Publications by authors named "Xiaohuan Li"

37 Publications

From encoding to retrieval: Change in level of unitization resolves debate about Unitization's effect on associative recognition.

Psychophysiology 2022 Aug 10:e14161. Epub 2022 Aug 10.

Beijing Key Laboratory of Learning and Cognition, Department of Psychology, Capital Normal University, Beijing, China.

Although it is widely accepted that familiarity could support associative recognition when the to-be-learn items are 'unitized' into a new representation, the effects of unitization on associative recognition and recollection remain much debated. The current study aimed to explain these debates by exploring when and how unitization benefits associative recognition using event-related potentials (ERPs). During the encoding phase, participants learned compound words and unrelated word pairs (i.e., High vs. Low level of unitization). At retrieval, the compound words were rearranged into new compound words (i.e., no-change) and unrelated word pairs (i.e., change). Similarly, the unrelated word pairs were rearranged into new unrelated word pairs (i.e., no-change) and compound words (i.e., change). Results showed that under the no-change condition, unitization did not affect associative recognition, nor its underlying processes. In contrast, under the change condition, unitization improved associative recognition by increasing both familiarity-related FN400 effect and recollection-related LPC effect. In addition, a planned comparison between the compound-change and unrelated-no change conditions-a common index for unitization effect in past studies-revealed that unitization could not only elicit significant FN400 effect, but also improve associative recognition by increasing LPC effect. Collectively, these results not only allowed to explain the current discrepancies in the literature concerning the effect of unitization on associative recognition, but also emphasized the importance of matching the level of unitization between the studied and rearranged word pairs.
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http://dx.doi.org/10.1111/psyp.14161DOI Listing
August 2022

miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease.

Oxid Med Cell Longev 2022 29;2022:7671324. Epub 2022 Jul 29.

Department of Neurology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.

Background: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD.

Methods: Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay.

Results: Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model.

Conclusion: miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD.
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http://dx.doi.org/10.1155/2022/7671324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355771PMC
August 2022

Palladium-catalyzed stereoselective ring-opening reaction of aryl cyclopropyl ketones.

Org Biomol Chem 2022 07 13;20(27):5412-5415. Epub 2022 Jul 13.

Department of Pharmacy, The First Afflicted Hospital of Chengdu Medical College, Chengdu 610500, PR China.

Herein, we report that α,β-unsaturated ketones could be obtained by palladium-catalyzed ring-opening of mono-substituted cyclopropyl ketones efficiently and systematically. ()-1-Arylbut-2-en-1-ones were generated from aryl cyclopropyl ketones stereoselectively in yields of 23-89% by the Pd(OAc)/PCy catalytic system. The reaction exhibited stereoselectivity (only products were found) and was suitable for both phenyl and heteroaryl cyclopropyl ketones.
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http://dx.doi.org/10.1039/d2ob00719cDOI Listing
July 2022

Negatively Charged MOF-Based Composite Anion Exchange Membrane with High Cation Selectivity and Permeability.

Membranes (Basel) 2022 Jun 10;12(6). Epub 2022 Jun 10.

Key Laboratory of Environment-Friendly Polymeric Materials of Anhui Province, School of Chemistry & Chemical Engineering, Anhui University, Hefei 230601, China.

Every metal and metallurgical industry is associated with the generation of wastewater, influencing the living and non-living environment, which is alarming to environmentalists. The strict regulations about the dismissal of acid and metal into the environment and the increasing emphasis on the recycling/reuse of these effluents after proper remedy have focused the research community's curiosity in developing distinctive approaches for the recovery of acid and metals from industrial wastewaters. This study reports the synthesis of UiO-66-(COOH) using dual ligand in water as a green solvent. Then, the prepared MOF nanoparticles were introduced into the DMAM quaternized QPPO matrix through a straightforward blending approach. Four defect-free UiO-66-(COOH)/QPPO MMMs were prepared with four different MOF structures. The BET characterization of UiO-66-(COOH) nanoparticles with a highly crystalline structure and sub-nanometer pore size (~7 Å) was confirmed by XRD. Because of the introduction of MOF nanoparticles with an electrostatic interaction and pore size screening effect, a separation coefficient (S) of 565 and U of 0.0089 m·h for U-C(60)/QPPO were perceived when the loading dosage of the MOF content was 10 wt%. The obtained results showed that the prepared defect-free MOF membrane has broad prospects in acid recovery applications.
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http://dx.doi.org/10.3390/membranes12060601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9227639PMC
June 2022

The neural correlates of social anxiety modulating conflict-driven cognitive control: An ERP study.

Neurosci Lett 2022 07 8;783:136721. Epub 2022 Jun 8.

Beijing Key Laboratory of Learning and Cognition, School of Psychology, Capital Normal University, No. 23 Baiduizijia, Fuwaidajie St, Haidian District, Beijing 100048, China. Electronic address:

According to attentional control theory and processing efficiency theory, anxiety impairs top-down cognitive control and processing efficiency under threat-related stimuli conditions. However, what is the resulting pattern under an emotionally neutral condition? Therefore, the study examined whether individuals with social anxiety exhibited the cognitive control deficiency in absence of emotional information and how social anxiety modulated cognitive control performance by recording the N2, N450, and SP components in the Stroop task. Behavioral data showed that participants with high social anxiety (HSA) showed slower response times than low social anxiety (LSA). ERP data showed that in HSA participants, congruent trials elicited more negative N2 than incongruent trials, but this was not for LSA ones. The N450 was more negative under incongruent condition than congruent ones. This effect was noticeable in LSA participants, but not in HSA ones. The conflict SP was more positive under incongruent condition than congruent one in HSA participants but not in LSA ones. The significant group differences of the N450 and SP were found mainly for incongruent condition. The present findings indicate that individuals with HSA exhibited cognitive control deficiency for neutral stimuli and an individual's social anxiety modulates the neural correlates of conflict-driven cognitive control.
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http://dx.doi.org/10.1016/j.neulet.2022.136721DOI Listing
July 2022

Primary hepatic neuroendocrine carcinoma with colon adenoma: A case report with literature review.

Int J Surg Case Rep 2022 Jun 10;95:107176. Epub 2022 May 10.

Department of General Surgery, The First Hospital of Jiaxing (The First Affiliated Hospital of Jiaxing University), Jiaxing, Zhejiang 314001, PR China.

Introduction And Importance: Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare, and the clinical symptoms, test results, and imaging characteristics are nonspecific in most patients; thus, it is difficult to differentiate from other liver masses before surgery. Histopathology and immunohistochemistry are the main basis for the diagnosis. PHNETs and colon tumors co-occur in a patient and are non-homologous, as reported in the English-language literature for the first time.

Case Presentation: We present a case of a 60-year-old woman with right hepatic lobe mass accidentally discovered on abdominal ultrasonography during a routine examination. Preoperative liver contrast-enhanced computed tomography suggested hepatocellular carcinoma; then, surgery were performed. Pathological results revealed a Grade 2 neuroendocrine tumor of the liver. In search of the primary tumor, upper and lower endoscopy of the GI tract was performed and revealed a mass in the ascending colon. Ascending colon cancer was considered; then, laparoscopic right hemicolectomy was performed. Pathological results suggested tubular villous adenoma of the ascending colon. The final diagnosis was not colon cancer with liver metastases but was PHNETs with colon adenoma.

Clinical Discussion: PHNETs are rare cancers that are difficult to diagnose, requiring not only differentiation from other liver masses but also exclusion of metastases from extrahepatic sources. The pathological results play an important in making an accurate diagnosis.

Conclusion: Pathology, postoperative follow-up, and comprehensive imaging examinations are powerful tools in the diagnosis of PHNETs. Currently, surgery is the best treatment to achieve a potential cure and prolong the patient's survival.
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http://dx.doi.org/10.1016/j.ijscr.2022.107176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9157444PMC
June 2022

Genome-wide characterization of the Elovl gene family in Gymnocypris przewalskii and their potential roles in adaptation to cold temperature.

Comp Biochem Physiol B Biochem Mol Biol 2022 Oct-Dec;262:110759. Epub 2022 May 20.

Qinghai Provincial Key Laboratory of Animal Ecological Genomics, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China. Electronic address:

The elongase of the very long-chain fatty acids (Elovls) gene family in fish has more diversity than in other vertebrates, which plays several critical roles in fatty acid synthesis and low-temperature stress adaptation. Gymnocypris przewalskii settles in plateau lakes with cold and resource-poor settings, and the evolution and function of Elovl genes in this fish are unknown. In the study, to identify the Elovl genes in G. przewalskii, the genome-wide identification and phylogenetic analysis of the gene members have been conducted with the expression profile of different tissues under cold stress. Fatty acid compositions, meanwhile, were detected in both the hepatopancreas and skeletal muscle during cold adaptation. A total of 21 Elovl members have been identified from the genome of G. przewalskii, belonging to Elovl1, Elovl2, Elovl4, Elovl5, Elovl6, Elovl7, and Elovl8 subgroups, with conserved ELO domain and four common motifs. Phylogenetic analysis revealed that subfamilies Elovl1 and Elovl7, Elov2, and Elovl5 have a closer genetic relationship, while the Elovl6 class was classed into an independent clade. Synteny analysis showed that whole-genome duplication, tandem duplicates, and gene conversion could drive the Elovls family expansion in G. przewalskii. The Ka/Ks and RELAX analysis showed distinguishing positive selection traces in ORF sequences of gpElovl2. Transcriptional data showed that different gpElovl subtypes exhibited a tissue-specific expression. Subtypes gpElovl1a, gpElovl2 and gpElovl6l were highly expressed induced by cold stress, as well as fatty acid metabolism-related genes, including Acyl-CoA synthetase long-chain gene (Ascl1a-1) and Stearyl-CoA desaturase gene (Scd1a-1). In addition, monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) contents of the hepatopancreas and skeletal muscle were significantly increased under 15-day cold stress. These results provide a better understanding of fish Elovl genes and their roles in cold adaptation.
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http://dx.doi.org/10.1016/j.cbpb.2022.110759DOI Listing
August 2022

Dihydroartemisinin attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting oxidative stress.

Mol Brain 2022 04 28;15(1):36. Epub 2022 Apr 28.

Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

Neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia is a major cause of neurological disability among infants. Dihydroartemisinin (DHA), derived from artemisinin, well known as an anti-malarial medicine, was proved to be able to inhibit oxidative stress and inflammation. However, whether those functions of DHA play roles in hypoxic-ischemic brain damage (HIBD), an animal model of HIE in patient which also been observed to have oxidative stress and inflammation, is unknown. In this study, we demonstrated that the DHA treatment on newborn rats significantly relieved the neuron loss and motor and cognitive impairment caused by HIBD. One of the underlying mechanisms is that DHA enhanced the anti-oxidant capacity of HIBD rats by up-regulating the total antioxidant capacity (T-AOC), gluathione reductase (GR) and catalase (CAT) while down regulating the pro-oxidative substances including hydrogen peroxide (HO), total nitric oxide synthase (T-NOS) and inducible nitric oxide synthase (iNOS). Thus, our study illustrated that DHA could alleviate the damage of brains and improve the cognitive and motor function of HIBD rats by inhibiting oxidative stress, provided an opportunity to interrogate potential therapeutics for affected HIE patients.
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http://dx.doi.org/10.1186/s13041-022-00921-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052669PMC
April 2022

Combining network pharmacology with chromatographic fingerprinting and multicomponent quantitative analysis for the quality evaluation of Astragali Radix.

Biomed Chromatogr 2022 Apr 2;36(4):e5319. Epub 2022 Feb 2.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.

Nowadays, cultivated variants and adulterants of Astragali Radix (AR) have flooded the market, causing the quality assurance of AR to be challenging. To address this issue, we combined network pharmacology with chromatographic fingerprinting and multicomponent quantitative analysis for the quality evaluation of AR. Specifically, through network pharmacology, a complete understanding of the active components and pharmacological activities of AR was established. In addition, establishing fingerprint profiles and multicomponent quantitation by high-performance liquid chromatography (HPLC) is convenient and comprehensive, and can more fully reflect the overall situation of the distribution of various chemical components. To evaluate and differentiate AR from different origins, hierarchical cluster analysis and principal component analysis were performed. The result showed that AR acts synergistically through multiple targets and pathways. The content of chemical components in AR from different origins varied significantly. Combining network pharmacology and multicomponent quantification results, astragaloside II and IV and formononetin can be used as quality markers for the quality control of AR. This study provides a comprehensive and reliable strategy for the quality evaluation of AR and identifies its quality markers to ensure the quality of the herb.
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http://dx.doi.org/10.1002/bmc.5319DOI Listing
April 2022

Pd-Catalyzed Direct Modification of an Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues.

ACS Omega 2021 Sep 1;6(36):23347-23354. Epub 2021 Sep 1.

School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.

Palladium/BuAdP efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue () shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against HO-induced damage in SH-SY5Y cells. Docking results of compound also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).
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http://dx.doi.org/10.1021/acsomega.1c03103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444293PMC
September 2021

Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of -Aryl Huperzine A Analogues.

J Nat Prod 2021 08 16;84(8):2374-2379. Epub 2021 Aug 16.

School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.

The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of -(hetero)aryl analogues (-) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the -aryl-huperzine A (-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in experiments. Three arylated huperzine A analogues (, , and ) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue () displayed the most potent AChE inhibition activity, with an IC value of 1.5 μM, which was 7.6-fold more active than HPA. Compound also exhibited better neuroprotective activity for HO-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00600DOI Listing
August 2021

Three New C-Diterpenoid Alkaloids from Aconitum novoluridum.

Chem Pharm Bull (Tokyo) 2021 ;69(8):811-816

School of Life Science and Engineering, Southwest Jiaotong University.

Three new aconitine-type C-diterpenoid alkaloid namely novolunines A (1), B (2), and C (3), along with fifteen known diterpenoid alkaloids were isolated from the roots of Aconitum novoluridum, whose phytochemical investigations have never been reported before. The structures of three new alkaloids were established on the basis of spectra data (high-resolution electrospray ionization (HR-ESI)-MS, IR, one dimensional (1D)- and 2D-NMR). Noteworthily, novolunines A (1) and B (2) are two diterpenoid alkaloids bearing conformational isomerism. In addition, the diterpenoid alkaloids 1-3 did not show any anti-acetylcholinesterase (AChE) or anti-inflammatory activities.
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http://dx.doi.org/10.1248/cpb.c21-00262DOI Listing
September 2021

Iron-Catalyzed Skeletal Conversion of Lathyrane to Premyrsinane Diterpenes and Their Cytotoxic Activities.

J Nat Prod 2021 06 21;84(6):1838-1842. Epub 2021 May 21.

School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.

Two new premyrsinane-type diterpenes ( and ) as diastereomers were synthesized from lathyrane-type diterpene euphorbia factor L () for the first time via an efficient Fe(acac)-catalyzed skeleton conversion process. This conversion features a biogenetically inspired strategy that relies on a concise reductive olefin coupling involving intramolecular Michael addition with free radicals. The structures of and were elucidated by a combination of the interpretation of their spectroscopic data and single-crystal X-ray diffraction analysis. The premyrsinane diterpenes and exhibited cytotoxic activity against the 4T1 breast cancer cell line, while the parent compound euphorbia factor L () was inactive. The current results not only confirmed the biogenetic relationship between lathyranes and premyrsinanes for the first time but also suggested a novel method for the preparation of naturally rare premyrsinane diterpenes with high bioactivity from the more abundant natural lathyrane diterpenes.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01363DOI Listing
June 2021

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of -Aryltacrine Derivatives.

ACS Omega 2021 Apr 2;6(14):9960-9972. Epub 2021 Apr 2.

School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.

A new series of -aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, -(4-(trifluoromethyl)phenyl)-tacrine () and -(4-methoxypyridin-2-yl)-tacrine () showed the most potent activity against AChE (IC values of 1.77 and 1.48 μM, respectively). The anti-AChE activity of and was 3.5 times more than that of tacrine (IC value of 5.16 μM). Compound also displayed anti-BuChE activity with an IC value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against HO-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound a new promising multifunctional candidate for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1021/acsomega.1c01404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047743PMC
April 2021

Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage.

Cell Death Differ 2021 08 12;28(8):2367-2384. Epub 2021 Mar 12.

Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.

Hypoxic-ischemic encephalopathy (HIE) is a main cause of mortality and severe neurologic impairment in the perinatal and neonatal period. However, few satisfactory therapeutic strategies are available. Here, we reported that a rapid nuclear translocation of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) is an essential step in hypoxic-ischemic brain damage (HIBD)- and oxygen-glucose deprivation (OGD)-induced neuronal injures both in vivo and in vitro. In addition, we found that OGD-induced nuclear translocation of PTEN is dependent on PTEN mono-ubiquitination at the lysine 13 residue (K13) that is mediated by neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1). Importantly, we for the first time identified α- and γ-adaptin binding protein (Aagab) as a novel NEDD4-1 regulator to regulate the level of NEDD4-1, subsequently mediating Pten nuclear translocation. Finally, we demonstrated that genetic upregulation of Aagab or application of Tat-K13 peptide (a short interference peptide that flanks K13 residue of PTEN) not only reduced Pten nuclear translocation, but also significantly alleviated the deficits of myodynamia, motor and spatial learning and memory in HIBD model rats. These results suggest that Aagab may serve as a regulator of NEDD4-1-mediated Pten nuclear translocation to promote functional recovery following HIBD in neonatal rats, and provide a new potential therapeutic target to guide the clinical treatment for HIE.
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http://dx.doi.org/10.1038/s41418-021-00757-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328997PMC
August 2021

Isolation, Structure Elucidation, Semi-Synthesis, and Structural Modification of C-Diterpenoid Alkaloids from and Their Neuroprotective Activities.

J Nat Prod 2021 04 5;84(4):1067-1077. Epub 2021 Mar 5.

School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.

Five new aconitine-type C-diterpenoid alkaloids, apetalrines A-E (-), were isolated from . Their structures were determined by analysis of 1D and 2D NMR, IR, and HRESIMS data. Semisynthesis of apetalrine B () from its parent compound aconorine was achieved to confirm the structure proposed. Twenty derivatives of (-, , , , , , , , ) were synthesized via a unified approach relying on simple coupling reactions. The evaluation of neuroprotective effects of compounds (-, , , -, , , , , , , ) with low cytotoxicity revealed compound to exhibit good neuroprotective effects in HO-treated SH-SY5Y cells at a concentration of 50 μM. A series of studies using flow cytometry, staining, and Western blotting on indicated that its neuroprotective effects may arise from inhibiting cell apoptosis.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01111DOI Listing
April 2021

The neurocognitive features in survival processing: An ERP study.

Int J Psychophysiol 2020 03 16;149:35-47. Epub 2019 Nov 16.

Beijing Key Laboratory of Learning and Cognition, School of Psychology, Capital Normal University, Beijing, China; Beijing Advanced Innovation Center for Imaging Technology, Capital Normal University, Beijing, China. Electronic address:

Recent behavioral studies used a survival processing task to investigate our memory systems from an evolutionary perspective. These results showed a memory advantage for the words rated for their relevance to a survival scenario compared with the words processed under numerous other tasks. However, the proximate explanations for the survival processing effect were mainly investigated through the subsequent retention data. By using event-related potentials, the present study was aimed to explore the neurocognitive features when we perform the survival-relevance-rating task. We used a pleasantness rating task and a moving processing task as control conditions in Experiments 1 and 2, respectively. Our results showed a larger parietal P600 for the words processed in the survival task compared with those processed in the pleasantness task and the moving task, indicating more elaborative encoding were obtained for the words processed in the survival task. Furthermore, an attenuated N400 was observed for the survival-relevant words in the survival task, indicating the survival scenario could facilitate the retrieval of these survival-relevant words. More importantly, a larger right frontal P600 was also observed for these survival-relevant words. This component might reflect the cognitive processes when we attempt to use the objects at hand to solve the fitness-relevant problems which we are facing. The present study supports the elaborative encoding hypothesis, and found the right frontal cortex plays an important role when we perform the survival task.
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http://dx.doi.org/10.1016/j.ijpsycho.2019.10.012DOI Listing
March 2020

Animate words facilitate noun-noun integration during an imagery task: an event-related potential study.

Neuroreport 2019 07;30(10):713-717

Beijing Key Laboratory of Learning and Cognition, Department of Psychology, School of Psychology.

The animate-inanimate distinction is fundamental to understand our physical world and language processing. Previous studies have shown that animate nouns are more prone to be assigned the actor role and are easier to integrate with a verb than inanimate nouns. On the basis of these characteristics of animate nouns, this study aimed to investigate whether animate nouns could facilitate the noun-noun integration. Animate-inanimate noun pairs and inanimate-inanimate noun pairs were used in an imagery task. With electroencephalogram recording, participants were instructed to integrate the two unrelated nouns in each pair to form an interactive mental imagery. These results showed a larger P600 for the animate-inanimate pairs than the inanimate-inanimate pairs. As the P600 component reflects the integration process, specifically, the more elaborate the encoding, the larger the P600 amplitude. Thus, this larger P600 amplitude indicated that a more vivid mental imagery was formed when integrating an animate noun and an inanimate noun than integrating two inanimate nouns. Thus, these results suggest that animate nouns could facilitate the integration of two unrelated nouns during the imagery task.
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http://dx.doi.org/10.1097/WNR.0000000000001264DOI Listing
July 2019

The application value of capsule endoscopy in diagnosing small intestinal carcinoma.

J Cancer Res Ther 2018 Jan;14(1):57-60

Department of Endoscopy, Xinxiang Central Hospital, Henan Province, PR China.

Objective: The aim of this study was to explore the clinical value of capsule endoscopy in the diagnosis of small intestine neoplastic lesions.

Materials And Methods: A retrospective analysis was conducted on the clinical data of 108 patients who underwent capsule endoscopic examination in the Endoscopy Center of Xinxiang Central Hospital from February 2010 to January 2014. The characteristics of different small bowel diseases were observed, and the prevalence rates of different small bowel lesions were calculated.

Results: Of the included 108 patients who received capsule endoscopic examination, 74 cases showed lesions, with a detection rate of 68.52%. Of these 74 patients, 56 cases (51.85%) suffered from small bowel diseases and 18 cases (16.67%) were manifested with other gastrointestinal lesions. Moreover, obvious lesion was not observed in 34 cases (31.48%). Among the patients with lesions, we observed seven cases of submucosal tumor in small intestines, five cases of small intestinal carcinoma, two cases of small intestinal polyps, two cases of small intestinal roundworm, eight cases of small intestine ulcer, one case of Crohn's disease, 18 cases of enteritis, two cases of small intestine diverticula, four cases of small intestine hemangioma, one case of small intestine vascular malformation, one case of intestinal lymphangiectasia, one case of small intestine compression, two cases of small intestine hemorrhage, and two cases of small intestinal lipoma. Among the patients who showed other gastrointestinal lesions, we observed one case of esophageal diverticula, three cases of gastric erosion, six cases of superficial gastritis, four cases of gastric ulcer, one case of pyloric ulcer, one case of colonic polyps, and two cases of colon tumor.

Conclusion: Capsule endoscopy demonstrated a high diagnostic value for various small bowel diseases, including both tumor and inflammatory lesions. Given its simplicity, safety, and reliability, capsule endoscopy was an important examination tool for the diagnosis of small bowel diseases.
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http://dx.doi.org/10.4103/jcrt.JCRT_584_17DOI Listing
January 2018

Food allergy induces alteration in brain inflammatory status and cognitive impairments.

Behav Brain Res 2019 05 12;364:374-382. Epub 2018 Jan 12.

Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Brain Research Centre, University of British Columbia, Vancouver, BC, V6T 2B5, Canada. Electronic address:

Accumulating evidence supports an increase in emotional and behavioral problems in patients with food allergy, but the underlying mechanism remains poorly understood. Here we found that in addition to inducing an increase of allergic factors in serum, food allergy also increased levels of antigen-specific immunoglobulins and mast cell marker in the brain. In particular, food allergy increased the number of total microglia and the percentage of active microglia in the cerebral cortex and hippocampal CA1 areas, and induced the increase of TNF-α in the cerebral cortex. Importantly, these brain allergic responses were associated with behavioral impairments, including motor and learning deficits. Taken together, our study provides some evidence for profound effects of food allergy on brain functions, and thereby provides scientific basis for a better explanation of emotional and behavioral problems among patients with food allergy.
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http://dx.doi.org/10.1016/j.bbr.2018.01.011DOI Listing
May 2019

Reversing the polarization of tumor-associated macrophages inhibits tumor metastasis.

Int Immunopharmacol 2017 Aug 25;49:30-37. Epub 2017 May 25.

Center Laboratory, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China. Electronic address:

Objective: The M2 phenotype is dominant in tumor associated macrophages (TAM), and plays a key role in promoting tumor growth, invasion and metastasis. Converting TAM polarization from M2 to M1 may contribute to eliciting anti-tumor-specific immune responses and inhibiting tumor metastasis. In this study, the effect of reversing the polarization of TAM on tumor metastasis was investigated.

Methods: Peritoneal macrophages were obtained from BABL/c mice, and M2 polarization was induced by IL-4. In an in vivo experiment, BABL/c mice were transplanted with 4T1 tumor cells. In vitro and in vivo experimental studies, M2 macrophage polarization was reversed with CpG-DNA or CpG-DNA combined with anti-IL-10R Ab. CD68, MHCII and FRβ molecular expression in macrophages were examined with immunofluorescence staining. The mRNA expression of IL-2, IL-6, IL-13, VEGF and MMP-9 were detected with RT-PCR. VEGF and MMP-9 protein expression of tumors in situ was measured by western blot assay. Lung-metastasis of the tumor was observed and assessed by micro-CT.

Results: CpG-DNA and CpG-DNA combined with anti-IL-10R Ab could promote MHCII, IL-2, IL-6 and IL-13 molecular expression, and suppress the expression of FRβ, MMP-9 and VEGF, in both freshly isolated peritoneal macrophages and M2 macrophages. In the CpG-DNA combined with anti-IL-10R Ab injecting group, the percentage of CD68 MHCII cells were significantly higher than that of CD68FRβ cells (P<0.05). This was distinct from the result of the control group, which CD68 FRβ was higher than CD68MHCIIcells (P<0.01). Furthermore, VEGF-A and MMP-9 level in primary tumor tissues in the experimental group was significantly lower (P<0.01), compared to the control group. Moreover, the number of detectable lung-metastasis foci was significantly lower in the experimental group than in the control group (P<0.05).

Conclusion: Reversing the polarization of TAM from M2 to M1 phenotype can inhibit tumor metastasis.
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http://dx.doi.org/10.1016/j.intimp.2017.05.014DOI Listing
August 2017

An Uncommon Case of Lower Limb Deep Vein Thrombosis with Multiple Etiological Causes.

Am J Case Rep 2017 Mar 28;18:313-316. Epub 2017 Mar 28.

Department of Internal Medicine, Montefiore Mount Vernon Hospital, Mount Vernon, NY, USA.

BACKGROUND Deep vein thrombosis (DVT) is a type of venous thromboembolism with diverse clinical and environmental risk factors. Very few cases of DVT with multiple high risk factors have been reported. Here, we report an uncommon DVT case with multiple etiological causes, including appendicitis/appendectomy, morbid obesity, immobilization, positive phosphatidylserine IgG, and heterozygous factor V Leiden mutation. CASE REPORT A 43-year-old female was brought to the emergency room because of 2-week history of pain and swelling and ultrasound revealing evidence of DVT in the right leg. One month ago, she underwent an exploratory laparotomy because of subacute appendicitis. After surgery, the patient stayed at home in bed with very limited activity. She did not have a cough, hemoptysis, chest pain, or shortness of breath. She was morbidly obese, and had a past medical history of diabetes, hypertension, and hyperlipidemia. A full coagulation workup was completed, including Protein C, Protein S, and antiphospholipid antibody, as well as factor V and prothrombin gene mutation screen. Her D-dimer was positive. Computed tomography (CT) angiography of the lungs ruled out major emboli but was unable to rule out minor emboli. A heterozygous factor V Leiden R506Q mutation was detected. Of interest was a significantly positive phosphatidylserine IgG with a value of over 42. She was started with enoxaparin (120 mg, twice a day), and warfarin was added on day 2 when pulmonary embolism was ruled out by CT angiography. The International Normalized Ratio (INR) was monitored daily to adjust warfarin dose. CONCLUSIONS Multiple etiological factors present in this patient may have contributed to her lower-limb DVT, including appendicitis/appendectomy, morbid obesity, immobilization, positive phosphatidylserine IgG, and factor V Leiden mutation. Therefore, it is important to follow the complete workup for hypercoagulable states. This can help with diagnosis and therapy, and also give insight into the pathogenicity, which can help with prevention of recurrence and severe complications of DVT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380192PMC
http://dx.doi.org/10.12659/ajcr.902391DOI Listing
March 2017

Application value of endoscopic submucosal dissection and endoscopic mucosal resection for treatment of rectal carcinoids.

J Cancer Res Ther 2016 Oct;12(Supplement):43-46

Department of Medical (Endoscopy), Xinxiang Central Hospital of Henan Province, Xinxiang 453000, PR China.

Objective: The objective of this study is to explore the clinical effect and safety of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for treatment of rectal carcinoids.

Methods: A retrospective analysis was conducted on 42 patients with rectal carcinoids who were hospitalized and subjected to surgical treatment in our hospital from January 2010 to November 2015. The patients were categorized into two groups based on treatment received: ESD (n = 22) and EMR (n = 20). The patients were analyzed and compared to determine differences in lesion size, operation time, histopathologically curative resection rate, intraoperative complications, complete lesion resection rate, and postoperative recurrence rate between the two groups.

Results: Operation time (25.2 ± 20.1 min) and wound surface diameter (36.2 ± 10.1 mm) were significantly higher in the ESD group than those in the EMR group (12.6 ± 8.4 min and 18.6 ± 5.9 mm, respectively) (P < 0.05). The differences in complete lesion and histopathologically curative resection rates between the two groups were not statistically significant (P > 0.05). Delayed hemorrhage was the primary postoperative complication in both groups. Postoperative follow-up was performed for 3-71 months, and the median follow-up time was 45 months. Recurrence was noted 32 months after surgery in one patient in the EMR group (4.5%), whereas recurrence was not detected in the ESD group.

Conclusion: ESD and EMR are safe and effective methods for treatment of rectal carcinoids. Moreover, ESD had less risk of recurrence, more complete resection rate which could provide more information for postoperative treatment.
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http://dx.doi.org/10.4103/0973-1482.191628DOI Listing
October 2016

Achaete scute-like 2 suppresses CDX2 expression and inhibits intestinal neoplastic epithelial cell differentiation.

Oncotarget 2015 Oct;6(31):30993-1006

Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China.

The role of Achaete scute-like 2 (Ascl2) in colorectal cancer (CRC) cell differentiation is unknown. LS174T, HT-29 and Caco-2 cells have high Ascl2 expression, while Lovo and SW480 cells have low Ascl2 expression. LS174T and HT-29 cells with Ascl2 knockdown were transfected with caudal type homeobox 2 (CDX2) promoter constructs and used for luciferase assays and chromatin immunoprecipitation (ChIP) assays. Ascl2 knockdown promoted differentiation of CRC cells into a goblet cell phenotype, as determined by increased expression of MUC2, TFF3, and CDX2. Ascl2 knockdown activated CDX2 expression through a transcriptional mechanism via direct binding of Ascl2 to the proximal E-box of the CDX2 promoter. Ascl2 over-expression in Lovo and SW480 cells inhibited a goblet cell phenotype, as determined by reduced CDX2 and MUC2 expression. Inverse correlations between Ascl2 and CDX2, and Ascl2 and MUC2 mRNA levels, as well as Ascl2 and CDX2 protein levels were observed in CRC cancerous samples. This study demonstrates CDX2 repression by Ascl2 and highlights a role for Ascl2 in CRC cell differentiation. These findings suggest that the Ascl2/CDX2 axis may serve as a potential therapeutic target in colorectal cancer.
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http://dx.doi.org/10.18632/oncotarget.5206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741583PMC
October 2015

Specific cellular immune response elicited by the necrotic tumor cell-stimulated macrophages.

Int Immunopharmacol 2015 Jul 14;27(1):171-6. Epub 2015 May 14.

Affiliated Hospital of Dalian University, Dalian 116001, PR China.

Objective: To determine whether the necrotic tumor cell-stimulated macrophages (NTCSM) could elicit specific immune response.

Methods: Mice were immunized with the necrotic H22 tumor cell lysate-stimulated macrophages and the specific immune responses against the same tumor challenge were examined. The morphologic characteristics were observed with the transmission electron microscope and scanning electron microscopy. The expression of CD14, CD68, CD80 and CD86 were detected with the flow cytometer. The cytotoxicity and cytokine production of splenocytes were measured with the MTT assay and ELISA assay respectively.

Results: Our research results reveal that NTCSMs are larger cells which generally generate spherical and elongated protrusions, folding membrane, and vesicles on their surface. Also, abundant lysosomes, secondary lysosomes, phagosomes, rough endoplasmic reticulum, and lipid bodies were found in their cytoplasm. The flow cytometry results show that the necrotic H22 tumor cell lysate could enhance the expression of CD14 and CD86 molecules and the NTCSM was characterized by the expression of CD14+/-CD68+CD80-CD86+. After the mice were vaccinated with NTCSMs, the tumor forming rate, tumor volume and weight of the NTCSM-vaccinated group were significantly lower than those of the sterile saline-injected group and untreated macrophage-vaccinated group (p<0.05). The cytotoxicity to H22 tumor cells of the splenocytes obtained from the NTCSM-immunized group was higher than that of the sterile saline-injected group and untreated macrophage-vaccinated group (p<0.05). Meanwhile, the levels of IL-2 and IFN-γ in the culture supernatant of the NTCSM-immunized group were higher significantly than those of the saline-injected group and untreated macrophage-vaccinated group. The level of IL-4 of the NTCSM-immunized group was significantly lower than those of the other two groups.

Conclusion: Our results indicated that NTCSMs could elicit specific cellular immune responses in vivo.
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http://dx.doi.org/10.1016/j.intimp.2015.04.056DOI Listing
July 2015

Necrotic cells induce nonadherent peritoneal exudate cells to proliferate and differentiate into macrophage-like cells.

Immunol Invest 2013 ;42(7):623-38

The Affiliated Zhongshan Hospital of Dalian University, Dalian, PR China.

In a previous study, we noticed that some ascitic cells isolated from melanoma patients survive, proliferate, and differentiate into giant phagocytes after the other cells died. Similar phenomena were observed in the primary cultures of mouse lung and liver cells. In the present study, the effects of dying cells on abdominal exudate cells, and the biological characteristics of the differentiated cells were studied. The results indicate that necrotic cells induce CD14(-)/CD68(+) fraction of abdominal exudate cells to proliferate and differentiate into giant phagocytes; however, apoptotic cells had no such effect. Morphologic studies revealed that the large phagocytes possess characteristics of macrophages. Moreover, necrotic cells enhance the expression of CD14, CD68, CD80, and CD86, and the differentiated cells expressed high levels of CD68 and CD86. Our results indicate that necrotic cells induce CD14(-)/CD68(+) fraction of abdominal exudate cells to proliferate and differentiate, and the differentiated cells possess characteristics similar to macrophages.
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http://dx.doi.org/10.3109/08820139.2013.822388DOI Listing
March 2014

The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats.

J Gynecol Oncol 2013 Apr 5;24(2):177-85. Epub 2013 Apr 5.

Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

Objective: Cisplatin is a widely used chemotherapeutic agent in the treatment of cancers in clinic; but it often induces adverse effects on ovarian functions such as reduced fertility and premature menopause. Mesna could attenuate the cisplatin-induced ovarian damages; however, the underlying mechanism is still unknown. This study aimed to figure out the underlying mechanism of the protection of mesna for ovaries against cisplatin therapy in cancers.

Methods: We performed female adult Sprague-Dawley rats into normal saline control (NS), low-dose cisplatin (CL), high-dose cisplatin (CH), CL plus mesna (CL+M), and CH plus mesna (CH+M) groups and detected anti-Müllerian hormone (AMH)-positive follicle, oxidative stress status and anti-oxidative capability in ovaries.

Results: AMH-positive follicles were significantly decreased after cisplatin administration, which was significantly reversed when mesna was co-administered with cisplatin. The end product of lipid peroxidation, malondialdehyde (MDA), was significantly increased, but the anti-oxidative enzymatic activity of superoxide dismutase (SOD) and glutathione (GSH) were significantly decreased in cisplatin groups when compared with NS group. In contrast, after co-administration of cisplatin with mesna, MDA was significantly decreased whereas the activity of SOD and the concentration of GSH were increased. Moreover, mesna did not decrease the anti-tumor property of cisplatin in HePG2 cell lines.

Conclusion: Cisplatin damages the granulosa cells by oxidative stress to deplete the ovarian reserve and mesna could protect ovarian reserve through anti-oxidation. These results might highlight the mechanism of the protection of mesna for ovarian reserve and open an avenue for the application of mesna as a protective additive in cisplatin chemotherapy in clinical practise.
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http://dx.doi.org/10.3802/jgo.2013.24.2.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644695PMC
April 2013

Enhanced membrane-tethered mucin 3 (MUC3) expression by a tetrameric branched peptide with a conserved TFLK motif inhibits bacteria adherence.

J Biol Chem 2013 Feb 10;288(8):5407-16. Epub 2013 Jan 10.

Department of Gastroenterology, Southwest Hospital, Chongqing, 400038 China.

We investigated whether a synthetic tetrameric branched peptide based on the conserved TFLK motif from mammary-associated serum amyloid A3 (M-SAA3) is more efficient than the monomeric peptide at up-regulating MUC3 expression and examined the possible mechanism(s) and biological significance of this process. We used standard solid-phase methods to synthesize a tetrameric branched peptide (sequence GWLTFLKAAG) containing a trilysine core, termed the TFLK-containing 10-mer BP. The aberrant expression of transcription factors was analyzed using a transcription factor protein/DNA array. MUC3 and relevant transcription factors were detected using real-time PCR and/or Western blots. The luciferase assay, EMSA, and ChIP assays were used to analyze the activity of the human MUC3 promoter. The bacterial adherence assay was used to evaluate the in vitro inhibition of enteropathogenic Escherichia coli or enterohemorrhage E. coli serotype O157:H7 (EHEC O157:H7) adherence to HT-29-Gal cells after treatment with the TFLK-containing 10-mer BP. In HT-29-Gal cells, the TFLK-containing 10-mer BP induced higher levels of MUC3 expression than the M-SAA3-derived N-terminal 10-mer monomeric peptide, and MUC3 expression was activated through transcriptional mechanisms, including the induction of multiple transcription factors and further binding with their cis-elements between nucleotides -242 and -62 within MUC3 promoter. Interestingly, the TFLK-containing 10-mer BP dramatically inhibited enteropathogenic E. coli and EHEC O157:H7 adherence to the HT-29-Gal cells compared with the controls. This finding suggests a potential therapeutic use for this peptide to prevent gastrointestinal infection.
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http://dx.doi.org/10.1074/jbc.M112.408245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581376PMC
February 2013

H. pylori induces the expression of Hath1 in gastric epithelial cells via interleukin-8/STAT3 phosphorylation while suppressing Hes1.

J Cell Biochem 2012 Dec;113(12):3740-51

Department of Gastroenterology, Southwest Hospital, Chongqing 400038, People's Republic of China.

Chronic gastritis associated with Helicobacter pylori is a leading cause of gastric intestinal metaplasia (IM), which arises from abnormal cell differentiation of the epithelium in the gastric mucosa. However, the mechanisms involved in H. pylori-mediated IM remain elusive. The aim of our study was to explore the effects and the underlying mechanisms of H. pylori on the abnormal expression of Hath1 and Sox2 and to reveal its relationship to the development of gastric IM. We found that Hath1 and Sox2 were overexpressed in gastric IM tissue. Hath1 expression was up-regulated, whereas Sox2 expression, which was independent of the CagA virulence factor, was down-regulated in gastric epithelial cells and coincided with increased IL-6 and IL-8 levels in the culture media. Stimulation with H. pylori-related cytokine IL-8, but not IL-6 or IL-1β, was induced by Hath1 expression in the gastric epithelial cells. Although IL-8 and IL-6 levels correlated with STAT3 (signal transducer and activator of transcription) phosphorylation before and after H. pylori eradication in the gastric mucosa, only the blocking of IL-8-induced STAT3 activation using AG490 or STAT3-targeting RNA interference altered Hath1 expression. Additionally, we found that H. pylori down-regulated Hes1, which is a direct downstream target gene of Notch signaling and a repressor of Hath1 expression. These findings suggest that H. pylori induced inflammation up-regulate Hath1 expression via interleukin-8/STAT3 (IL-8) phosphorylation while suppressing Hes1, which provides a novel molecular connection between a H. pylori infection and intestinal metaplasia.
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http://dx.doi.org/10.1002/jcb.24248DOI Listing
December 2012

Ascl2 knockdown results in tumor growth arrest by miRNA-302b-related inhibition of colon cancer progenitor cells.

PLoS One 2012 23;7(2):e32170. Epub 2012 Feb 23.

Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.

Background: Achaete scute-like 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor, controls the fate of intestinal stem cells. However, the role of Ascl2 in colon cancer progenitor cells remains unknown. The cell line HT-29 (47.5-95% of CD133(+) population) and LS174T (0.45% of CD133(+) population) were chosen for functional evaluation of Ascl2 in colon cancer progenitor cells after gene knockdown by RNA interference.

Methodology/principal Findings: Immunohistochemistry demonstrated that Ascl2 was significantly increased in colorectal adenocarcinomas. Downregulation of Ascl2 using RNA interference in cultured colonic adenocarcinoma HT-29 and LS174T cells reduced cellular proliferation, colony-forming ability, invasion and migration in vitro, and resulted in the growth arrest of tumor xenografts in vivo. The Ascl2 protein level in CD133(+) HT-29 cells was significantly higher than in CD133(-) HT-29 cells. Ascl2 blockade via shRNA interference in HT-29 cells (shRNA-Ascl2/HT-29 cells) resulted in 26.2% of cells staining CD133(+) compared with 54.7% in control shRNA-Ctr/HT-29 cells. The levels of 'stemness' associated genes, such as CD133, Sox2, Oct4, Lgr5, Bmi1, and C-myc, were significantly decreased in shRNA-Ascl2/HT-29 and shRNA-Ascl2/LS174T cells in vitro as well as in the corresponding tumor xenograft (CD133 was not performed in shRNA-Ascl2/LS174T cells). The shRNA-Ascl2/HT-29 cells had inhibited abilities to form tumorspheres compared with control. The microRNA (miRNAs) microarrays, identified 26 up-regulated miRNAs and 58 down-regulated miRNAs in shRNA-Ascl2/HT-29 cells. Expression levels of let-7b, miRNA-124, miRNA-125b, miRNA-17, miRNA-20a and miRNA-302b, involved in the regulation of 'stemness', were quantified with qPCR, which confirmed their identities. Restoration of miRNA-302b, via its mimic, led to the restoration of shRNA-Ascl2/HT-29 'stemness' characteristics, including tumorsphere formation and 'stemness' associated genes levels, and the recovery of cellular behaviors, including colony-forming ability, invasion and migration in vitro.

Conclusions/significance: Ascl2 may be a potential target for the inhibition of colon cancer progenitor cells, and functions through a miR-302b-related mechanism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032170PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285660PMC
August 2012
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