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1.
PLoS One ; 15(12): e0243195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33264366

RESUMO

BACKGROUND: The current worldwide pandemic of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, and the mortality rate of critical ill patients remains high. The purpose of this study was to identify factors that early predict the progression of COVID-19 from severe to critical illness. METHODS: This retrospective cohort study included adult patients with severe or critical ill COVID-19 who were consecutively admitted to the Zhongfaxincheng campus of Tongji Hospital (Wuhan, China) from February 8 to 18, 2020. Baseline variables, data at hospital admission and during hospital stay, as well as clinical outcomes were collected from electronic medical records system. The primary endpoint was the development of critical illness. A multivariable logistic regression model was used to identify independent factors that were associated with the progression from severe to critical illness. RESULTS: A total of 138 patients were included in the analysis; of them 119 were diagnosed as severe cases and 16 as critical ill cases at hospital admission. During hospital stay, 19 more severe cases progressed to critical illness. For all enrolled patients, longer duration from diagnosis to admission (odds ratio [OR] 1.108, 95% CI 1.022-1.202; P = 0.013), pulse oxygen saturation at admission <93% (OR 5.775, 95% CI 1.257-26.535; P = 0.024), higher neutrophil count (OR 1.495, 95% CI 1.177-1.899; P = 0.001) and higher creatine kinase-MB level at admission (OR 2.449, 95% CI 1.089-5.511; P = 0.030) were associated with a higher risk, whereas higher lymphocyte count at admission (OR 0.149, 95% CI 0.026-0.852; P = 0.032) was associated with a lower risk of critical illness development. For the subgroup of severe cases at hospital admission, the above factors except creatine kinase-MB level were also found to have similar correlation with critical illness development. CONCLUSIONS: Higher neutrophil count and lower lymphocyte count at admission were early independent predictors of progression to critical illness in severe COVID-19 patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33314677

RESUMO

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

3.
Front Pharmacol ; 11: 570450, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178020

RESUMO

Fungal secondary metabolites serve as a rich resource for exploring lead compounds with medicinal importance. Diorcinol N (DN), a fungal secondary metabolite isolated from an endophytic fungus, Arthrinium arundinis, exhibits robust anticancer activity. However, the anticancer mechanism of DN remains unclear. In this study, we examined the growth-inhibitory effect of DN on different human cancer cell lines. We found that DN decreased the viability of A3 T-cell leukemia cells in a time- and concentration-dependent manner. Transcriptome analysis indicated that DN modulated the transcriptome of A3 cells. In total, 9,340 differentially expressed genes were found, among which 4,378 downregulated genes and 4,962 upregulated genes were mainly involved in autophagy, cell cycle, and DNA replication. Furthermore, we demonstrated that DN induced autophagy, cell cycle arrest in the G1/S phase, and downregulated the expression of autophagy- and cell cycle-related genes in A3 cells. By labeling A3 cells with acridine orange/ethidium bromide, Hoechst 33,258, and monodansylcadaverine and via transmission electron microscopy, we found that DN increased plasma membrane permeability, structural disorganization, vacuolation, and autophagosome formation. Our study provides evidence for the mechanism of anticancer activity of DN in T-cell leukemia (A3) cells and demonstrates the promise of DN as a lead or even candidate molecule for the treatment of acute lymphoblastic leukemia.

4.
Nat Prod Res ; : 1-7, 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33016130

RESUMO

One new xanthone, chryxanthone C (1), together with four known analogues (2-5), were isolated from the cultures of Paecilamyces sp. TE-540, an endophytic fungus obtained from the leaves of Nicotiana tabacum L. The structure of 1 was elucidated by comprehensive spectral analysis including HRESIMS and 1D/2D NMR, which were confirmed by Cu Kα X-ray crystallography. Compound 1 featured an unusual dihydropyran ring fused to an aromatic ring, rather than the commonly occurring prenyl moiety. The cytotoxicity of compounds 1-5 were evaluated against five human tumour cell lines and 4 exhibited moderate to strong cytotoxicities with IC50 values ranging from 5.6 to 14.2 µM.

5.
Planta Med ; 86(12): 805-821, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32645741

RESUMO

Fungi are well known for their ability to synthesize secondary metabolites, which have proven to be a rich resource for exploring lead compounds with medicinal and/or agricultural importance. The genera Aspergillus, Penicillium, and Talaromyces are the most widely studied fungal groups, from which a plethora of bioactive metabolites have been characterized. However, relatively little attention has been paid to the genus Paecilomyces, which has been reported to possess great potential for its application as a biocontrol agent. Meanwhile, a wide structural array of metabolites with attractive bioactivities has been reported from this genus. This review attempts to provide a comprehensive overview of Paecilomyces species, with emphasis on the chemical diversity and relevant biological activities of these metabolic products. Herein, a total of 148 compounds and 80 references are cited in this review, which is expected to be beneficial for the development of medicines and agrochemicals in the near future.


Assuntos
Paecilomyces , Penicillium , Talaromyces , Aspergillus , Fungos
6.
Neurochem Int ; 138: 104771, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32450184

RESUMO

Tryptophan (TRP) metabolism could occur both peripherally and centrally, which plays an essential role in brain and gastrointestinal disorders. The participation of TRP metabolism in the bidirectional brain-gut interactions is of value to better understand the mechanism of the pathophysiology of depression. To compare the difference between peripheral and cerebral TRP metabolism in depression, the chronic unpredicted mild stress (CUMS) was used to induce depressive-like syndrome in rats. After the rats were subjected to CUMS for five weeks, TRP and its metabolites were determined by prominence ultrafast liquid chromatography (UFLC) coupled with a QTRAP 5500 mass spectrometer (UFLC-QTRAP-5500/MS), and the expression of TRP metabolic enzymes were examined by Real-time quantitative PCR (qRT-PCR). CUMS induced TRP metabolism abnormalities in the colon, cortex and hippocampus of rats. There were regional metabolism differences, but the common points were the upregulation of indoleamine-2,3-dioxygenase 1 (IDO1) and the increased contents of Kynurenine (KYN), which suggested that KYN pathway (KP) was more favored than the serotonin (5-HT) pathway in the TRP metabolism under CUMS in the three regions studied. More importantly, KYN was preferentially metabolized into neurotoxic 3-hydroxycaninuric acid (3-HK) branch in the cortex and hippocampus while Kynurenic acid (KA) branch in the colon under CUMS. Interestingly, according to the Pearson's correlation coefficients, there may be correlations between the colonic KYN and cerebral 3-HK and KA. It advances our understanding of the role of TRP metabolism in gut-brain communication and provides new research ideas and methods for depression.

7.
Chin Med ; 15: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411290

RESUMO

Background: Chronic alcohol consumption disrupts psychomotor and cognitive functions, most of which are subserved by the dysfunction of hippocampus. Dysregulated excitatory glutamatergic transmission is implicated in repeated alcohol induced psychomotor and cognitive impairment. Ginsenoside Rg1, one of the main active ingredient of the traditional tonic medicine Panax ginseng C.A. Meyer (Araliaceae), has been used to treat cognitive deficits. Particularly, Rg1 has been demonstrated to improve hippocampus-dependent learning in mice and attenuate glutamate-induced excitotoxicity in vitro. Thus, in the present research, we sought to investigate the therapeutic effects of Ginsenoside Rg1 on repeated alcohol induced psychomotor and cognitive deficits in hippocampal-dependent behavioral tasks and unravel the underpinnings of its neuroprotection. Methods: Male ICR (CD-1) mice were consecutively intragastrically treated with 20% (w/v) alcohol for 21 days. Then, behavior tests were conducted to evaluate repeated alcohol induced psychomotor and cognitive deficits. Histopathological changes, and biochemical and molecular alterations were assessed to determine the potential neuroprotective mechanism of Rg1. Results: The results suggested that Rg1, at the optimal dose of 6 mg/kg, has the potential to ameliorate repeated alcohol induced cognitive deficits by regulating activities of NR2B containing NMDARs and excitotoxic signaling. Conclusion: Our findings further provided a new strategy to treat chronic alcohol exposure induced adverse consequences.

8.
Life Sci ; 252: 117669, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298740

RESUMO

Chronic social defeat stress (CSDS) is an ethologically relevant psychosocial stress animal model and has been widely used in depression studies. Ginsenoside Rg1 (Rg1) is the major active ingredients of ginseng with low toxicity and neuroprotective effects. The present study aims to investigate the antidepressant effects of Rg1 in CSDS mice and explore its molecular mechanism. We found that Rg1 (20 or 40 mg/kg, i.g.) administration significantly alleviated depressive-like behaviors caused by 4-week CSDS exposure, as measured by social interaction test and sucrose preference test, tail suspension test and forced swim test. Additionally, Rg1 treatment inhibited CSDS-induced production of IL-6, TNF-α and IL-1ß, decreased the expression of iNOS, COX2, and caspase-9 and -3, and inhibited microglial activation (Iba1) in the hippocampus. Rg1 was found to significantly downregulate p-JNK1/2 and p-P38 MAPK levels, upregulate p-ERK1/2 levels and inhibit the expression of phosphorylated NF-κB in the hippocampus. Meanwhile, Rg1 regulated SIRT1 and decreased the levels of acetylated p65 (ac-p65) in the hippocampus. Moreover, the reduction in adult hippocampal neurogenesis in CSDS mice was reversed by Rg1 treatment. In conclusion, our findings suggest that Rg1 prevents depressive-like behavior in CSDS-exposed mice, partially through the downregulation of hippocampal neuroinflammation and the upregulation of adult hippocampal neurogenesis and that these changes presumably occur through increased anti-inflammatory effects and the inhibition of proinflammatory cytokine and neurotoxic mediator expression and microglial activation, which is partly mediated by the regulation of the MAPK and SIRT1 signaling pathways and results in the inhibition of NF-κB transcriptional activity.


Assuntos
Antidepressivos/farmacologia , Depressão/prevenção & controle , Ginsenosídeos/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ginsenosídeos/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neurogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
J Vis Exp ; (157)2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32202532

RESUMO

Sexual behavior is highly species-specific. Although rodents have slightly different sexual behaviors, mice and rats have a similar sexual behavioral pattern. The purpose of this article is to describe the hormone-induced estrus ovariectomized female model and the experimental procedure for the assessment of sexual behavior of male mice. The most important sexual behavioral elements are demonstrated in the video and illustrations. The critical steps, advantages, and limitations of the sexual behavior test are explained as well. Finally, the behavior parameters are presented, and mounting, intromission, and ejaculation processes in mating are distinguished. Behavioral parameters are assessed in terms of the occurred duration and counts during the test period.


Assuntos
Comportamento Sexual Animal/fisiologia , Animais , Bioensaio , Ejaculação/fisiologia , Estro/efeitos dos fármacos , Feminino , Habituação Psicofisiológica , Hormônios/farmacologia , Masculino , Camundongos , Ovariectomia , Ratos
10.
Fitoterapia ; 141: 104450, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31837410

RESUMO

Cajaninstilbene acid (CSA), a bioactive constituent isolated from pigeon pea leaves, exhibited neuroprotective activities in previous studies. The present study aims to evaluate the antidepressant effects of CSA by using behavioral despair models of tail suspension test (TST) and forced swimming test (FST), and a chronic unpredictable mild stress (CUMS) model. CSA (30 or 60 mg/kg), intragastrically administrated for 7 days, could significantly reduce the immobility time of mice in TST and FST. CSA treatment (15 or 30 mg/kg) significantly reversed the depressive-like behavioral changes of mice induced by 3 or 6 weeks CUMS that caused the decrease of sucrose preference, the increase of latency to feed in the novelty-suppressed feeding test, and the increase of immobility time in TST of mice. Furthermore, the related mechanisms of the effect were explored by accessing the metabolite levels of kynurenine pathway of tryptophan metabolism and the expression of some related proteins in cerebral cortex of CUMS mice. Our results showed that the kynurenine pathway was upregulated after CUMS, while the alteration could be significantly reversed by CSA. CSA also reversed the CUMS-induced decrease in the levels of BDNF, PSD-95, p-Akt/Akt and p-mTOR/mTOR. Therefore, the antidepressant-like effects of CSA might be achieved through regulating tryptophan metabolism, promoting BDNF and PSD-95 expression, and activating Akt/mTOR pathway in the cerebral cortex.


Assuntos
Antidepressivos/farmacologia , Cajanus/química , Salicilatos/farmacologia , Estilbenos/farmacologia , Animais , Antidepressivos/química , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Folhas de Planta/química
11.
Chin Med J (Engl) ; 133(2): 221-228, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31764175

RESUMO

OBJECTIVE: Alternative splicing can generate various structural and functional protein isoforms. Recently, accumulating evidence shows a relationship between alternative splicing and cancer. Cancer is a complex and chronic disease that involves malignant transformation. In this review, we consider alternative splicing events in relation to the hallmarks of cancer cells, and discuss current therapies to treat cancer-related to alternative splicing. DATA SOURCES: Data cited in this article are from the PubMed and Embase database, primarily focusing on research published from 2000 to 2018. STUDY SELECTION: Articles were selected with the search terms "alternative splicing," "cancer cell," "tumor microenvironment," and "therapy." RESULTS: Alternative splicing plays an important role in tumorigenesis, development, and escape from cell death. Taking this trait of cancer cells into consideration will allow more definite diagnoses of cancer, and allow the development of more effective medicines to intervene in cancer that could focus on controlling alternative splicing or competitively binding to the final products. CONCLUSIONS: Alternative splicing is common in cancer cells. Consideration of alternative splicing may allow different strategies for cancer therapy or the identification of novel biomarkers for cancer diagnosis.


Assuntos
Processamento Alternativo/fisiologia , Processamento Alternativo/genética , Animais , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
12.
Front Pharmacol ; 10: 1084, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680939

RESUMO

Amyloid-ß1-42 (Aß1-42) oligomers play an important role at the early stage of Alzheimer's disease (AD) and have been a vital target in the development of therapeutic drugs for AD. Cajaninstilbene acid (CSA), a major bioactive stilbene isolated from pigeon pea (Cajanus cajan) leaves, exerted the neuroprotective property in our previous studies. The present study utilized a validated mouse model of early-stage AD induced by bilateral injection of Aß1-42 oligomers into hippocampal CA1 regions (100 pmol/mouse) to investigate the cognitive enhancing effects of CSA and the underlying mechanism, by a combination of animal behavioral tests, immunohistochemistry, liquid chromatography-tandem mass spectrometry analysis, and Western blot methods. Intragastric administration of CSA (7.5, 15, and 30 mg/kg) attenuated the impairment of learning and memory induced by Aß1-42 oligomers. CSA stimulated Aß clearance and prevented microglial activation and astrocyte reactivity in the hippocampus of model mice. It also decreased the high levels of Glu but increased the low levels of GABA. In addition, CSA inhibited excessive expression of GluN2B-containing NMDARs and upregulated the downstream PKA/CREB/BDNF/TrkB signaling pathway. These results suggest that CSA could be a potential therapeutic agent at the early stage of AD.

13.
Brain Res Bull ; 153: 239-249, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542427

RESUMO

Chronic social defeat stress (CSDS) is a widely used behavioural paradigm of psychosocial stress that can be used to research the pathogenesis of depression and seek antidepressant drugs. Dammarane sapogenins (DS), the deglycosylated product of ginsenosides, has a wide range of biological activities, including immunomodulatory, antifatigue, antitumour and antidepressant activities. However, whether DS has antidepressant-like effects in a CSDS mouse model remains unknown. Therefore, the present study was conducted to evaluate the antidepressant properties of DS in CSDS mice and its underlying mechanisms. The results showed that the oral administration of DS (40 and 80 mg/kg) increased the time spent in the interaction zone in the social interaction test and the sucrose intake in the sucrose preference test, decreased the latency in the novelty-suppressed feeding test, and reduced the immobility time in both the tail suspension test and forced swimming test. Biochemical analyses of brain tissue and serum showed that DS treatment significantly decreased serum corticosterone levels and enhanced brain monoamine neurotransmitter levels in CSDS mice. In addition, an impairment in hippocampal neurogenesis that paralleled a reduced BDNF level in the hippocampus was observed in the mice that were subjected with CSDS for 3 weeks, while treatment with DS reversed these changes. Moreover, DS treatment significantly upregulated BDNF, pTrkB/TrkB, pAkt/Akt, pPI3K/PI3K, pCREB/CREB, pERK1/2/ERK1/2 and pmTOR/mTOR protein expression in the hippocampus. In conclusion, our results showed that DS exerts antidepressant-like effects in mice with CSDS-induced depression, that the effects may be mediated by the normalization of monoamine neurotransmitter levels, the prevention of HPA axis dysfunction and the impairment of hippocampal neurogenesis, and that this occurs partly through the ability of DS to enhance BDNF expression by increasing the TrkB/CREB/ERK pathway and the PI3K/AKT/mTOR pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Sapogeninas/farmacologia , Animais , Antidepressivos/farmacologia , Corticosterona/sangue , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Sapogeninas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Triterpenos/metabolismo , Triterpenos/farmacologia
14.
Life Sci ; 234: 116751, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415771

RESUMO

AIMS: The present study aims to investigate the impacts of olfactory bulbectomy (OBX) on urinary metabolic profile and tryptophan metabolites in prefrontal cortex (PFC) of rats, and to explore the regulation effects of fluoxetine. MAIN METHODS: OBX model was developed by aspiration of olfactory bulbs. After fluoxetine treatment (10 mg/kg) for 14 days, urine samples were collected and behavior tests were applied. Tryptophan (TRP) metabolites and neurotransmitters in PFC were determined by prominence ultrafast liquid chromatography-QTRAP-mass spectrometry, and tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) were evaluated by western blot. Urinary metabolites were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomics strategy. KEY FINDING: OBX rats showed hyperlocomotion in open field, hyperactivity in open arm and despair status, and fluoxetine reserved these behavioral abnormalities. The levels of TRP, 5-HIAA, 5-HIAA/5-HT ratio and DA increased, while kynurenine and 5-HT decreased in PFC of OBX rats. The activities of TPH2 and IDO1were inhibited after OBX. Twenty-six altered metabolites were identified as potential biomarkers in OBX rats involved in tryptophan metabolism, gut microbiota metabolism, energy metabolism, purine metabolism, ascorbate and aldarate metabolism, and tyrosine metabolism. Among them, 15 abnormal metabolites were corrected by fluoxetine to some extent. SIGNIFICANCE: Our results revealed that urinary metabolic profile changed greatly in OBX rats, and identified biomarkers might be helpful for the diagnosis of agitated depression. The regulation effects of fluoxetine on urinary metabolic profile and tryptophan metabolites in PFC might contribute to its antidepressant action in OBX rats.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Fluoxetina/uso terapêutico , Metaboloma/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/urina , Modelos Animais de Doenças , Fluoxetina/farmacologia , Masculino , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley , Triptofano/metabolismo
15.
Phytother Res ; 33(10): 2726-2736, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31353678

RESUMO

20(S)-Protopanaxadiol (PPD) is a basic aglycone of the dammarane triterpenoid saponins and exerts antidepressant-like effects on behaviour in the forced swimming test (FST) and tail suspension test (TST) and in rat olfactory bulbectomy depression models. However, the antidepressant effects of PPD have not been studied thoroughly. The objective of the present study was first to investigate the effect of PPD on depression behaviours induced by chronic social defeat stress (CSDS) in mice. The results showed that CSDS was effective in producing depression-like behaviours in mice, as indicated by decreased responses in the social interaction test, sucrose preference test, TST, and FST, and that this effect was accompanied by noticeable alterations in the levels of oxidative markers (superoxide dismutase, catalase, and lipid peroxidation) and monoamines (5-HT and NE) in the hippocampus and serum corticosterone levels. Additionally, western blot analysis revealed that CSDS exposure significantly downregulated BDNF, p-TrkB/TrkB, p-Akt/Akt, and p-mTOR/mTOR protein expression in the hippocampus. Remarkably, chronic PPD treatment significantly ameliorated these behavioral and biochemical alterations associated withCSDS-induced depression. Our results suggest that PPD exerts antidepressant-like effects in mice with CSDS-induced depression and that this effect may be mediated by the normalization of neurotransmitter and corticosterone levels and the alleviation of oxidative stress, as well as the enhancement of the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Sapogeninas/farmacologia , Estresse Psicológico/complicações , Animais , Doença Crônica , Corticosterona/sangue , Depressão/etiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Ratos , Sapogeninas/uso terapêutico
16.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052148

RESUMO

Due to the importance of proanthocyanidin bioactivity and its relationship with chemical structure, ultrasound-assisted extraction and purification schemes were proposed to evaluate the proanthocyanidin content and analyze the structural composition and potential bioactivities of different proanthocyanidin fractions from Chinese wild rice (Zizania latifolia). Following an optimized extraction procedure, the crude wild rice proanthocyanidins (WRPs) were purified using n-butanol extraction, chromatography on macroporous resins, and further fractionation on Sephadex LH-20 to yield six specific fractions (WRPs-1-WRPs-6) containing proanthocyanidin levels exceeding 524.19 ± 3.56 mg/g extract. Structurally, (+)-catechin, (-)-epicatechin, and (-)-epigallocatechin were present as both terminal and extension units, and (-)-epicatechin was the major extension unit, in each fraction. This is the first preparation of WRP fractions with a different mean degree of polymerization (mDP), ranging from 2.66 ± 0.04 to 10.30 ± 0.46. A comparison of the bioactivities of these fractions revealed that fractions WRPs-1-WRPs-5 had significant DPPH radical scavenging activities, whereas fraction WRPs-6 with a high mDP showed better α-glucosidase and pancreatic lipase inhibitory effects. These findings should help define possible applications of WRPs to functional foods or nutraceuticals.


Assuntos
Oryza/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proantocianidinas/química , Proantocianidinas/isolamento & purificação , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Ativação Enzimática , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/isolamento & purificação , Depuradores de Radicais Livres/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30836315

RESUMO

l-Tryptophan (Trp) metabolites and related neurotransmitters play crucial roles in physiological functions, and their imbalances are implicated in the pathology of depression, Alzheimer's disease and other diseases. Measurement of Trp metabolites and related neurotransmitters possesses a great potential to elucidate the disease mechanisms and evaluate the outcomes of therapeutic interventions. A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of Trp, l-kynurenine (Kyn), kynurenic acid (Kyna), 3-hydroxykynurenine (3-HK), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE), l-glutamic acid (Glu), γ-aminobutyric acid (GABA) and acetylcholine (ACh) in mice serum and the brain tissues in a single chromatographic run. Samples were spiked with the internal standard, mixed with trifluoroacetic acid to precipitate protein and analyzed by LC-MS/MS. Chromatographic separation was achieved using a Restek Ultra Aqueous C18 column in combination with a gradient elution within 8 min. Mass spectrometric detection was performed using multiple reaction monitoring with electrospray ionization source in positive mode. The method exhibited good selectivity and correlation coefficient values for the calibration curves of each analyte were >0.99. The limit of detection and quantification ranged from 0.96 to 24.48 nmol/L and 3.42 to 244.82 nmol/L, respectively. The intra- and inter-day precision were ≤13.92%. All analytes were stable in prepared samples at room temperature in the autosampler for 24 h. This method was successfully applied to the analysis of biological samples from control and chronic mild stress (CMS) induced depression mice. It was found that Kyn and 3-HK pathways were enhanced by CMS, while the levels of Trp, Kyna, 5-HIAA, Glu, GABA and ACh were significantly reduced. The changes in 5-HT and NE levels were not uniform in the periphery and the brain. This method can therefore be applied to analyze Trp metabolites and related neurotransmitters levels to monitor disease states, study the mechanisms and outcomes of therapeutic interventions.


Assuntos
Química Encefálica/fisiologia , Cromatografia Líquida/métodos , Neurotransmissores/análise , Espectrometria de Massas em Tandem/métodos , Triptofano/análise , Animais , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurotransmissores/sangue , Neurotransmissores/metabolismo , Reprodutibilidade dos Testes , Triptofano/sangue , Triptofano/metabolismo
18.
Front Behav Neurosci ; 13: 21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873013

RESUMO

Objective: No study has comprehensively evaluated the effect of postweaning isolation on the social and sexual behaviors of a certain strain of rodents in ethology. The present study aims to explore how and to what extent isolation rearing after postweaning affects the social and sexual behaviors of male CD-1 mice in adulthood systematically. Methods: Male CD-1 mice were randomly assigned to two groups: isolation reared (IS, one mouse per cage, n = 30) and group housed (GH, five mice per cage, n = 15). The mice underwent isolation rearing from postnatal day 23 to day 93. Then, social affiliation, recognition and memory were measured through selection task experiments. Social interaction under a home cage and novel environment were measured via resident-intruder and social interaction test, respectively. Furthermore, sexual preference, homosexual and heterosexual behaviors were measured. Results: Our study found that postweaning isolation increased the social affiliation for conspecifics (p = 0.001), reduced social recognition (p = 0.042) and impaired social memory. As for social interaction, isolated mice showed a remarkably increased aggression toward the intruder male in a home cage or novelty environment. For instance, isolated mice presented a short attack latency (p < 0.001), high attack frequency (p < 0.001) and long attack duration (p < 0.001). In addition, isolated mice exhibited further social avoidance. Contrastingly, isolated mice displayed a reduced sexual preference for female (IS: 61.47 ± 13.80%, GH: 70.33 ± 10.06%, p = 0.038). As for heterosexual behavior, isolated mice have a short mating duration (p = 0.002), long mounting latency (p = 0.002), and long intromission latency (p = 0.015). However, no association was observed between postweaning isolation and homosexual behavior in male CD-1 mouse. Conclusion: Postweaning isolation increased the social affiliation, impaired the social cognition and considerably increased the aggression in social interaction of adult male CD-1 mice. Postweaning isolation induced a decreased sexual preference for female in adulthood. Postweaning isolation extended the latency to mate, thereby reducing mating behavior. No association was observed between isolation and homosexual behavior.

19.
J Pharm Biomed Anal ; 166: 119-127, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30639931

RESUMO

In vitro incubation of rat liver microsomes with 30 µL of 100 µmol·L-1 dapoxetine and 30 µL of 10, 100, 250, 500, 1000, 2500, or 5000 µg·mL-1 Wuziyanzong pill was performed at 37 °C for 60 min. Dapoxetine concentration was analyzed by high performance liquid chromatography (HPLC). The half maximal inhibitory concentration (IC50) of Wuziyanzong pill on metabolism of dapoxetine was 296.10 µg mL-1in vitro. Twelve SD rats were randomly divided into 2 groups: Control group and Wuziyanzong pill group. The two groups were administrated with 10 mL·kg-1 saline (Control group) or 10 mL·kg-1 Wuziyanzong pill solution (Experimental group, solution contained 200 mg mL-1 Wuziyanzong pill) for 15 consecutive days. Following administration of saline or Wuziyanzong pill on the 15th day, 20 mg kg-1 dapoxetine was administered to all rats. Blood was collected from the tail vein (0.3 mL) at multiple time points, and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was used to determine the concentration of dapoxetine and its main metabolites, dapoxetine-N-oxide and desmethyldapoxetine in rats. Pharmacokinetic analysis of dapoxetine showed that area under the concentration-time curve (AUC) and mean maximum plasma concentration (Cmax) of the Wuziyanzong pill group were decreased, while plasma clearance (CLz) was increased compared with control group (P < 0.01). The HPLC method for determination of dapoxetine in vitro was accurate and specific. The UHPLC-MS/MS method established for determination of dapoxetine and its major metabolites in rat plasma was rapid and specific, which met the requirements of pharmacokinetic guidelines. Wuziyanzong pill had a weak inhibitory effect on metabolism of dapoxetine in vitro, but had a very strong induction effect in vivo, suggesting the dosage of dapoxetine should be increased when administered in combination with Wuziyanzong pill.


Assuntos
Benzilaminas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Naftalenos/farmacocinética , Animais , Benzilaminas/sangue , Cromatografia Líquida de Alta Pressão , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Naftalenos/sangue , Ratos , Espectrometria de Massas em Tandem
20.
ACS Appl Mater Interfaces ; 11(6): 5821-5833, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30645095

RESUMO

In this study, we established a long-term three-dimensional (3D) culture system by using integrin ligand modified alginate hydrogels to encapsulate and differentiate neural progenitor cells (NPCs) toward oligodendrocyte (OL) lineage cells. The porosity of the hydrogel was optimized by varying the alginate concentrations and then characterized by scanning electronic microscopy (SEM). The surface plasmon resonance (SPR) test was used to confirm the ligand-integrin interactions indicating adherence between the NPC surfaces and the hydrogels. Following encapsulation in the hydrogels, both mouse and human NPC sphere cultures could be maintained up to 90 days. Mouse NPC spheres were differentiated into viable neurons, astrocytes and mature OLs by day 60 in all groups whereas human NPC spheres were differentiated into neurons and later into GFAP positive astrocytes and O4 positive pre-OL within 90 days. The species difference in the timeline of OL development between mouse and human was reflected in this system. The ligand LXY30 interacting with the α3ß1 integrin receptor was more effective in promoting the differentiation of hNPCs to OL lineage cells compared with the ligand LXW64 interacting with the αvß3 integrin receptor, hyaluronic acid interacting with CD44 receptor or without any ligand. This study is the first to differentiate O4+ pre-OLs from hNPCs in a LXY30-α3ß1 (integrin-ligand) modified alginate 3D hydrogel culture. This 3D platform could serve as a valuable tool in disease modeling, drug discovery, and NPC transplantation.


Assuntos
Alginatos/química , Diferenciação Celular/efeitos dos fármacos , Hidrogéis/química , Integrina alfa3beta1/metabolismo , Ligantes , Animais , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Hidrogéis/metabolismo , Hidrogéis/farmacologia , Integrina alfa3beta1/química , Camundongos , Microscopia Eletrônica de Varredura , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo
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