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1.
Food Chem ; 304: 125397, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31479996

RESUMO

Branched polyethyleneimine functionalized reduced graphene oxide (BPEIGn) was prepared by a one-step reaction, catalyzed by NaOH, using branched polyethyleneimine (BPEI) and graphene oxide (GO) without reductant hydrazine hydrate or sodium borohydride. The branched polyethylenimine acted as both a grafting agent and a reducing agent of GO. An competitive electrochemical immunosensor based on the Au/sodium mercaptopropanesulfonate/BPEIGn/gold nanoparticles/melamine (Au/MPS/BPEIGn/AuNPs/Mel) modified electrode was constructed for the determination of melamine. The double amplification of BPEIGn and AuNPs increased the sensitivity of the sensor. The melamine was detected by differential pulse voltammetry (DPV) in buffer solution (pH 7.4) containing K3(Fe(CN)6]/K4[Fe(CN)6]. Under optimized conditions, the proposed melamine immunosensor showed a linear relationship in the concentration range of 1 × 10-6 to 1 µM, with a detection limit of 2.66 × 10-7 µM.

2.
J Ethnopharmacol ; 246: 112227, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509780

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Most cardiovascular diseases ultimately result in heart failure, an intractable problem in modern medicine. Yangxinshi tablet (YXS) is a Chinese medicine formula that is used clinically to treat coronary heart disease. However, the active compounds, potential targets, and pharmacological and molecular mechanism of its anti-heart failure activity remain unclear. Therefore, further investigation is required. AIM OF STUDY: Active ingredients and potential targets of YXS for treating heart failure have been reported previously. However, the molecular functions or biological processes of YXS in energy metabolism have not been discovered. To date, no experimental study to validate the potential anti-heart failure mechanism of YXS. The aim of this study was to study the therapeutic effect of YXS on rats with chronic ischemic heart failure by evaluating rat cardiac function and exercise tolerance, and to explore its potential mechanism by network pharmacology, western blotting, quantitative RT-PCR and histological analysis. MATERIALS AND METHODS: In this investigation, chronic ischemic heart failure rats were randomly assigned to five groups: control group (sham operation), model group (0.5% CMC-Na), trimetazidine group (positive control) and two YXS groups (low- and high-dose groups). Experimental rats were treated by gavage with 10 mg/kg/d (clinical equivalent dose) trimetazidine (TMZ), 500 mg/kg/d (clinical equivalent dose) YXS and 1000 mg/kg/d YXS, respectively, for 5 weeks. The cardiac functions of rats were detected by High-Resolution In Vivo Imaging System. We elucidated novel understanding of the active compounds of YXS in rat plasma and predicted the energy metabolism related targets and processes for heart failure. Then, we validated experimentally the targets and mechanism of YXS on these pathological processes in vivo. RESULTS: It was found that YXS was able to effectively improve cardiac LVIDs, LVEDV, LVESV and EF, decrease myocardial oxygen consumption and reduce myocardial infarct size in rats with chronic ischemic heart failure was similar to that of TMZ. We identified 63 major candidate targets for YXS that are closely to heart failure progression. Enrichment analysis revealed key targets for YXS associated to oxygen delivery, glucose utilization, and mitochondrial biogenesis. Meanwhile, we validated that YXS could promote the expression of downstream HIF-1α, PGC1α and GLUT4 by increasing phosphorylation of PI3K, Akt, mTOR, rpS6 and AMPK. The results show that YXS could activate related PI3K/Akt/mTOR/rpS6/HIF-1α and AMPK/PGC1α/GLUT4 signaling pathways in chronic ischemic heart failure rats. Further experiments demonstrated that YXS increased mitochondrial biogenesis in chronic ischemic heart failure rats and improved exercise tolerance CONCLUSION: YXS treated chronic ischemic heart failure through activating its targets which play pivotal roles in oxygen delivery, glucose utilization and mitochondrial biogenesis to improve energy metabolism through a multi-component, multi-level, multi-target, multi-pathway and multi-mechanism approaches.

3.
Environ Int ; 134: 105278, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31711021

RESUMO

Glucocorticoids (GCs) have been increasingly reported to have adverse effects on aquatic organisms, but the lack of comprehensive analytical methods for a broad number of GCs has limited the effective management of pollution by these molecules in surface and coastal waters. In this study, we developed an original analytical method for simultaneously monitoring 25 natural GCs, and 43 synthetic GCs (4 hydrocortisone types, 6 acetonide types, 8 betamethasone types, 14 halogenated esters, and 11 labile prodrug esters) in water samples. Of the river samples investigated, 15 natural and 25 synthetic compounds were detected with the concentrations ranging from 0.13 ng/L (11-epitetrahydrocortisol) to 433 ng/L (cortisone) and from 0.05 (clobetasol) to 94 ng/L (prednisolone), respectively. Thirteen natural metabolites of cortisol (CRL) were first detected, and their concentrations were up to 36 times higher than that of CRL. Hydrocortisone-type GCs were the dominant synthetic compounds (≤154 ng/L), followed by halogenated esters (≤81 ng/L), acetonide type GCs (≤57 ng/L), betamethasone type GCs (≤32 ng/L), and labile prodrug esters (≤22 ng/L). Considering the relative potencies for detected GCs compared to dexamethasone, halogenated esters predominantly contributed to the GC activities in the samples. Notably, this is the first report of the halogenated esters 11-oxo fluticasone propionate (OFP) and cloticasone propionate (CTP) in environmental waters. Untreated wastewater is the main source of GCs in the studied waters, and the concentration ratios between natural and synthetic GCs can be used as potential indicators of sewage input. Because of the high detected concentrations and bioactivity potency of halogenated GCs, they are the main contributors to GC activities in the studied waters, and deserved more study in the future.

4.
Phytomedicine ; 65: 153091, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31654988

RESUMO

BACKGROUND: The development of rheumatoid arthritis (RA) is related to germinal center (GC) response and autoreactive T cells, which mediate adaptive immunity and play an important role in stimulating the production of autoantibodies and pro-inflammatory cytokines by B cells and macrophages. Total Glucosides of Paeony (TGP) has anti-inflammatory, immunomodulatory and analgesic effects and is widely used to treat RA. However, few studies investigated whether the therapeutic effect of TGP is associated with the inhibition of autoimmune response. PURPOSE: The aim of this study was to investigate the effects and mechanisms of TGP on RA. STUDY DESIGN: Type II collagen-induced arthritis (CIA) mouse model was used, and TGP and paeoniflorin were intragastrically treated. METHODS: DBA/1 mice were divided into 5 groups: control, model, positive drug (paeoniflorin) and high- and low-dose TGP group. After 21 days of intragastric administration, the pathological change, inflammation expression and molecular mechanism of each group of mice were detected by Micro-CT, histochemical analysis, ELLSA, Western blot, RT-qPCR and flow cytometry. RESULTS: Our study found that TGP treatment effectively improved inflammation and joint destruction in CIA mice. It reduced the production of serum IgG2a and pro-inflammatory cytokines, including serum interleukin (IL)-21, tumor necrosis factor (TNF)-α and IL-6, and the phosphorylation of NF-κB p65 and STAT3 in a dose-dependent manner. More importantly, TGP could suppress the frequency of germinal center B cells and Tfh cells in the spleen. CONCLUSION: TGP can not only improve symptoms, but also inhibit bone destruction. The therapeutic effect of TGP on CIA is mainly achieved by inhibiting spleen Tfh cell differentiation and GC formation through STAT3 signaling pathway.

5.
Water Res ; 165: 114991, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442757

RESUMO

Progestins (PGs) are a group of steroid hormones known to have endocrine-disrupting effects. These compounds can enter the aquatic environment via the discharge of treated or untreated wastewater and the disposal of sludge from sewage treatment plants (STPs); thus, their removal in STPs are of great importance. The present study simultaneously investigated the occurrences and fates of 62 PGs in a municipal STP in Beijing, China. Progesterone (P) and its metabolites were found to be the predominant compounds, with total dissolved concentrations of 1866 ng/L in the influent. About 11 P metabolites were newly detected, accounting for 25-55% and 75-91% of the total concentrations in wastewater and sludge, respectively. For the other three groups of PGs derived from different parent compounds, P derivatives were first detected in the STP with the highest concentration in the wastewater and sludge, followed by 19-nortestosterone (NT) derivatives and 17α-hydroxyprogesterone (17α-OHP) derivatives. The removal efficiencies in the dissolved phase of wastewater were relatively high for P and its metabolites (95-99%) and P derivatives (91-99%). And the relative persistence of NT (68-99%) and 17α-OHP derivatives (79-99%) was observed during the wastewater treatment processes. Mass balance analysis showed that the lost mass proportions were as high as 41-99%, the mass fractions in sludge were in the range of 0-55%, and 0.24-25% of the initial mass loadings was present in the effluent. These results indicated that biodegradation was the major removal mechanism of PGs in the STP.

6.
Int Immunopharmacol ; 74: 105721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255881

RESUMO

Glucocorticoids (GCs) exposure has deleterious alteration on the structure and function in hippocampal neurons. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in neurological diseases, and NLRP1 inflammasome can be activated in response to oxidative stress. We hypothesize that inhibition of NOX2-mediated NLRP1 inflammasome activation may protect against chronic GCs exposure-induced neuronal injury. In this study, the lentivirus with NLRP1-siRNA was injected into the hippocampus of male mice which were then treated with dexamethasone (DEX, 5 mg/kg) for 28 d. The data indicated that NLRP1-siRNA treatment down-regulated the NLRP1 expression and significantly improved the exploratory behavior and spatial memory deficits in open field tests and Morris water maze which were deteriorated by chronic DEX treatment in mice. Additionally, inhibition of NLRP1 expression significantly alleviated neuronal degeneration and increased MAP2 expression in the hippocampus in mice. Meanwhile, the results showed that DEX exposure increased NOX2, p22phox and p47phox expression in hippocampus tissue in mice. We further examined the effect of tempol (ROS scavenger) and apocynin (NOX inhibitor) treatment on NLRP1 inflammasome activation in chronic DEX-treated hippocampal neurons. The results revealed that the tempol (50 µM) and apocynin (50 µM) treatment significantly decreased generation of ROS, expression of NOX2 and NLRP1-related protein in DEX-treated hippocampal neurons. These data indicate that NOX2-mediated NLRP1 activation involves in chronic GCs exposure-induced neuronal injury and inhibition of NOX2-NLRP1 signaling pathway protects against GCs-induced neuronal damage.

7.
Biomed Chromatogr ; 33(10): e4628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243781

RESUMO

Wang-Bi tablet (WB) is popularly used for the treatment of rheumatoid arthritis. However, few studies have been carried out on its active ingredients and mechanism. In this study, the effect of WB medicated serum on the changes in differentiation and function in osteoblast was investigated, the results showed that WB induced the production of ALP and mineralized nodules to promote the final maturation of osteoblasts and enhance the function of osteoblasts. The potential mechanism may that WB significantly inhibits gene expressions of RANKL and miR-141, up-regulates the gene expressions of RUNX2 and OPG, decreases expression of DKK-1 and increases levels of ß-catenin protein to promote the activation of Wnt/ß-catenin signaling pathways, which enhances osteogenesis and bone repair function. To investigate which compounds contributed to the activity and mechanisms, a total of 138 compounds were characterized from WB, and 13 parent molecules and eight metabolites in rat serum were rapidly characterized by UPLC-Q-TOF/MS. Total glycosides of paeony, loganin, α-linolenic acid, linoleic acid and naringin from WB may contribute to the actions on osteoblasts according to our study and literature review. Our research provides a method to explore the bioactive ingredients and action mechanisms of WB.

8.
Autophagy ; : 1-15, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31208298

RESUMO

The non-receptor tyrosine kinase SRC is a key mediator of cellular protumorigenic signals. SRC is aberrantly over-expressed and activated in more than 80% of colorectal cancer (CRC) patients, therefore regulation of its stability and activity is essential. Here, we report a significant down regulation of SNX10 (sorting nexin 10) in human CRC tissues, which is closely related to tumor differentiation, TNM stage, lymph node metastasis and survival period. SNX10 deficiency in normal and neoplastic colorectal epithelial cells promotes initiation and progression of CRC in mice. SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation. These mechanisms ensure proper controlling of the activities of SRC-STAT3 and SRC-CTNNB1 signaling pathways by up-regulating SNX10 expression under stress conditions. These findings suggest that SNX10 acts as a tumor suppressor in CRC and it could be a potential therapeutic target for future development. Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG12: autophagy related 12; CQ: chloroquine; CRC: colorectal cancer; CTNNB1: catenin beta 1; EBSS: Earle's balanced salt solution; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; MAP1LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; mRNA: messenger RNA; PX: phox homology; RT-qPCR: real time quantitative polymerase chain reaction; siRNA: small interfering RNA; SNX10: sorting nexin 10; SQSTM1: sequestosome 1; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; WT: wild type.

9.
J Cell Physiol ; 234(12): 22311-22320, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074035

RESUMO

To seek out novel promising biomarkers for predicting lung adenocarcinoma (LUAD) prognosis, we conducted this study. First, 279 upregulated and 37 downregulated differentially expressed genes were obtained from LUAD and para-carcinoma tissues by the Affymetrix GeneChip Human Transcriptome Array. Then, we randomly classified samples of LUAD data set GSE31210 as training and testing sets in a 1:1 ratio. Alcohol dehydrogenase 1C (ADH1C) and secreted phosphoprotein 1 (SPP1) were finally identified correlating with the LUAD survival through least absolute shrinkage and selection operator penalized Cox proportion hazards regression model, and applied to build a 2-gene signature related to prognosis in training set. Univariate and multivariable survival analyses suggested that overall survival (OS) and relapse-free survival (RFS) in the 2-gene signature low-risk group were better than the high-risk group. Kaplan-Meier curves proved that elevated ADH1C expression and reduced SPP1 expression were related to better OS and RFS. Besides, the SPP1 expressed higher in LUAD than para-carcinoma tissues using quantitative reverse transcription polymerase chain reaction assay. Finally, the association between the two genes and clinicopathological parameters in 80 LUAD were analyzed, it is suggested that SPP1 was relevant to epidermal growth factor receptor mutation. These findings indicated that ADH1C and SPP1 might be novel promising biomarkers for predicting LUAD prognosis.

10.
Biomed Res Int ; 2019: 8171897, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139653

RESUMO

Physical activity or appropriate exercise prevents the development of osteoporosis. However, the exact mechanism remains unclear although it is well accepted that exercise or mechanical loading regulates the hormones, cytokines, signaling pathways, and noncoding RNAs in bone. Accumulating evidence has shown that bone is a highly vascularized tissue, and dysregulation of vasculature is associated with many bone diseases such as osteoporosis or osteoarthritis. In addition, exercise or mechanical loading regulates bone vascularization in bone microenvironment via the modulation of angiogenic mediators, which play a crucial role in maintaining skeletal health. This review discusses the effects of exercise and its underlying mechanisms for osteoporosis prevention, as well as an angiogenic and osteogenic coupling in response to exercise.

11.
J Cell Biochem ; 120(9): 15604-15615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31111546

RESUMO

ß-amyloid peptide (Aß) deposition derived from sequential cleavage of the amyloid precursor protein (APP) through the amyloidogenic pathway is an important characteristic feature of Alzheimer's disease (AD). During this process, cellular trafficking plays a crucial role. A large Sec7-domain containing ADP-ribosylation factor guanine nucleotide exchange factor (ARF-GEF), Golgi brefeldin A resistance factor 1 (GBF1) has been reported to initiate the ADP-ribosylation factor (Arf) activation cascade at trans-Golgi network, which plays a crucial function at the endoplasmic reticulum-Golgi interface. In this study, we investigated the role of GBF1 in APP transmembrane transport and Aß formation. Using APP/PS1 (presenilin 1) overexpressing transgenic mice, we demonstrate that GBF1 has upregulated the expression of APP, indicating a role for GBF1 in APP physiological process. Knocking down of GBF1 using small interfering has significantly increased the intracellular but not the surface expression of APP. In contrast, overexpression of wild-type (WT) and guanine nucleotide exchange factor (GEF) in the activated form but not the GEF deficient mutation induced continuous activation of GBF1, which subsequently increased the surface level of APP. Interestingly, inhibition of GBF1 by c(BFA) also impaired APP trafficking and induced endoplasmic reticulum (ER) stress in SH-SY5Y cells. Our results thus for identified the role of GBF1 in APP trafficking and cleavage, and provide evidence for GBF1 as a possible therapeutic target in AD.

12.
J Ethnopharmacol ; 238: 111861, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954617

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Wang-bi tablet (WB) consists of 17 traditional Chinese medicines and has been used for treating rheumatoid arthritis (RA) in China for many years, however, its pharmacologic mechanism is not clear. AIM OF STUDY: The aim of this study was to investigate the therapeutic effect of WB on collagen-induced mouse arthritis and explored the underlying mechanism. MATERIALS AND METHODS: DBA/1 mice were used to establish a type II collagen-induced arthritis (CIA) model. From the day of arthritis onset, mice were treated daily by gavage with either total glucosides of paeony (TGP, 0.37  g/kg/d) or WB at a lower (1.11  g/kg/d, WBL) or higher dose of (3.33  g/kg/d, WBH) for 8 weeks. The severity of arthritis, levels of cytokines and the activation of signaling pathways were determined. RESULTS: Our results revealed that WB treatment effectively alleviated inflammatory symptoms and prevented bone erosions and joint destructions. It obviously decreased the serum concentration of pro-inflammatory cytokines TNF-α, IL-6 and IL-17α, while increased the concentration of anti-inflammatory cytokine IL-10. Interestingly, the proportion of splenic Treg cells were increased significantly. In vitro experiments showed that WB inhibited the differentiation of osteoclasts. Consistently, the mRNA levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CtsK), and the activation of NF-κB and JAK-STAT3 signaling pathways in the paws of CIA mice were inhibited by WB treatment. On the other hand, up-regulation of osteogenic genes Runx2, Osterix mRNA, and activation of Wnt/ß-catenin signaling pathway along with a decreased receptor activator of nuclear factor κB ligand (RANKL) expression were found in WB treated mice. CONCLUSION: Our results suggest that the therapeutic effect of Wang-bi tablet could be attributed to its inhibitory activity on NF-κB and STAT3 signaling pathway-mediated osteoclast differentiation, and its enhancement on Wnt/ß-catenin signaling pathway-mediated osteoblast functions.

13.
Trials ; 20(1): 34, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626424

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50-75% of patients have a treatment response but require 4-6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD. METHODS: This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items. DISCUSSION: In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation. TRIAL REGISTRATION: NCT03138681 . Registered on 3 May 2017. First patient: 4 May 2017.


Assuntos
Trifosfato de Adenosina/administração & dosagem , Afeto/efeitos dos fármacos , Antidepressivos de Segunda Geração/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/administração & dosagem , Fosfocreatina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Trifosfato de Adenosina/efeitos adversos , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , China , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Estudos de Viabilidade , Feminino , Fluoxetina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Questionário de Saúde do Paciente , Fosfocreatina/efeitos adversos , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Captação de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Int Immunopharmacol ; 69: 60-70, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30677569

RESUMO

Oxidative stress and inflammation are closely related to neuron ageing. NADPH oxidase 2 (NOX2) is a major source of reactive oxygen species (ROS) generation in brain. The nucleotide-binding oligomerisation domain (NOD)-like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of proinflammatory molecules in neurons. We hypothesize that NOX2-derived ROS accumulation mediates activation of NLRP1 inflammasome, which is involved in age-related neuronal damage. In the present study, we investigated the changes of NOX2-NLRP1 signaling pathway in primary hippocampal neurons cultured for different time (6, 9 and 12 days, d). Meanwhile, we further examined the effect of ROS inhibitor and NLRP1-siRNA on neuronal senescence. The results showed that, compared with 6 d group, the neuronal apoptosis and ß-Galactosidase (ß-Gal) expression were significantly increased, and the microtubule-associated protein 2 (MAP2) expression significantly decreased in primary hippocampal neurons cultured for 12 d. In addition, the results also showed that the production of ROS, the expressions of NOX2 and NLRP1 inflammasome were significantly increased with the prolongation of culture time in hippocampal neurons. Moreover, the NOX inhibitor (apocynin) and ROS scavenger (tempol) significantly decreased ROS production and alleviated neuronal damage. Meanwhile, the tempol and apocynin treatment significantly decreased the expression of NLRP1 inflammasome in hippocampal neurons. Furthermore, the NLRP1-siRNA and caspase-1 inhibitor treatment also alleviated neuronal damage. These results suggest that NOX2-derived ROS generation may induce brain inflammation via NLRP-1 inflammasome activation and lead to age-related neuronal damage. The NADPH oxidase and NLRP1 inflammasome may be important therapeutic targets for age-related neuronal damage.


Assuntos
Hipocampo/patologia , Inflamação/metabolismo , NADPH Oxidase 2/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Animais , Apoptose , Células Cultivadas , Senescência Celular , Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/genética , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Int J Mol Med ; 43(2): 717-726, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535505

RESUMO

Oxidative stress and neuroinflammation are important in the pathogenesis of ageing and age­related neurodegenerative diseases, including Alzheimer's disease. NADPH oxidase 2 (NOX2) is a major source of reactive oxygen species (ROS) in the brain. The nucleotide­binding oligomerisation domain (NOD)­like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro­inflammatory molecules in neurons. Whether the NOX2­NLRP1 inflammasome signalling pathway is involved in neuronal ageing and age­related damage remains to be elucidated. Ginsenoside Rg1 (Rg1) is a steroidal saponin found in ginseng. In the present study, the primary hippocampal neurons were treated with H2O2 (200 µM) and Rg1 (1, 5 and 10 µM) for 24 h to investigate the protective effects and mechanisms of Rg1 on H2O2­induced hippocampal neuron damage, which mimics age­related damage. The results showed that H2O2 treatment significantly increased ROS production and upregulated the expression of NOX2 and the NLRP1 inflammasome, and led to neuronal senescence and damage to hippocampal neurons. Rg1 decreased ROS production, reducing the expression of NOX2 and the NLRP1 inflammasome in H2O2­treated hippocampal neurons. Furthermore, Rg1 and tempol treatment significantly decreased neuronal apoptosis and the expression of ß­galactosidase, and alleviated the neuronal senescence and damage induced by H2O2. The present study indicates that Rg1 may reduce NOX2­mediated ROS generation, inhibit NLRP1 inflammasome activation, and inhibit neuronal senescence and damage.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Ginsenosídeos/farmacologia , Hipocampo/patologia , Inflamassomos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 1/metabolismo , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Peróxido de Hidrogênio , Inflamassomos/efeitos dos fármacos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , Proteínas NLR/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , beta-Galactosidase/biossíntese
16.
FASEB J ; 33(3): 4212-4224, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30526049

RESUMO

Hepatic gluconeogenesis makes a significant contribution to the pathogenesis of obesity and its related insulin resistance. Cystathionine γ-lyase (CSE; also cystathionase), a principal hydrogen sulfide (H2S)-synthesizing enzyme in the liver, is involved in glucose and lipid metabolism disorders. However, the roles and precise mechanisms of CSE/H2S in obesity and its related insulin resistance remain obscure. Here we show that CSE knockout exacerbated high-fat diet-induced mouse obesity as well as its related insulin resistance. Further study elucidated that the inhibition of insulin and AMPK signaling pathways by CSE deficiency resulted in nuclear accumulation of Forkhead box protein O1 and subsequently promoted hepatic gluconeogenesis. These phenomena can be reversed by NaHS supplementation. However, in wild-type mice, NaHS treatment ameliorates high fat diet-induced obesity and metabolism disorders, indicating that maintaining an appropriate level of H2S is critical for its mutual change of positive and negative effects of obesity-associated insulin resistance. Our study reveals a double-edged sword effect and a novel mechanism for CSE/H2S in obesity associated with insulin resistance and provides evidence for CSE/H2S as a promising therapeutic potential target for obesity-related insulin resistance.-Guo, W., Li, D., You, Y., Li, W., Hu, B., Zhang, S., Miao, L., Xian, M., Zhu, Y., Shen, X. Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis.

17.
Adv Exp Med Biol ; 1072: 423-430, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178382

RESUMO

Neurotransmitters play a major role in shaping everyday life and functions. Accurate analytical methods are needed for detection of neurotransmitters. Packed-fiber solid-phase extraction (PFSPE) has been developed and seems to be an efficient method. This novel method is based on use of an electrospun polymer device, based on nanofibers. This strategy will be helpful for the development of real-time methods and techniques with high sensitivity to detect target neurotransmitters with high efficiency. Here we provide a brief overview of PFSPE and its applications for the determination of neuro-active molecules.

18.
Adv Exp Med Biol ; 1072: 431-436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178383

RESUMO

BACKGROUND: Understanding individual differences of these indexes in response to stress is important for developing effective interventions. The Tridimensional Personality Questionnaire (TPQ), which has three dimensions, may reflect such individual differences. Meanwhile, there is increasing interest in the relationship between mental stress and non-invasive markers. OBJECTIVES: We examined whether these three dimensions were associated with cognitive behavior tests and the related sAA responses. METHODS: All subjects were divided into different groups based on the scores of the TPQ measuring temperament dimensions. Patterns of Stroop combined with mental arithmetic stress tests were presented, and the sAA responses were recorded as the index of stress responses, and compared between groups. RESULTS: The sAA levels in the post stress test and the recovery period of the high reward-dependence (RD) group were significantly greater than in the low-RD group. The number of trials of Stroop in the high novelty-seeking (NS) group was significantly greater than in the low-NS group. CONCLUSIONS: Individual differences in TPQ personality traits may be associated with different patterns of stress responses.

19.
Exp Dermatol ; 27(11): 1245-1253, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30120801

RESUMO

Human prolactin (PRL) is a well-known hormone for pituitary of lactation and reproduction, but it also has immunostimulatory effect in some inflammatory or autoimmune diseases including psoriasis, which has not been well elucidated. This study aimed to determine the relationship between PRL and psoriasis through clinical case-control studies, and explore the function of PRL in the pathogenesis of imiquimod (IMQ)-induced psoriasis-like mouse model. Serum from patients with psoriasis vulgaris (PsV), patients with erythrodermic psoriasis, and healthy controls (HCs) were collected for PRL test. Skin biopsies were collected for PRL, PRL receptors (PRLRs), cytokines mRNA level determination, PRL immunohistochemistry and PRL Western blotting. Mice were divided into four groups (each n = 6): control group (CON), IMQ group, anti-PRL group and solvent group. Anti-PRL group and solvent group mice were treated with PRL antagonist (cabergoline) and the solvent (0.25% methylcellulose) separately. The serum PRL level of PsV patients was significantly higher than that of HCs (P < 0.001). Compared with HCs, the mRNA levels of PRL and Th1/Th17 cytokines in skin lesions increased significantly (P < 0.05), and the PRL protein level was also significantly elevated in the epidermis and dermis of PsV patients. In IMQ-induced psoriasis-like mouse model, the mRNA and protein levels of PRL in skin lesions were significantly higher than CON group (P < 0.01). Comparing to solvent group, serum PRL level and PRL, cytokines mRNA levels in skin lesions all decreased significantly and the skin inflammatory condition was also alleviated obviously in anti-PRL group. This study suggests that local production of PRL is the main resource of PRL in skin lesions and may play an important role in skin inflammatory of psoriasis.

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