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1.
Therap Adv Gastroenterol ; 12: 1756284819890537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803253

RESUMO

Background: The aim of the current systematic review and network meta-analysis (NMA) was to assess the diagnostic characteristics of the gastroesophageal reflux disease questionnaire (GERDQ), proton-pump inhibitor (PPI) test, baseline impedance, mucosal impedance, dilated intercellular spaces (DIS), salivary pepsin, esophageal pH/pH impedance monitoring and endoscopy for gastroesophageal reflux disease (GERD). Methods: We searched PubMed and the Cochrane Controlled Trial Register database (from inception to 10 April 2018) for studies assessing the diagnostic characteristics of the GERDQ, PPI test, baseline impedance, mucosal impedance, DIS, or salivary pepsin and esophageal pH/pH impedance monitoring/endoscopy in patients with GERD. Direct pairwise comparison and a NMA using Bayesian methods under random effects were performed. We also assessed the ranking probability. Results: A total of 40 studies were identified. The NMA found no significant difference among the baseline impedance, mucosal impedance, and esophageal pH/pH impedance monitoring and endoscopy in terms of both sensitivity and specificity. It was also demonstrated that the salivary pepsin detected by the Peptest device had comparable specificity to esophageal pH/pH impedance monitoring and endoscopy. Results of ranking probability indicated that esophageal pH/pH impedance monitoring and endoscopy had highest sensitivity and specificity, followed by mucosal impedance and baseline impedance, whereas GERDQ had the lowest sensitivity and PPI test had the lowest specificity. Conclusions: In a systematic review and NMA of studies of patients with GERD, we found that baseline impedance and mucosal impedance have relatively high diagnostic performance, similar to esophageal pH/pH impedance monitoring and endoscopy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31674057

RESUMO

BACKGROUND AND AIMS: The efficacy of herbal medicines (HMs) for functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS), functional dyspepsia (FD) and functional constipation (FC) is controversial. A systematic review with meta-analysis was conducted to determine their effectiveness for FGIDs. METHODS: We searched the following electronic databases till July 2019 with English language restriction: The Cochrane Library, EMBASE and PUBMED. Randomized double-blind controlled trials of HMs compared with placebo or conventional pharmacological drugs for adult FGIDs patients were included. RESULTS: In total, 49 trials involving 7396 participants with FGIDs were included. The risk of bias was low in 9, unclear in 36, and high in 4 trials. More than 33 different herbal formulae were tested. HMs demonstrated statistically significant benefits for symptom improvement compared with placebo in 46 trials (RR = 1.67, 95% CI 1.48-1.88). When compared with conventional pharmacological therapy in 5 trials, HMs were found to be non-inferior (RR = 1.10, 95% CI 1.03-1.18). The number of trials with regards to FD, IBS and FC were 19, 23 and 7 respectively. Subgroup analysis found that HMs were better than placebo in alleviating symptoms for FD (RR = 1.50, 95% CI 1.32-1.69), IBS (RR = 1.62, 95% CI 1.32-1.97) and FC (RR = 3.83, 95% CI 2.26-6.50). HMs tended to have more patients with adverse events than placebo, but similar to conventional pharmacological drugs. CONCLUSIONS: Our findings provide a positive signal for HMs as a potentially well-tolerated and effective treatment for FGIDs, deserving further examination in high-quality trials.

3.
FASEB J ; 33(12): 14690-14702, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702961

RESUMO

Almost all the outer membrane proteins (OMPs) fold into an invariant ß-barrel fold via the polypeptide-transport-associated (POTRA) motif and ß-barrel assembly machinery (BAM). However, whether and how poly-POTRAs interact with OMPs remain largely unknown. Here, we have characterized the structures of Haemophilus influenzae poly-POTRAs via X-ray crystallography, small angle X-ray scattering, and molecular dynamics simulation. Unexpectedly, crystal packing reveals a putative OMP travel pathway spiraled by the conserved α2-ß2 edges in poly-POTRAs. Supportively, the structure-based mutations targeting the OMP binding sites significantly disrupt OMP biogenesis, resulting in severe cell growth defects. Another notable feature in H. influenzae POTRA structures is flexibility. As characterized by ELISA assays, poly-POTRAs could recruit OMP substrates in a step-wise manner. More importantly, the restriction of POTRA-POTRA linkage and flexibility significantly impairs the BamA function and causes cell growth defect. Altogether, these results suggest that the ß-strand augmentations and intrinsic flexibility are important factors for BamA-OMP recruitment.-Ma, X., Wang, Q., Li, Y., Tan, P., Wu, H., Wang, P., Dong, X., Hong, L., Meng, G. How BamA recruits OMP substrates via poly-POTRAs domain.

4.
Small ; 15(43): e1901940, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31486591

RESUMO

The construction of efficient, durable, and non-noble metal electrocatalysts for oxygen evolution reaction (OER) is of great value but challenging. Herein, a facile method is developed to synthesize a series of trimetallic (W/Co/Fe) metal-organic frameworks (MOFs)-derived carbon nanoflakes (CNF) with various Fe content, and an Fe-dependent volcano-type plot can be drawn out for WCoFex -CNF. The optimized WCoFe0.3 -CNF (when the feed ratio of Fe/Co is 0.3) demonstrates superior electrocatalytic performance with a low overpotential of only 254 mV@10 mA cm-2 and excellent durability of 100 h. Further researches show that appropriate amount of iron doping can regulate the electronic structure, resulting in a favorable synergistic environment. This method may stimulate the exploration of electrocatalysts by utilizing MOFs as precursors while realizing electronic modulation by multimetal doping.

5.
Neurogastroenterol Motil ; 31(12): e13702, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407469

RESUMO

BACKGROUND & AIMS: The Lyon Consensus defines LA grades C&D erosive esophagitis (EE) or acid exposure time (AET) >6% as the conclusive evidence for gastro-esophageal reflux disease (GERD). However, most of EE is LA grade A&B and the rate of AET exceeding 6% is low in China. We aimed to evaluate patients with EE in the Chinese population based on the Lyon Criteria. METHODS: A retrospective study was performed among patients with EE who had esophageal function tests performed in a tertiary hospital from 2013 to 2017. Erosive esophagitis was staged according to the Los Angeles classification. Their motor profiles from high-resolution manometry (HRM), reflux profiles from multichannel intraluminal impedance-pH (MII-pH) monitoring and proton pump inhibitor (PPI) efficacy were analyzed. Patients were categorized as conclusive or inconclusive GERD. RESULTS: Among 112 patients with EE who underwent esophageal function tests, EE of LA grade C&D was found in only 4.46% (N = 5). Almost 35% (N = 37) of patients with LA grade A&B EE had AET exceeded 6%, who had good PPI response similar to those with LA grade C&D EE (77.42% vs 100%, P = .559). The remaining 70 patients (62.50%) were inconclusive GERD, of whom 56.25% responded to PPI. Inconclusive GERD patients had a wide range (7.14%-97.14%) of positive adjunctive evidences from HRM and MII-pH monitoring without significant correlation to PPI response rate. CONCLUSIONS: The reflux burden within patients with EE is predominantly low in China, and adjunctive HRM and MII-pH profiles from Lyon criteria do not segregate PPI response.

6.
Chem Asian J ; 14(19): 3357-3362, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31448868

RESUMO

The preparation of noble metal-free catalysts for water splitting is the key to low-cost, sustainable hydrogen generation. Herein, through a pyrolysis-oxidation process, we prepared a series of Co-Fe-Ni trimetallic oxidized carbon nanocubes (Co1-X FeX Ni-OCNC) with a continuously changeable Co/Fe ratio (X=0, 0.1, 0.2, 0.5, 0.8, 0.9, 1). The Co1-X FeX Ni-OCNC shows a volcano-type oxygen evolution reaction (OER) activity. The optimized Co0.1 Fe0.9 Ni-OCNC achieves a low overpotential of 268 mV at 10 mA cm-2 with a very low Tafel slope of 48 mV dec-1 in 1 m KOH. At the same time, the stability of the Co0.1 Fe0.9 Ni-OCNC is also outstanding; after 1000 CV cycles, the LSV plot is almost coincident. Moreover, the potential remains almost of the same value at 10 mA cm-2 after 12 h in comparison to the initial value. The excellent electrocatalytic properties can be attributed to the synergistic cooperation between each component. Therefore, the Co0.1 Fe0.9 Ni-OCNC is a promising candidate instead of precious metal-based electrocatalysts for OER.

7.
Cancer Genet ; 238: 37-43, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31425924

RESUMO

Intrachromosomal amplification of chromosome 21 (iAMP21) is a rare occurrence in acute myeloid leukemia (AML). We describe here a case of AML with apparent amplification of RUNX1 by cytogenetics and FISH. A 39-year-old female in remission from stage IIIa breast cancer was diagnosed with therapy-related AML (t-AML). The patient's bone marrow was hypocellular for her age (30-40%) with 25% blasts. Cytogenetic analyses revealed a complex karyotype, characterized by rearrangements in chromosomes 1, 5, 17, 20, an additional unidentified marker chromosome, and apparent amplification of chromosome 21. Fluorescence in situ hybridization detected deletions of CKS1B, EGR1, TP53, and apparent amplification of RUNX1 (6-8 signals). Array comparative genomic hybridization (array-CGH) detected amplification of the 5' non-coding region of RUNX1 and deletion of the 3' coding region of RUNX1. These results show that this is not a true case of iAMP21 and suggest that RUNX1 is not the primary target of amplification.

8.
Nat Commun ; 10(1): 3789, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439836

RESUMO

ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 µm in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 Å) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RARα (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RARα-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.


Assuntos
Carcinogênese , Leucemia Promielocítica Aguda/patologia , Proteína da Leucemia Promielocítica/metabolismo , Multimerização Proteica , Animais , Técnicas de Inativação de Genes , Células HeLa , Humanos , Leucemia Promielocítica Aguda/genética , Camundongos , Camundongos Transgênicos , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/ultraestrutura , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/ultraestrutura , Domínios Proteicos/genética , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/ultraestrutura , Espalhamento a Baixo Ângulo , Análise de Sequência de RNA , Análise de Célula Única , Sumoilação , Difração de Raios X
9.
J Pharmacol Exp Ther ; 370(3): 399-407, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31253692

RESUMO

Inhibition of phosphodiesterase 2A (PDE2A) has been proposed as a potential approach to enhance cognitive functioning and memory through boosting intracellular cGMP/cAMP and enhancing neuroplasticity in memory-related neural circuitry. Previous preclinical studies demonstrated that PDE2A inhibitors could reverse N-methyl-D-aspartate receptor antagonist (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]-imidazo[5,1-f][1,2,4]triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg. Target engagement at this efficacious dose was explored using in vivo autoradiography. Converse to the results of a decrease of PDE2A binding (target occupancy) by the PDE2A inhibitor, a paradoxical increase (up to 40%) in PDE2A binding was detected. However, a typical target occupancy curve could be generated by PF-05180999 at much higher doses. In vitro experiments using recombinant PDE2A protein or rat brain homogenate that contains native PDE2A protein demonstrated that increased cGMP after initial PDE2A inhibition could be responsible for the activation of PDE2A enzyme via allosteric binding to the GAF-B domain, leading to positive cooperativity of the dormant PDE2A enzymes. Our results suggest that when evaluating target engagement of PDE2A inhibitors for memory disorder in clinical setting with occupancy assays, the efficacious dose may not fall on the typical receptor/target curve. On the contrary, an increase in PDE2A tracer binding is likely seen. Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Memória de Longo Prazo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Relação Dose-Resposta a Droga , Ligantes , Masculino , Ratos
10.
Biol Open ; 8(5)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31064740

RESUMO

Six2+ cap mesenchyme cells, also called nephron progenitor cells (NPC), are precursors of all epithelial cell types of the nephron, the filtering unit of the kidney. Current evidence indicates that perinatal 'old' NPC have a greater tendency to exit the progenitor niche and differentiate into nascent nephrons than their embryonic 'young' counterpart. Understanding the underpinnings of NPC development may offer insights to rejuvenate old NPC and expand the progenitor pool. Here, we compared the chromatin landscape of young and old NPC and found common features reflecting their shared lineage but also intrinsic differences in chromatin accessibility and enhancer landscape supporting the view that old NPC are epigenetically poised for differentiation. Annotation of open chromatin regions and active enhancers uncovered the transcription factor Bach2 as a potential link between the pro-renewal MAPK/AP1 and pro-differentiation Six2/b-catenin pathways that might be of critical importance in regulation of NPC fate. Our data provide the first glimpse of the dynamic chromatin landscape of NPC and serve as a platform for future studies of the impact of genetic or environmental perturbations on the epigenome of NPC.

11.
Medicine (Baltimore) ; 98(8): e14537, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813161

RESUMO

RATIONALE: Acute fibrinous and organizing pneumonia (AFOP) is an uncommon type of acute lung injury associated with infection, connective tissue disorders, drug exposure, and hematologic malignancies. PATIENT CONCERNS: A 53-year-old female presented with intermittent fever, chills, and dry cough since 10 days. Chest computed tomography scan showed multiple bilateral patchy infiltrates. PPD skin test was positive but tuberculosis antibody test and T-SPOT were negative. DIAGNOSES: Histologic examination revealed massive fibrinous exudation with organization within alveolar spaces and scattered neutrophilic infiltrates, which was consistent with AFOP. INTERVENTIONS: This patient was treated with prednisolone therapy. OUTCOMES: Chest radiograph improvement and symptom improvement, including fever and respiratory symptoms, was observed after 2 week of oral prednisolone treatment. After 9-month of treatment, the patient was asymptomatic with stable disease and improved quality of life. LESSONS: AFOP has unique pathologic manifestations; however, the condition is liable to be misdiagnosed as community-acquired pneumonia ortuberculosis. Antibiotics are ineffective, while some patients show good response to glucocorticoid therapy.


Assuntos
Pneumonia em Organização Criptogênica/diagnóstico , Glucocorticoides/uso terapêutico , Pulmão/patologia , Prednisolona/uso terapêutico , Pneumonia em Organização Criptogênica/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
12.
Chem Asian J ; 14(9): 1590-1594, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30919584

RESUMO

Non-noble metal-based metal-organic framework (MOF)-derived electrocatalysts have recently attracted great interest in the oxygen evolution reaction (OER). Here we report a facile synthesis of nickel-based bimetallic electrocatalysts derived from 2D nanosheet-assembled nanoflower-like MOFs. The optimized morphologies and large Brunauer-Emmett-Teller (BET) surface area endow FeNi@CNF with efficient OER performance, where the aligned nanosheets can expose abundant active sites and benefit electron transfer. The complex nanoflower morphologies together with the synergistic effects between two metals attributed to the OER activity of the Ni-based bimetallic catalysts. The optimized FeNi@CNF afforded an overpotential of 356 mV at a current density of 10 mA cm-2 with a Tafel slope of 62.6 mV dec-1 , and also exhibited superior durability with only slightly degradation after 24 hours of continuous operation. The results may inspire the use of complex nanosheet-assembled nanostructures to explore highly active catalysts for various applications.

13.
Mol Med Rep ; 19(5): 3367-3375, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896806

RESUMO

Leucine zipper/EF­hand­containing transmembrane protein 1 (LETM1) has been identified as the gene responsible for Wolf­Hirschhorn syndrome (WHS), which is characterized by intellectual disability, epilepsy, growth delay and craniofacial dysgenesis. LETM1 is a mitochondrial inner membrane protein that encodes a homolog of the yeast protein Mdm38, which is involved in mitochondrial morphology. In the present review, the importance of LETM1 in WHS and its role within the mitochondrion was explored. LETM1 governs the mitochondrion ion channel and is involved in mitochondrial respiration. Recent studies have reported that LETM1 acts as a mitochondrial Ca2+/H+ antiporter. LETM1 has also been identified as a K+/H+ exchanger, and serves a role in Mg2+ homeostasis. The function of LETM1 in mitochondria regulation is regulated by its binding partners, carboxyl­terminal modulator protein and mitochondrial ribosomal protein L36. Therefore, we describe the remarkable role of LETM1 in mitochondrial network physiology and its function in mitochondrion­mediated cell death. In the context of these findings, we suggest that the participation of LETM1 in tumorigenesis through the alteration of cancer metabolism should be investigated. This review provides a comprehensive description of LETM1 function, which is required for mitochondrial homeostasis and cellular viability.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Sobrevivência Celular/genética , Homeostase , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Animais , Proteínas de Ligação ao Cálcio/química , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Metabolismo Energético , Humanos , Proteínas de Membrana/química , Relação Estrutura-Atividade
14.
Oncol Rep ; 41(4): 2075-2088, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816485

RESUMO

Opa interacting protein 5 (OIP5) overexpression is associated with human carcinoma. However, its biological function, underlying mechanism and clinical significance in liver cancer remain unknown. In the present study, the effects of OIP5 expression on liver cancer, and the mechanisms regulating these effects, were investigated. OIP5 expression was measured in human hepatocellular carcinoma (HCC) tissues and liver cancer cell lines. The effect of OIP5 knockdown on tumorigenesis was also detected in nude mice, and differentially­expressed genes (DEGs) were identified and their biological functions were identified. The results indicated that OIP5 expression was significantly upregulated in HCC tissues and four liver cancer cell lines (P<0.01). Increased OIP5 protein expression significantly predicted reduced survival rate of patients with HCC (P<0.01). OIP5 knockdown resulted in the suppression of proliferation and colony forming abilities, cell cycle arrest at the G0/G1 or G2/M phases, and promotion of cell apoptosis. A total of 628 DEGs, including 87 upregulated and 541 downregulated genes, were identified following OIP5 knockdown. Functional enrichment analysis indicated that DEGs were involved in 'RNA Post­Transcriptional Modification, Cancer and Organismal Injury and Abnormalities'. Finally, OIP5 knockdown in Huh7 cells dysregulated bone morphogenetic protein receptor type 2/JUN/checkpoint kinase 1/Rac family small GTPase 1 expression. In conclusion, the overall results demonstrated the involvement of OIP5 in the progression of liver cancer and its mechanism of action.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas Cromossômicas não Histona/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Adulto , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Carcinogênese/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas Cromossômicas não Histona/genética , Progressão da Doença , Regulação para Baixo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rac1 de Ligação ao GTP/metabolismo
15.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

17.
J Psychopharmacol ; 33(1): 25-36, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30484737

RESUMO

BACKGROUND: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior. AIMS: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. METHODS AND RESULTS: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. CONCLUSION: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.

18.
J Gastroenterol Hepatol ; 34(3): 526-531, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30207000

RESUMO

BACKGROUND AND AIM: The treatment of patients with functional dyspepsia (FD) remains unsatisfactory. We assessed the efficacy of Zhizhu Kuanzhong (ZZKZ) capsule, a traditional Chinese medicine formula, in patients with postprandial distress syndrome (PDS) of FD. METHODS: The study was designed as a multicenter, randomized, double-blinded, controlled clinical trial. Three-hundred ninety-two patients with PDS defined by Rome III criteria from 16 centers in China were randomly assigned to receive either ZZKZ or placebo. The proportion of the responders at 4 weeks after randomization was considered primary endpoint. Secondary endpoint was the symptom score reduction of each dyspeptic symptom relative to the baseline at 4 weeks after randomization in all subjects. RESULTS: In terms of the primary endpoint, the proportion of the responders concerning the composite PDS symptom score was 38.8% and 54.7% in placebo group and ZZKZ group, respectively (P = 0.003), in per protocol analysis at 4 weeks after randomization. Concerning the individual evaluated upper gastrointestinal symptoms, only postprandial fullness and early satiety showed significant difference in symptom score reduction at 4 weeks after randomization between placebo and ZZKZ groups. CONCLUSIONS: Zhizhu Kuanzhong is superior to placebo in the treatment of PDS with FD. The exact mechanisms by which ZZKZ improves symptoms remain to be established (http://www.chictr.org.cn/ChinCTR-TRC-14004714).


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Dispepsia/tratamento farmacológico , Fitoterapia , Período Pós-Prandial , Adulto , Cápsulas , Método Duplo-Cego , Dispepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome , Resultado do Tratamento
19.
Stem Cells Int ; 2018: 7159465, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538751

RESUMO

Recent studies have described beneficial effects of an infusion of mesenchymal stem cells (MSCs) derived from Wharton's jelly tissue, for the treatment of acute liver failure (ALF). However, data on the therapeutic potential of culture-expanded MSCs are lacking. We examined the therapeutic potential of passage five (P5) and ten (P10) human umbilical cord- (hUC-) MSCs via their transplantation into Sprague-Dawley (SD) rats with D-galactosamine (D-GalN) and LPS-induced acute liver failure (ALF). SD rats were randomly divided into three groups: control group, P5 hUC-MSCs group, and P10 hUC-MSCs group. After transplantation, P5 hUC-MSCs provided a significant survival benefit. The analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels showed that transplantation with P5 hUC-MSCs was more effective than treatment with P10 hUC-MSCs. P5 hUC-MSCs also successfully downregulated the hepatic activity index (HAI) scores. Compared to P10 hUC-MSCs in vivo, P5 hUC-MSCs significantly enhanced the regeneration and inhibited the apoptosis of hepatocytes. CM-Dil-labeled hUC-MSCs were found to engraft within the recipient liver, whereas the homing of cells to the recipient liver in the P10 hUC-MSCs group was less effective compared to the P5 hUC-MSCs group. Previous studies have shown that the concentration of hepatocyte growth factor (HGF) in the injured liver was significantly increased. HGF is commonly known as the ligand of c-Met. The level of c-Met in hUC-MSCs as detected by Western blotting indicated that at a higher passage number, there is a decrease in c-Met. These data suggest that direct transplantation of P5 hUC-MSCs can more efficiently home to an injured liver. Subsequently, the P5 hUC-MSCs can rescue ALF and repopulate the livers of rats through the stimulation of endogenous liver regeneration and inhibition of hepatocellular apoptosis for compensated liver function, which is dependent on the higher level of c-Met than P10 hUC-MSCs.

20.
Physiol Meas ; 39(11): 115005, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30475743

RESUMO

OBJECTIVE: Sleep quality helps to reflect on the physical and mental condition, and efficient sleep stage scoring promises considerable advantages to health care. The aim of this study is to propose a simple and efficient sleep classification method based on entropy features and a support vector machine classifier, named SC-En&SVM. APPROACH: Entropy features, including fuzzy measure entropy (FuzzMEn), fuzzy entropy, and sample entropy are applied for the analysis and classification of sleep stages. FuzzyMEn has been used for heart rate variability analysis since it was proposed, while this is the first time it has been used for sleep scoring. The three features are extracted from 6 376 730 s epochs from Fpz-Cz electroencephalogram (EEG), Pz-Oz EEG and horizontal electrooculogram (EOG) signals in the sleep-EDF database. The independent samples t-test shows that the entropy values have significant differences among six sleep stages. The multi-class support vector machine (SVM) with a one-against-all class approach is utilized in this specific application for the first time. We perform 10-fold cross-validation as well as leave-one-subject-out cross-validation for 61 subjects to test the effectiveness and reliability of SC-En&SVM. MAIN RESULTS: The 10-fold cross-validation shows an effective performance with high stability of SC-En&SVM. The average accuracy and standard deviation for 2-6 states are 97.02 ± 0.58, 92.74 ± 1.32, 89.08 ± 0.90, 86.02 ± 1.06 and 83.94 ± 1.61, respectively. While for a more practical evaluation, the independent scheme is further performed, and the results show that our method achieved similar or slightly better average accuracies for 2-6 states of 94.15%, 85.06%, 80.96%, 78.68% and 75.98% compared with state-of-the-art methods. The corresponding kappa coefficients (0.81, 0.74, 0.72, 0.71, 0.67) guarantee substantial agreement of the classification. SIGNIFICANCE: We propose a novel sleep stage scoring method, SC-En&SVM, with easily accessible features and a simple classification algorithm, without reducing the classification performance compared with other approaches.


Assuntos
Entropia , Processamento de Sinais Assistido por Computador , Sono/fisiologia , Máquina de Vetores de Suporte , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletroencefalografia , Eletroculografia , Feminino , Voluntários Saudáveis , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade
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