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1.
Org Lett ; 24(14): 2684-2688, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35389665

RESUMO

Chevalinulins A (1) and B (2), two indole diketopiperazine alkaloids containing an unprecedented spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton, together with a known analogue neoechinulin B (3), were isolated from the deep-sea cold-seep-derived fungus Aspergillus chevalieri CS-122. Their structures were determined by spectroscopic analysis, single-crystal X-ray diffraction, specific rotation (SR), and NMR calculations. Compounds 1 and 2 exhibited significant in vivo proangiogenic activity in transgenic zebrafish.


Assuntos
Alcaloides , Dicetopiperazinas , Alcaloides/química , Animais , Aspergillus , Dicetopiperazinas/química , Fungos , Alcaloides Indólicos/química , Estrutura Molecular , Octanos , Esqueleto , Peixe-Zebra
2.
Physiol Genomics ; 54(4): 141-152, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35285753

RESUMO

Sick sinus syndrome (SSS) is a term used for a variety of disorders defined by abnormal cardiac impulse formation and by abnormal propagation from the heart's sinoatrial node. In this study, we present a case from a Chinese family in which two closely related individuals had the symptoms and electrocardiographic evidence of SSS. We hypothesized that multiple individuals affected by the disease in the family was an indication of its genetic predisposition, and thus performed high-throughput sequencing for the participants from the family to detect potential disease-associated variants. One of the potential variants that was identified was a KCNG2 gene variant (NC_000018.9: g.77624068_77624079del). Further bioinformatic analysis showed that the observed variant may be a pathogenic mutation. The results of protein-protein docking and whole cell patch-clamp measurements implied that the deletion variant in KCNG2 could affect its binding the KV2.1 protein, and finally affect the function of Kv channel, which is an important determinant in regulation of heartbeat. Therefore, we inferred that the variable KCNG2 gene may affect the function of Kv channel by changing the binding conformation of KCNG2 and KV2.1 proteins and then adversely affect propagation from the sinoatrial node and cardiac impulse formation by changing the action potential repolarization of heart cells. In summary, our findings suggested that the dominant KCNG2 deletion variant in the examined Chinese family with SSS may be a potential disease-associated variant.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização , Síndrome do Nó Sinusal , Nó Sinoatrial , Predisposição Genética para Doença , Humanos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Deleção de Sequência , Síndrome do Nó Sinusal/diagnóstico , Síndrome do Nó Sinusal/genética , Nó Sinoatrial/patologia , Sequenciamento Completo do Genoma
3.
J Appl Toxicol ; 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35315093

RESUMO

Airborne total suspended particles (TSP) and particulate matter (PM2.5 ) threaten global health and their potential impact on cardiovascular and respiratory diseases are extensively studied. Recent studies attest premature deaths, low birth weight, and congenital anomalies in the fetus of pregnant women exposed to air pollution. In this regard, only few studies have explored the effects of TSP and PM2.5 on cardiovascular and cerebrovascular development. As both TSP and PM2.5 differ in size and composition, this study is attempted to assess the variability in toxicity effects between TSP and PM2.5 on the development of cardiovascular and cerebrovascular systems and the underlying mechanisms in a zebrafish model. To explore the potential toxic effects of TSP and PM2.5 , zebrafish embryos/larvae were exposed to 25, 50, 100, 200, and 400 µg/ml of TSP and PM2.5 from 24 to 120 hpf (hours post-fertilization). Both TSP and PM2.5 exposure increased the rate of mortality, malformations, and oxidative stress, whereas locomotor behavior, heart rate, blood flow velocity, development of cardiovasculature and neurovasculature, and dopaminergic neurons were reduced. The expression of genes involved in endoplasmic reticulum stress (ERS), Wnt signaling, and central nervous system (CNS) development were altered in a dose- and time-dependent manner. This study provides evidence for acute exposure to TSP and PM2.5 -induced cardiovascular and neurodevelopmental toxicity, attributed to enhanced oxidative stress and aberrant gene expression. Comparatively, the effects of PM2.5 were more pronounced than TSP.

4.
Chemosphere ; 291(Pt 1): 132868, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34767848

RESUMO

Exorbitant substrates for Schizochytrium culture result in the high cost of docosahexaenoic acid (DHA) production. In order to develop a feasible approach that is expected to reduce DHA production cost, Schizochytrium sp. S31 cultivation with a mixture of saline wastewater (SWW) and tofu whey wastewater (TWW) was investigated in this study. Using glucose as the carbon source, the maximum biomass and DHA yield in cultures using mixed wastewater containing 5% SWW reached 19.08 and 2.66 g/L, respectively, which were 2.29 and 2.66 times higher than those of cultures using control medium. Moreover, a good wastewater treatment performance was achieved as approximately 60% of the COD, TN, and TP were reduced in the cultures using mixed wastewater with a SWW ratio of 5%. The mixed wastewater presented better performance on DHA production than control medium using all tested carbon sources including glucose, fructose, and pure and crude glycerol. The components of control medium can be completely replaced by the mixed wastewater and crude glycerol. It is expected to effectively decrease the medium cost for DHA production and reduce the environmental risk of food processing wastewater.


Assuntos
Ácidos Docosa-Hexaenoicos , Estramenópilas , Biomassa , Fermentação , Glicerol , Águas Residuárias
5.
Chin J Nat Med ; 19(10): 750-757, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34688465

RESUMO

Tripterygium wilfordii multiglycoside (GTW) is a commonly used compound for the treatment of rheumatoid arthritis (RA) and immune diseases in clinical practice. However, it can induce liver injury and the mechanism of hepatotoxicity is still not clear. This study was designed to investigate GTW-induced hepatotoxicity in zebrafish larvae and explore the mechanism involved. The 72 hpf (hours post fertilization) zebrafish larvae were administered with different concentrations of GTW for three days and their mortality, malformation rate, morphological changes in the liver, transaminase levels, and histopathological changes in the liver of zebrafish larvae were detected. The reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the levels of microRNA-122 (miR-122) and genes related to inflammation, apoptosis, cell proliferation and liver function. The results showed that GTW increased the mortality of zebrafish larvae, while significant malformations and liver damage occurred. The main manifestations were elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), significant liver atrophy, vacuoles in liver tissue, sparse cytoplasm, and unclear hepatocyte contours. RT-PCR results showed that the expression of miR-122 significantly decreased by GTW; the mRNA levels of inflammation-related genes il1ß, il6, tnfα, il10, cox2 and ptges significantly increased; the mRNA level of tgfß significantly decreased; the mRNA levels of apoptosis-related genes, caspase-8 and caspase-9, significantly increased; the mRNA level of bcl2 significantly decreased; the mRNA levels of cell proliferation-related genes, top2α and uhrf1, significantly reduced; the mRNA levels of liver function-related genes, alr and cyp3c1, significantly increased; and the mRNA level of cyp3a65 significantly decreased. In zebrafish, GTW can cause increased inflammation, enhanced apoptosis, decreased cell proliferation, and abnormal expression of liver function-related genes, leading to abnormal liver structure and function and resulting in hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Tripterygium , Animais , Apoptose , Doença Hepática Induzida por Substâncias e Drogas/genética , Inflamação/induzido quimicamente , Inflamação/genética , Transativadores , Peixe-Zebra/genética , Proteínas de Peixe-Zebra
6.
J Org Chem ; 86(16): 10954-10961, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-33052677

RESUMO

Asperfloketals A (1) and B (2), two 1(10 → 6)-abeo-14,15-secosteroids featuring a novel trioxahexaheterocyclic ring system, were isolated from the sponge-associated fungus Aspergillus flocculosus 16D-1. Their structures were elucidated by extensive spectroscopic analysis and NMR chemical shifts calculations, supported by DP4+ probability analysis, and their absolute configurations were determined by ECD calculations and the modified Mosher's method. Asperfloketals A and B showed strong anti-inflammatory activity in the CuSO4-induced transgenic fluorescent zebrafish but displayed no cytotoxicity against HeLa, HepG2, and SW480 cell lines.


Assuntos
Aspergillus , Peixe-Zebra , Animais , Ergosterol/análogos & derivados , Estrutura Molecular
7.
Chemosphere ; 265: 129109, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33280847

RESUMO

AIMS: This study evaluated the neurodevelopmental toxicity of isoniazid (INH) in zebrafish embryos and the underlying mechanism. METHODS: Zebrafish embryos were exposed to different concentrations (2 mM, 4 mM, 8 mM, 16 mM, 32 mM) INH for 120 hpf. During the exposure period, the percentage of embryo/larva mortality, hatching, and morphological malformation were checked every 24 h until 120 hpf. The development of blood vessels in the brain was observed at 72 hpf and 120 hpf, and behavioral capacity and acridine orange (AO) staining were measured at 120 hpf. Alterations in the mRNA expression of apoptosis and dopamine signaling pathway related genes were assessed by real-time quantitative PCR (qPCR). RESULTS: INH considerably inhibited zebrafish embryo hatching and caused zebrafish larval malformation (such as brain malformation, delayed yolk sac absorption, spinal curvature, pericardial edema, and swim bladder defects). High concentration of INH (16 mM, 32 mM) even induced death of zebrafish. In addition, INH exposure markedly restrained the ability of the zebrafish autonomous movement, shortened the length of dopamine neurons and inhibited vascular development in the brain. No obvious apoptotic cells were observed in the control group, whereas considerable numbers of apoptotic cells appeared in the head of INH-treated larvae at 120 hpf. PCR results indicated that INH significantly raised the transcription levels of caspase-3, -8, -9, and bax and significantly decreased bcl-2 and bcl-2/bax in the zebrafish apoptotic signaling pathway. INH also markedly decreased the genes related to dopamine signaling pathway (th1, dat, drd1, drd2a, drd3, and drd4b). CONCLUSIONS: Experimental results indicated that INH had obvious neurodevelopmental toxicity in zebrafish. Persistent exposure to INH for 120 h caused apoptosis, decreased dopaminergic gene expression, altered vasculature, and reduced behaviors.


Assuntos
Embrião não Mamífero , Peixe-Zebra , Animais , Dopamina , Isoniazida/toxicidade , Larva , Transdução de Sinais , Peixe-Zebra/genética
8.
Sci Total Environ ; 735: 139496, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480152

RESUMO

Pyriproxyfen (PPF), a broad-spectrum insecticide known to cause reproductive and endocrine disruption in invertebrates, while the data is scarce in aquatic vertebrates. The goal of this study is to investigate the impact of PPF on reproductive endocrine system of male and female zebrafish along hypothalamus-pituitary-gonadal (HPG) axis. In brain, PPF caused significant alteration in the transcripts of erα, lhß, and cyp19b genes in male and fshß, lhß, and cyp19b genes in female zebrafish. The downstream genes of steroidogenic pathway like, star, 3ßhsd, 17ßhsd, and cyp19a expression were significantly altered in gonad of both sexes. Subsequent changes in circulatory steroid hormone levels lead to imbalance in hormone homeostasis as revealed from estradiol/testosterone (E2/T) ratio. Further, the vitellogenin transcript level was enhanced in hepatic tissues and their blood plasma content was increased in male (16.21%) and declined in female (21.69%). PPF also induced histopathological changes in gonads such as, reduction of mature spermatocytes in male and vitellogenic oocytes in female zebrafish. The altered E2/T ratio and gonadal histopathology were supported by the altered transcript levels of HPG axis genes. Overall, these findings provide new insights of PPF in zebrafish reproductive system and highlights for further investigations on its potential risks in aquatic environment.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água/farmacologia , Animais , Sistema Endócrino/efeitos dos fármacos , Feminino , Gônadas/efeitos dos fármacos , Homeostase , Hipotálamo , Masculino , Piridinas , Reprodução , Vitelogeninas , Peixe-Zebra
9.
Chemosphere ; 250: 126288, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32114347

RESUMO

Particulate matter (PM10) is one of the most important indicators of the pollution that characterizes air quality. Epidemiological studies have shown that PM10 can cause cardiovascular-related diseases in the population. And, we studied the developmental toxicity of PM10 and the underlying mechanism of its effects on the cardiovascular system of zebrafish embryo/larva. Changes in cardiac morphology, sinus venosus and bulbus arteriosus (SV-BA) distance, heart rate, vascular subintestinalis, blood flow, returned blood volume, and reactive oxygen species (ROS) level were measured, and changes in the expression levels of certain genes were assessed via RT-PCR. The results showed that PM10 caused a significant increase in pericardial sac area and SV-BA distance, a decrease in heart rate, inhibition of vascular subintestinalis growth, blood flow obstruction, reduced venous return, and other cardiovascular toxicities. PM10 induced an increase in the ROS level and significant increases in the expression levels of ERS signalling pathway factors and Nrf2 signalling pathway factors. The expression levels of the Wnt pathway-related genes also showed significant changes. Furthermore, ROS inhibitor N-Acetyl-l-cysteine (NAC) could ameliorate the cardiovascular toxicity of PM10 in zebrafish larvae. It is speculated that PM10 may result in cardiovascular toxicity by inducing higher ROS levels in the body, which could then induce ERS and lead to defects in the expression of genes related to the Wnt signalling pathway. The Nrf2 signalling pathway was activated as a stress compensatory mechanism during the early stage of PM10-induced cardiovascular injury. However, it was insufficient to counteract the PM10-induced cardiovascular toxicity.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Larva/metabolismo , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Organogênese , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
10.
J Ethnopharmacol ; 253: 112679, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32101773

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia Fructus (GF), a traditional Chinese medicine for clearing heat and purging fire, has been reported to use to treat thrombotic related diseases, but the antithrombotic components are not clear. AIM OF THE STUDY: To develop efficient research methods for discovering some representative antithrombotic compounds of GF. MATERIALS AND METHODS: AB line zebrafish induced by arachidonic acid (AA) was used as a fast and trace-sample-required valuation model for antithrombptic effect of GF samples. Among nine samples of GF from different production areas, two samples with the largest difference in bioactivity were selected for downstream analysis. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF/MS) was applied to detect compounds in the GF samples. And herbal metabolomics and grey correlation analysis (GCA) were used to identify crucial compounds with potential antithrombotic activity. Then the bioactivity of those important compounds was verified on the zebrafish model. Network pharmacology was used to explore the protein targets and signaling pathways of these compounds. RESULTS: Among the GF samples, S1 (Huoshan City, Anhui Province), and S6 (Jichun City, Hubei Province), significantly differed in thrombus inhibiting bioactivity. HPLC-Q-TOF/MS identified a total of 614 compounds in each GF sample. 19 compounds were selected as important potential variables from metabolomics data by orthogonal partial least squares discriminant analysis (OPLS-DA). And 10 compounds among them were further found to be positively correlated with the antithrombotic bioactivity of GF by GCA. Finally, 3 compounds in them, geniposide, citric acid, and quinic acid, were confirmed as representative antithrombotic chemical markers of GF. Using network pharmacology analysis, some key protein targets, such as proto-oncogene tyrosine-protein kinase Src (SRC) and cyclin-dependent kinase 2 (CDK2), and some signaling pathways were found to supply powerful evidence about antithrombotic mechanisms of three compounds and GF. CONCLUSIONS: This research have succeeded to discover and identify three representative antithrombotic compounds of GF using an efficient integrated research strategy we established, an Omics Discriminant-Grey Correlation-Biological Activity strategy. The antithrombotic chemical makers we found could also contribute to provided more accurate index components for comprehensive quality control of GF.


Assuntos
Fibrinolíticos/uso terapêutico , Gardenia , Extratos Vegetais/uso terapêutico , Trombose/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Frutas , Masculino , Metabolômica , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Mapas de Interação de Proteínas , Trombose/metabolismo , Peixe-Zebra
11.
Fish Physiol Biochem ; 46(3): 1025-1038, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31993854

RESUMO

Type 1 diabetes is characterized by an increase in blood glucose levels resulting from damage to ß cells in pancreatic islets and the consequent absolute insufficiency of insulin. Animal models of type 1 diabetes were usually established using drugs toxic to ß cells, such as streptozotocin (STZ). To assess the application of zebrafish larvae in diabetes research, we explore the effects of STZ on pancreatic islets and glucose metabolism in zebrafish larvae. STZ was microinjected into the pericardial cavity of zebrafish larvae on alternate days for three times. At 2 days after the whole series of STZ injection (12 dpf), free-glucose level in larvae tissue shows a significant increase, and the fluorescence signal in immunohistochemistry, which indicates the insulin expression, was significantly weaker compared with the solution-injected control. Obvious apoptosis signals were also observed in the location of pancreatic islet, and insulin content decreased to be undetectable in STZ-injected larvae. Gene expression level of ins decreased to half of the solution injection control and that of casp3a was upregulated by 2.20-fold. Expression level of glut2 and gck decreased to 0.312-fold and 0.093-fold, respectively. pck1 was upregulated by 2.533-fold in STZ-injected larvae. By tracking detection, we found the free-glucose level in STZ-injected larvae gradually approached the level of the solution injection control and the insulin content recovered at 6 days post-STZ injection (16 dpf). Consistent with the change of the glucose level, the regeneration rate of the caudal fin in the STZ-injected group decreased initially, but recovered and accelerated gradually finally at 8 days post-amputation (20 dpf). These results indicate the generation of a transient hyperglycemia model due to ß-cell apoptosis caused by STZ, which is abated by the vigorous regeneration ability of ß cells in zebrafish larvae.


Assuntos
Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Estreptozocina/farmacologia , Nadadeiras de Animais/efeitos dos fármacos , Nadadeiras de Animais/fisiologia , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Feminino , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Insulina/metabolismo , Larva , Masculino , Regeneração/efeitos dos fármacos , Peixe-Zebra
12.
Theranostics ; 10(2): 797-815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903151

RESUMO

Background: Histone post-translational modifications (PTMs) are involved in various biological processes such as transcriptional activation, chromosome packaging, and DNA repair. Previous studies mainly focused on PTMs by directly targeting histone-modifying enzymes such as HDACs and HATs. Methods and Results: In this study, we discovered a previously unexplored regulation mechanism for histone PTMs by targeting transcription regulation factor 14-3-3ζ. Mechanistic studies revealed 14-3-3ζ dimerization as a key prerequisite, which could be dynamically induced via an allosteric effect. The selective inhibition of 14-3-3ζ dimer interaction with histone H3 modulated histone H3 PTMs by exposing specific modification sites including acetylation, trimethylation, and phosphorylation, and reprogrammed gene transcription profiles for autophagy-lysosome function and endoplasmic reticulum stress. Conclusion: Our findings demonstrate the feasibility of editing histone PTM patterns by targeting transcription regulation factor 14-3-3ζ, and provide a distinctive PTM editing strategy which differs from current histone modification approaches.


Assuntos
Proteínas 14-3-3/antagonistas & inibidores , Autofagia , Regulação da Expressão Gênica , Histonas/metabolismo , Fenóis/farmacologia , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Acetilação , Regulação Alostérica , Animais , Linhagem Celular , Histonas/química , Humanos , Masculino , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Modelos Animais , Fosforilação , Ratos , Ratos Sprague-Dawley
13.
Chem Biol Interact ; 316: 108928, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31857089

RESUMO

OBJECTIVE: Zebrafish inflammation models were used to evaluate the anti-inflammatory activity of isoniazid (INH) and preliminarily investigate the underlying mechanism. METHODS: Local, acute, and systemic zebrafish inflammation models were established by tail cutting, copper sulfate (CuSO4), and lipopolysaccharide (LPS) endotoxin treatments, respectively, to evaluate the anti-inflammatory activity of INH. Zebrafish in the inflammatory state were exposed to different concentrations of INH (1, 2, and 4 mM) for 72 h to observe changes in the migration and accumulation of inflammatory cells and measure the reactive oxygen species (ROS) content in zebrafish after INH treatment. The transcription levels of inflammation-related genes in zebrafish from all groups were measured using real-time polymerase chain reaction (RT-PCR). RESULTS: Compared to those observed in the control inflammation model group, the numbers of migrated and accumulated inflammatory cells in zebrafish in the INH-treated group significantly decreased. INH significantly decreased the ROS content induced by LPS. Compared to that observed in the LPS model group, INH at 1 and 2 mM significantly increased the expression of PPARγ and inhibited the expression of NF-κB, iκbαa, and AP-1 as well as the inflammatory factors TNF-ɑ, TGF-ß, IL-1b, and COX-2. CONCLUSION: In this study, different zebrafish inflammation models were used to confirm that INH has anti-inflammatory activity. The associated mechanism may occur through the inhibition of ROS release, activation of PPARγ expression, inhibition of the transcriptional regulatory activity of NF-κB and AP-1, and reduction of INH inflammatory factor expression to relieve inflammation. The results of this study provide references for the clinical application of INH.


Assuntos
Citocinas/metabolismo , Isoniazida/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/genética , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Feminino , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , NF-kappa B/metabolismo , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Peixe-Zebra/metabolismo
14.
Bioorg Chem ; 94: 103435, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812262

RESUMO

Two unique nitrogenous sesquiterpene quinone meroterpenoids, dysidinoid B (1) and dysicigyhone A (2), together with eight known analogues (3-10) were isolated and characterized from the marine sponge Dysidea septosa. Their structures with absolute configurations were established by a combination of extensive spectroscopic, electron circular dichroism (ECD) and single-crystal X-ray diffraction data analysis. Structurally, dysicigyhone A (2) possessed a unique benzo[d]oxazolidine-2-one unit. Additionally, dysidinoid B (1) exhibited significant anti-inflammatory effect by inhibiting TNF-α and IL-6 generation with IC50 values of 9.15 µM and 17.62 µM, respectively. Further in vivo anti-inflammatory assay verified that the dysidinoid B (1) alleviated the CuSO4-induced robust acute inflammatory response in zebrafish model.


Assuntos
Anti-Inflamatórios/farmacologia , Benzoquinonas/farmacologia , Inflamação/tratamento farmacológico , Nitrogênio/farmacologia , Poríferos/química , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Benzoquinonas/química , Células Cultivadas , Sulfato de Cobre , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Inflamação/induzido quimicamente , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Camundongos , Modelos Moleculares , Estrutura Molecular , Nitrogênio/química , Células RAW 264.7 , Sesquiterpenos/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Peixe-Zebra
15.
J Asian Nat Prod Res ; 22(4): 329-337, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31190553

RESUMO

Two novel glycosides, apostichoposide A1 (1) and B1 (2), were isolated from the viscera of Chinese sea cucumbers (Apostichopus japonicus, Selenka) collected in the Bohai sea. Both the isolated glycosides were characterized by non-holostane type aglycones having 18(16)-lactone and 7(8)-double bond. Cytotoxic activities of the two compounds were evaluated against three human cancer cell lines. Compound 1 had adequate cytotoxic activity against MGC-803 and PC-3M cell lines. Our results indicated that glycosides present in A. japonicus viscera are an important high value resource for biotechnological applications.


Assuntos
Pepinos-do-Mar , Stichopus , Triterpenos , Animais , Glicosídeos , Humanos , Estrutura Molecular , Vísceras
16.
Zhongguo Zhong Yao Za Zhi ; 44(13): 2662-2666, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31359674

RESUMO

Bupleuri Radix has both liver protection and hepatotoxicity. Saponins are the main pharmacodynamic and toxic components of Bupleuri Radix. Based on zebrafish physical model and the model of alcoholic fatty liver( AFL) pathology,the liver toxic and protective effect of saikosaponin a( SSa) were assessed. The results indicated that 1. 77 µmol·L-1 SSa showed protective effect to AFL zebrafish. 5. 30 µmol·L-1 SSa was hepatotoxic to healthy zebrafish,but it showed protective effect to AFL zebrafish. 5. 62 µmol·L-1 SSa was hepatotoxic to healthy and AFL zebrafish. This study is benefit for clinical safety of saikosaponin a.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fígado Gorduroso Alcoólico/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Saponinas/toxicidade , Animais , Ácido Oleanólico/farmacologia , Ácido Oleanólico/toxicidade , Peixe-Zebra
17.
Org Lett ; 21(16): 6190-6193, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31246040

RESUMO

The chemical investigation of the marine sponge Dysidea frondosa discovered a pair of unprecedented bioconjugates that are composed of a meroterpene and an unusual psammaplysin alkaloid. The structures of frondoplysins A (1) and B (2) were characterized by analysis of HRMS and NMR data coupled with single-crystal X-ray diffraction. Frondoplysin A was found to be a potent inhibitor targeting protein-tyrosine phosphatase 1B (PTP1B) with an IC50 value of 0.39 µM.


Assuntos
Alcaloides/química , Dysidea/química , Inibidores Enzimáticos/farmacologia , Alcaloides/farmacologia , Alcaloides/toxicidade , Animais , Animais Geneticamente Modificados , Antioxidantes/química , Antioxidantes/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Peixe-Zebra/genética
18.
J Enzyme Inhib Med Chem ; 34(1): 1083-1092, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117844

RESUMO

The work is focused on the design of drugs that prevent and treat Alzheimer's disease (AD) and its complications. A series of 3-(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 µM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 µM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Cloreto de Alumínio/farmacologia , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Peixe-Zebra
19.
Chemosphere ; 227: 541-550, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004821

RESUMO

Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6 mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6 mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6 mM) decreased expression levels of miR-122 and pparα but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Isoniazida/toxicidade , Larva/metabolismo , Espécies Reativas de Oxigênio , Peixe-Zebra/metabolismo , Animais , Antioxidantes/metabolismo , Antituberculosos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Larva/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/efeitos adversos , Transdução de Sinais , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 44(5): 849-860, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30989839

RESUMO

Traditional Chinese medicine(TCM) is a research area with highly original innovation features,and is also a Chinese name card to the world. However,TCM owns a unique theoretical system which is quite different from western modern medicine,leading to an awkward situation of deficient modern social identity as well as poor international spread. Therefore,how to establish a research strategy in line with the characteristics of TCM itself to systematically interpret the unique scientific connotation of TCM is always a public hot topic. Based on persistent practical exploration and scientific consideration in TCM,our group firstly promoted the concept of traditional Chinese medicine chemical biology(TCM chemical biology,TCMCB). The major idea of TCMCB is to clarify the nature of TCM regulating life progress to link TCM to modern medicine by using TCM components as chemical tools. Notably,TCMCB mainly focuses on TCM target identification and TCM-guided disease molecular mechanism exploration,further to clarify the basic law of TCM mediating disease process. Finally,TCMCB-guided scientific studies can help explain TCM theory and promote the developmentof modern innovative drugs based on identified targets using TCM active components. Moreover,TCMCB is of vital importance for investigating the scientific nature of biological progress and the pattern of disease occurrence and development,indicating a key significance for modern life science and medicine. This review introduces the definition of TCMCB as well as its academic thought,research method,technology system and scientific significance,for providing new research ideas and scientific thoughts for TCM development.


Assuntos
Pesquisa Interdisciplinar , Medicina Tradicional Chinesa , Biologia , Química , Medicina , Projetos de Pesquisa
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