiogenic activity at least in part through the regulation of the Akt and eNOS signaling pathways.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Catechols/pharmacology , Lignans/pharmacology , Nitric Oxide Synthase Type III/drug effects , Oncogene Protein v-akt/drug effects , Animal Fins/drug effects , Animal Fins/growth & development , Animals , Catechols/chemistry , Cell Movement/drug effects , Embryo, Nonmammalian , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Lignans/chemistry , Phosphorylation/drug effects , Regeneration/drug effects , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/pharmacology , Zebrafish
15.
Eur J Pharmacol ; 732: 76-85, 2014 Jun 05.
Article in English | MEDLINE | ID: mdl-24690262

ABSTRACT

Aß40-induced vascular dysfunction has been implicated in the pathogenesis of Alzheimer׳s disease (AD). In the present study, we investigated the possible protective effects of puerarin against Aß40-induced vascular damage and impairment to angiogenesis in transgenic TG (fli1:EGFP) zebrafish and human endothelial cells. Aß40 peptides at 5µM caused an obvious reduction of vessel branches in the subintestinal vein basket, induced NADPH oxidase-derived reactive oxygen species and impaired vascular endothelial growth factor (VEGF)-dependent angiogenesis. Pretreatment with puerarin attenuated Aß40-induced vessel reduction and impairment to angiogenesis in a dose-dependent manner. In addition, Aß40 decreased VEGF-dependent phosphorylation of Akt and eNOS, whereas puerarin treatment attenuated these detrimental effects. Furthermore, the restoration of Aß40-induced-angiogenesis impairment by puerarin was abolished by either the PI3 kinase inhibitor LY294002 (10µM) or eNOS inhibitor L-NAME. The present study suggests that puerarin exerts its protective action probably through reduction of NADPH oxidase-derived reactive oxygen species overproduction and activation of the PI3K/Akt/eNOS pathways.


Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/toxicity , Endothelial Cells/drug effects , Isoflavones/pharmacology , Neuroprotective Agents/pharmacology , Vascular Diseases/chemically induced , Vascular Diseases/prevention & control , Animals , Humans , Neovascularization, Physiologic/drug effects , Reactive Oxygen Species/metabolism , Respiratory Burst/drug effects , Vascular Diseases/pathology , Zebrafish
16.
PLoS One ; 8(7): e68106, 2013.
Article in English | MEDLINE | ID: mdl-23874513

ABSTRACT

Mutations in the TARDBP gene, which encodes the Tar DNA binding protein, have been shown to causes of both familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS). Recently, several novel TARDBP exon 6 mutants have been reported in patients with ALS in Europe and America but not in Asia. To further examine the spectrum and frequency of TARDBP exon 6 mutations, we investigated their frequency in ethnic Chinese patients with sporadic ALS. TARDBP exon 6 was screened by direct sequencing in 207 non-SOD1 SALS patients and 230 unrelated healthy controls but no mutations were identified. Our data indicate that exon 6 mutations in TARDBP are not a common cause of SALS in Han Chinese population from Southern Mainland China.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Asian People/genetics , DNA-Binding Proteins/genetics , Exons , Mutation , Adult , China , Female , Genetic Association Studies , Humans , Male , Middle Aged
17.
PLoS One ; 8(5): e64720, 2013.
Article in English | MEDLINE | ID: mdl-23724084

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder mainly affecting motor neurons. Mutations in superoxide dismutase-1 (SOD-1) account for about 20% of familial ALS patients. A robust supply of motoneurons carrying the mutated gene would help understand the causes of motoneuron death and develop new therapeutics for the disease. Here, we established induced pluripotent stem (iPS) cell lines from SOD1G93A mice and compared their potency in motoneuron generation with normal iPS cells and mouse embryonic stem cells (E14). Our results showed that iPS cells derived from SOD1G93A mice possessed the similar potency in neuronal differentiation to normal iPS cells and E14 cells and can be efficiently driven to motoneuron-like phenotype. These cells exhibited typical neuronal morphology, expressed key motoneuron markers, including ChAT and HB9, and generated repetitive trains of action potentials. Furthermore, these neurons highly expressed human SOD-1 and exhibited shorter neurites compared to controls. The present study provides evidence that ALS-iPS cells can be used as disease models in high-throughput screening and mechanistic studies due to their ability to efficiently differentiate into specific neuronal subtypes.


Subject(s)
Cell Differentiation , Induced Pluripotent Stem Cells/cytology , Motor Neurons/cytology , Superoxide Dismutase/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Cell Line , Fibroblasts/cytology , Fibroblasts/metabolism , Green Fluorescent Proteins/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Promoter Regions, Genetic/genetics , Superoxide Dismutase-1 , Tail , Transduction, Genetic , Tubulin/metabolism
18.
Mar Drugs ; 10(6): 1307-1320, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22822374

ABSTRACT

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.


Subject(s)
Angiogenesis Inducing Agents/pharmacology , Aquatic Organisms/chemistry , Neovascularization, Physiologic/drug effects , Nitric Oxide Synthase Type III/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Angiogenesis Inducing Agents/chemical synthesis , Angiogenesis Inducing Agents/chemistry , Angiogenesis Inducing Agents/isolation & purification , Animals , Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacology , Cell Line , Chromones/pharmacology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Fungi/chemistry , Human Umbilical Vein Endothelial Cells , Humans , Morpholines/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Zebrafish/metabolism
19.
J Cardiovasc Pharmacol ; 59(4): 352-62, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22286127

ABSTRACT

We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration, and endothelial cell tube formation of human umbilical vein endothelial cells in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 inhibitor; U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; cavtratin, an endothelial nitric oxide synthase (eNOS) inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and fibroblast growth factor receptor 2 expression, which were inhibited by U0126. NBP increased the phosphorylation of Akt and eNOS at serine 1177, which was blocked by LY294002. NBP-stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that (1) NBP promoted angiogenesis and (2) the angiogenic effects of NBP were mediated by the ERK1/2 and phosphatidylinositol 3-kinase/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.


Subject(s)
Benzofurans/pharmacology , Neovascularization, Physiologic/drug effects , Neuroprotective Agents/pharmacology , Signal Transduction/drug effects , Animals , Benzofurans/administration & dosage , Dose-Response Relationship, Drug , Human Umbilical Vein Endothelial Cells , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neuroprotective Agents/administration & dosage , Nitric Oxide Synthase Type III/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Zebrafish/embryology
20.
Neuroreport ; 22(14): 689-95, 2011 Oct 05.
Article in English | MEDLINE | ID: mdl-21849916

ABSTRACT

Induced pluripotent stem (iPS) cells have been generated from somatic cells by ectopic expression of defined transcription factors. The important issues for clinical applications of iPS cells are the defined methods for somatic cell differentiation and how to effectively enrich desired cell population. Here we used humanized renilla green fluorescent protein under the control of Tα1 α-tubulin promoter as lineage selection marker for neuronal differentiation of iPS cells. Using fluorescence-activated cell sorting, green fluorescent protein positive cells were isolated and enriched to near-purity. These results indicated that the neuronal differentiation potential of iPS cells derived from adult somatic cells is similar to that of embryonic stem cells and the high-purity neurons may have important implications for neurodevelopmental studies, safety pharmacological studies, and transplantation studies.


Subject(s)
Cell Differentiation , Embryonic Stem Cells/cytology , Induced Pluripotent Stem Cells/cytology , Neurons/cytology , Age Factors , Animals , Cell Differentiation/physiology , Cells, Cultured , Embryonic Stem Cells/physiology , Induced Pluripotent Stem Cells/physiology , Mice , Mice, Inbred C57BL , Neurons/physiology
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