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1.
Int J Nanomedicine ; 15: 1149-1160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110013

RESUMO

Purpose: Alzheimer's disease (AD) is a growing concern in the modern society. The current drugs approved by FDA are not very promising. Rhynchophylline (RIN) is a major active tetracyclic oxindole alkaloid stem from traditional Chinese medicine uncaria species, which has potential activities beneficial for the treatment of AD. However, the application of rhynchophylline for AD treatment is restricted by the low water solubility, low concentration in brain tissue and low bioavailability. And there is no study of brain-targeting therapy with RIN. In this work, we prepared rhynchophylline loaded methoxy poly (ethylene glycol)-poly (dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPS-RIN), which coupled with Tween 80 (T80) further for brain targeting delivery (T80-NPS-RIN). Methods: Preparation and characterization of T80-NPS-RIN were followed by the detection of transportation across the blood-brain barrier (BBB) model in vitro, biodistribution and neuroprotective effects of nanoparticles. Results: The results indicated T80-NPS-RIN could usefully assist RIN to pass through the BBB to the brain. T80-NPS-RIN treatment regulated the activity of neurons in vitro. Conclusion: The presented data confirmed that rhynchophylline encapsulated mPEG-PLGA nanoparticles coated with Tween 80 could across through the BBB and exhibited efficient neuroprotective effects. The T80-NPS-RIN nanoparticles have a chance to be an alternative drug to the therapy of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oxindois/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxindois/farmacocinética , Oxindois/farmacologia , Células PC12 , Poliésteres/química , Polietilenoglicóis/química , Polissorbatos/química , Coelhos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
2.
Artigo em Inglês | MEDLINE | ID: mdl-32058315

RESUMO

Mitragyna speciosa (kratom) is a drug that is increasingly used recreationally and "therapeutically", in the absence of medical supervision. The drug has been associated with a growing number of fatalities, and although its medicinal properties as an atypical opioid require further study, there are legitimate concerns regarding its unregulated use. Mitragynine is the most widely reported alkaloid within the plant, although more than forty other alkaloids have been identified. 7-Hydroxymitragynine is reported to have greater abuse liability due to its increased potency relative to mitragynine. In this report, biomarkers for mitragynine were investigated using liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF-MS). Speciociliatine and speciogynine were identified as alternative biomarkers, often exceeding the concentration of mitragynine in unhydrolyzed urine. 9-O-Demethylmitragynine and 7-hydroxymitragynine were identified in unhydrolyzed urine in 75% and 63% of the cases. Deconjugation of phase II metabolites using chemical hydrolysis was not suitable due to degradation of the Mitragyna alkaloids. Enzymatic hydrolysis was evaluated using three traditional glucuronidases, four sulfatases and four recombinant enzymes. Although enzymatic hydrolysis increased the concentration of 16-carboxymitragynine, it had nominal benefit for other metabolites. Deconjugation of urine was not necessary due to the abundance of parent drug (mitragynine), its diastereoisomers (speciociliatine and speciogynine) or metabolites (9-O-demethylmitragynine and 7-hydroxymitragynine).


Assuntos
Biomarcadores/urina , Mitragyna/metabolismo , Oxindois/urina , Extratos Vegetais/metabolismo , Alcaloides de Triptamina e Secologanina/metabolismo , Cromatografia Líquida de Alta Pressão , Glucuronídeos/análise , Glucuronídeos/metabolismo , Hidrólise , Metaboloma , Mitragyna/química , Extratos Vegetais/análise , Alcaloides de Triptamina e Secologanina/análise , Sulfatases/análise , Sulfatases/metabolismo , Espectrometria de Massas em Tandem
4.
Eur J Med Chem ; 186: 111859, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735574

RESUMO

The scaffold proteins prohibitins-1 and 2 (PHB1/2) play many important roles in coordinating many cell signaling pathways and represent emerging targets in cardiology and oncology. We previously reported that a family of natural products derivatives, flavaglines, binds to PHB1/2 to exert cardioprotectant and anti-cancer effects. However, flavaglines also target the initiation factor of translation eIF4A, which doesn't contribute to cardioprotection and may even induce some adverse effects. Herein, we report the development of a convenient and robust synthesis of the new PHB2 ligand 2'-phenylpyrrolidinyl-spirooxindole, and its analogues. We discovered that these compounds displays cardioprotective effect against doxorubicin mediated cardiotoxicity and uncovered the structural requirement for this activity. We identified in particular some analogues that are more cardioprotectant than flavaglines. Pull-down experiments demonstrated that these compounds bind not only to PHB2 but also PHB1. These novel PHB ligands may provide the basis for the development of new drugs candidates to protect the heart against the adverse effects of anticancer treatments.


Assuntos
Cardiotônicos/farmacologia , Descoberta de Drogas , Miócitos Cardíacos/efeitos dos fármacos , Oxindois/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Compostos de Espiro/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/síntese química , Cardiotônicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/antagonistas & inibidores , Doxorrubicina/farmacologia , Humanos , Ligantes , Estrutura Molecular , Miócitos Cardíacos/metabolismo , Oxindois/síntese química , Oxindois/química , Proteínas Repressoras/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 185: 111781, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31654879

RESUMO

We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125-0.25 µg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Oxindois/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Oxindois/síntese química , Oxindois/química , Relação Estrutura-Atividade
6.
Life Sci ; 239: 116935, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610203

RESUMO

BACKGROUND: The protective effects of gastrodin and rhynchophylline in ischaemic injury have been reported. However, the underlying mechanism and the effect of the combination of these two drugs in ischaemic injury remain unclear. Herein, we aimed to explore the effects of the combination of gastrodin and rhynchophylline on ischaemia-induced inflammasome activation as well as the underlying mechanism. METHODS: Middle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD)-treated BV2 cells were used as in vivo and in vitro models of ischaemia, respectively. Cerebral injury was determined by TTC staining, H&E staining and neurological deficit scores. The effects of the combination of gastrodin and rhynchophylline on inflammasome activation were measured by the MTT assay, Western blotting and ELISA. The expression of miR-21-5p and miR-331-5p was measured by qRT-PCR. The potential binding between miR-21-5p and TXNIP and between miR-331-5p and TRAF6 was analysed with Targetscan and a luciferase assay. RESULTS: MCAO-induced tissue infarction, neurological deficits, inflammasome activation, and downregulation of miR-21-5p and miR-331-5p were all mitigated by the combination of gastrodin and rhynchophylline. In OGD-treated BV2 cells, the combination of gastrodin and rhynchophylline also alleviated inflammasome activation and restored the expression of miR-21-5p and miR-331-5p. TXNIP and TRAF6 were confirmed to be targets of miR-21-5p and miR-331-5p, respectively. Moreover, OGD-induced inflammasome activation was attenuated by the overexpression of either miR-331-5p or miR-21-5p and was further attenuated by the overexpression of both. Finally, we demonstrated that a miR-21-5p inhibitor and/or a miR-331-5p inhibitor counteracted the protective effects of gastrodin and/or rhynchophylline. CONCLUSIONS: The combination of gastrodin and rhynchophylline exerts neuroprotective effects by preventing ischaemia-induced inflammasome activation via upregulating miR-21-5p and miR-331-5p.


Assuntos
Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , MicroRNAs/metabolismo , Oxindois/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Inflamassomos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fármacos Neuroprotetores , Ativação Transcricional/efeitos dos fármacos
7.
Molecules ; 24(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575030

RESUMO

The Pd-catalyzed intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as ß-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2-H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3-H insertion leading to ß-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations.


Assuntos
Acetamidas/química , Compostos de Diazônio/química , Paládio/química , Catálise , Modelos Moleculares , Estrutura Molecular , Oxindois/metabolismo , Paládio/metabolismo , beta-Lactamas/metabolismo
8.
Fitoterapia ; 138: 104357, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521701

RESUMO

Three new 3-hydroxy-N-methyl-2-oxindole (1 and 2) and 4-hydroxy-pyran-2-one (3) derivatives, along with the known 3-hydroxy-N-methyl-2-oxindole (4) and 6-methoxy-N-methylisatin (5) were isolated from a marine Salinispora arenicola strain from sediments of the St. Peter and St. Paul Archipelago, Brazil. The structures of the new compounds were elucidated by a combination of spectroscopic (1D and 2D NMR and HR-ESIMS) data, including single-crystal X-ray diffraction analysis for 2 and 3. Compounds 1 to 5 were assayed for their antimicrobial properties, but only 4 and 5 were active against Enterococcus faecalis with MIC value of 15.6 µg/mL.


Assuntos
Antibacterianos/farmacologia , Sedimentos Geológicos/microbiologia , Micromonosporaceae/química , Oxindois/farmacologia , Antibacterianos/isolamento & purificação , Brasil , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxindois/isolamento & purificação , Água do Mar/microbiologia
9.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510078

RESUMO

Uncaria tomentosa (Rubiaceae) has a recognized therapeutic potential against various diseases associated with oxidative stress. The aim of this research was to evaluate the antioxidant potential of an aqueous leaf extract (ALE) from U. tomentosa, and its major alkaloids mitraphylline and isomitraphylline. The antioxidant activity of ALE was investigated in vitro using standard assays (DPPH, ABTS and FRAP), while the in vivo activity and mode of action were studied using Caenorhabditis elegans as a model organism. The purified alkaloids did not exhibit antioxidant effects in vivo. ALE reduced the accumulation of reactive oxygen species (ROS) in wild-type worms, and was able to rescue the worms from a lethal dose of the pro-oxidant juglone. The ALE treatment led to a decreased expression of the oxidative stress response related genes sod-3, gst-4, and hsp-16.2. The treatment of mutant worms lacking the DAF-16 transcription factor with ALE resulted in a significant reduction of ROS levels. Contrarily, the extract had a pro-oxidant effect in the worms lacking the SKN-1 transcription factor. Our results suggest that the antioxidant activity of ALE in C. elegans is independent of its alkaloid content, and that SKN-1 is required for ALE-mediated stress resistance.


Assuntos
Antioxidantes/química , Unha-de-Gato/química , Alcaloides Indólicos/farmacologia , Oxindois/farmacologia , Alcaloides/química , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oxindois/química , Extratos Vegetais/química , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo
10.
Mol Cell Biochem ; 461(1-2): 205-212, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420791

RESUMO

Migraine causes severe health and social issues worldwide. Rhynchophylline (Rhy) is one of the major active components of Uncaria rhynchophylla that is used for the treatment of headache in Traditional Chinese Medicine. In the current study, the effect of Rhy on nitroglycerin (NTG)-induced migraine was assessed and the associated mechanism was also explored to explain its function. Rats were pre-treated with Rhy of two doses (10 mg/kg and 30 mg/kg) and then subjected to NTG to induce migraine symptoms. Thereafter, the electroencephalogram (EEG) signaling, spontaneous behaviors, levels of indicators related to oxidative stress, and expression of calcitonin gene-related peptide (CGRP) were measured to assess the anti-migraine function of Rhy. Moreover, the activities of MAPK/NF-κB pathway under the administrations of Rhy were also detected. The results showed that NTG induced EEG and behavior disorders in rats, which was associated with the initiation of oxidative stress and increased expression of CGRP. Nevertheless, the pre-treatments with Rhy attenuated the damages induced by NTG by reversing the levels of all the above indicators. The results of western blotting demonstrated that the anti-migraine effect of Rhy was accompanied by the inhibition of MAPK/NF-кB pathway. The findings outlined in the current study revealed an alternative mechanism of Rhy in protecting brain tissues against migraine: the agent exerted its effect by suppressing MAPK/NF-кB pathway, which would ameliorate impairments associated with migraine.


Assuntos
Sistema de Sinalização das MAP Quinases , Transtornos de Enxaqueca/tratamento farmacológico , NF-kappa B/metabolismo , Oxindois/uso terapêutico , Núcleos do Trigêmeo/patologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Eletroencefalografia , Masculino , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/induzido quimicamente , Nitroglicerina , Estresse Oxidativo/efeitos dos fármacos , Oxindois/administração & dosagem , Oxindois/farmacologia , Ratos Sprague-Dawley , Núcleos do Trigêmeo/efeitos dos fármacos
11.
Org Biomol Chem ; 17(32): 7517-7525, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31368474

RESUMO

Site- and regio-selective aromatic C-H bond benzoxylations were found to take place using biologically appealing N-arylisoindolinones under ruthenium(ii) catalysis in the presence of (hetero)aromatic carboxylic acid derivatives as coupling partners. Besides the presence of two potential C(sp2)-H sites available for functionalization in the substrates, exclusive ortho selectivity was achieved in the phenyl ring attached to the nitrogen atom. Notably, the reactions occurred in a selective manner as only mono-functionalized products were formed and they tolerated a large number of functional chemical groups. The ability of the cyclic tertiary amide within the isoindolinone skeleton to act as a weak directing group in order to accommodate six-membered ring ruthenacycle intermediates appears to be the key to reach such high levels of selectivity. In contrast, the more sterically demanding cyclic imides were unreactive under identical reaction conditions.


Assuntos
Oxindois/química , Rutênio/química , Amidas/química , Benzoatos/química , Carbono/química , Catálise , Nitrogênio/química , Oxindois/síntese química
12.
Mar Drugs ; 17(8)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395834

RESUMO

In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.


Assuntos
Alcaloides/farmacologia , Callyspongia/química , Oxindois/farmacologia , Animais , Anti-Infecciosos/farmacologia , Antiprotozoários/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Células HT29 , Halogenação , Humanos , Oceano Índico , Testes de Sensibilidade Microbiana/métodos
13.
Biopolymers ; 110(11): e23320, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31268558

RESUMO

Shp2 and Shp1 make up a small family of protein tyrosine phosphatases. Finding selective inhibitors for Shp2 is useful because although its inhibition is advantageous for the treatment of some types of cancer, inhibition of Shp1 may have the opposite effect, since it acts as a suppressor of tumors. We combined molecular docking and semiempirical molecular orbital-based calculations to produce data that were effective for the identification of selective inhibitors for Shp2. After definition of the interaction modes of the inhibitors with Shp2 and Shp1 by molecular docking, the resulting interaction enthalpy values were calculated following refinement of the enzyme/inhibitor complexes' geometries with the PM7 semiempirical molecular orbital method. Despite the complexity of the thermodynamics involved in the enzyme/inhibitor interaction, the selectivity for Shp2 of a series of 76 inhibitors, divided in two groups, could be effectively correlated with the difference in their interaction enthalpy values with both enzymes. For the first group, composed by 52 Shp2-selective indoline inhibitors for which only Shp2 inhibition activity data are available, we demonstrated that the interaction enthalpy can be used as a criterion for identification of selective Shp2 inhibitors, as it is significantly more favorable for Shp2 than Shp1 at a 99% confidence level. For the second group, composed by 24 oxindole derivatives with available Shp2 and Shp1 inhibition activity data, a satisfactory correlation (R = 0.70) could be obtained between the selectivity, based on the IC50 data, and the relative percentage difference of the calculated interaction enthalpies with the two enzymes.


Assuntos
Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Oxindois/química , Oxindois/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Termodinâmica
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117185, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31177005

RESUMO

Density functional theory is one of the most popular accepted computational quantum mechanical techniques used in the analysis of molecular structure and vibrational spectra. Experimental and theoretical investigations of the molecular structure, electronic and vibrational characteristics of 4-[2-(Dipropylamino) ethyl]-1,3-dihydro-2H-indol-2-one are presented in this work. The title compound was characterized using FT-IR, FT-Raman and UV-Vis spectroscopic techniques. The results were compared with the theoretical calculations obtained using DFT/B3LYP with 6-311++G(d,p) as basis sets and was found to be in good agreement. The complete optimization of the molecular geometry of the title compound was carried out. Further, the vibrational assignments and calculation of potential energy distribution (PED) were reported. NLO has emerged as a key factor in recent researches. Materials showing nonlinear optical properties form the basis of nonlinear optics and development of such materials plays an important role in the present scenario. The current work provides sufficient justification for the title compound to be selected as a good non-linear optical (NLO) candidate. The electronic properties were reported using TD-DFT approach. The HOMO (EHOMO = -5.96 eV), LUMO (ELUMO = -0.80 eV) energies, energy gap and electrophilicity (2.22) was calculated in order to understand the stability, reactivity and bioactivity of the compound under investigation. To comprehend the bonding interactions we have performed the total (TDOS), partial (PDOS) and overlap population or COOP (Crystal Orbital Overlap Population) density of states. The drug likeness values were analyzed to evaluate the potential of the title compound to be an active pharmaceutical component. As a positive proof the paper further explains the molecular docking studies of the said compound. In addition, the stereochemistry of the protein structure was checked using Ramachandran plot. The title compound is a directly acting dopamine D2 agonist. In order to establish relationship between molecular descriptors of compound and its biological activity, QSAR studies have been done within the framework of DFT for 10 dopamine agonist including the title compound. Hence, the research exploration provides requisite information pertaining to the geometry, stability, reactivity and bioactivity of the compound through spectroscopic and quantum chemical methods.


Assuntos
Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Oxindois/química , Oxindois/farmacologia , Receptores de Dopamina D2/metabolismo , Teoria da Densidade Funcional , Humanos , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
15.
Environ Toxicol ; 34(10): 1114-1120, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231976

RESUMO

The aim of this study was designed to investigate the effects of rhynchophyllin (RH) on neuroinflammation in Tourette syndrome (TS) rats. TS model was established in rats by the injection of selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior in DOI-induced rats was tested. Inflammatory cytokines levels such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The expression levels of janus kinase 2 (JAK2)/signal transducer and transcription activator 3 (STAT3) and nuclear factor (NF)-κB pathways in striatum were measured by Western blot. Data indicated that RH can significantly reduce the numbers of nodding experiment of TS rats. RH significantly decreased IL-6, IL-1ß, and TNF-α in serum and striatum of TS rats, with altered expression of P-JAK2, P-STAT3, P-NF-κBp65, and P-IκBα in TS rats, as evidenced by Western blot analysis and immunohistochemistry, suggesting that the regulation of JAK2/STAT3 and NF-κB pathways might be involved in the mechanism of RH on TS.


Assuntos
Corpo Estriado/imunologia , Medicamentos de Ervas Chinesas/administração & dosagem , Janus Quinase 2/imunologia , Oxindois/administração & dosagem , Síndrome de Tourette/tratamento farmacológico , Uncaria/química , Animais , Corpo Estriado/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Masculino , NF-kappa B/genética , NF-kappa B/imunologia , Propano/efeitos adversos , Propano/análogos & derivados , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/genética , Síndrome de Tourette/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
Neurotox Res ; 36(4): 756-763, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31243645

RESUMO

Tourette syndrome (TS) is characterized by one of the chronic neuropsychiatric disorders in multiple children, and the pathogenesis of Tourette syndrome (TS) has not been previously elucidated.The aim of this study was designed to investigate the effects of rhynchophylline (RH) on Tourette syndrome (TS) in rats.TS model was established in rats and BV2 cells by the selective 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior evaluations including stereotypy recording and autonomic activity test were performed. Inflammatory cytokine levels such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum, striatum, and cell supernatant were detected. The expression levels of BDNF/NF-κB pathway in striatum and BV2 cells were measured by Western blot. Dopamine (DA) and dopamine receptor D 2 (D2) in striatum were also measured.Data indicated that RH significantly decreased IL-6, IL-1ß, and TNF-α in serum, striatum, and cell supernatant of TS model, with altered expression of P-NF-κBp65, P-IκBα, and BDNF in TS rats, and DOI-induced BV2 cells, as evidenced by Western blot analysis and immunohistochemistry analysis. RH also significantly reduced the levels of DA and D2 in striatum.Our results shown that the regulation of BDNF/NF-κB pathway might be involved in the effects of RH on TS model.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Oxindois/administração & dosagem , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Encefalite/complicações , Encefalite/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Transdução de Sinais , Síndrome de Tourette/complicações
17.
Neurotox Res ; 36(4): 679-687, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31115771

RESUMO

Tourette syndrome (TS) is a chronic neuropsychiatric disorder with clinical manifestations of involuntary and repeated muscle twitching and vocal twitching. The drugs used to treat TS are relatively limited. The aim of this study was to investigate the effects of rhynchophylline (RH) and the underlying mechanism in 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced neurotoxicity in a TS rat model. A TS model was induced with DOI. The rats were divided into control, TS, TS + tiapride (25 mg/kg), and TS + RH (20 and 40 mg/kg) groups. Behavioral tests were performed 24 h after the last administration by nodding and stereotype experiments. Interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) levels in striatum and serum were detected with an enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the expression levels of Toll-like receptor (TLR)/nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3)/nuclear factor kappa B (NF-κB) signal proteins in the striatum. The expression of TLR2 and NF-κB p65 subunit was detected with immunohistochemical analysis. RH may significantly improve behavioral changes in rats with DOI-induced TS and reduce the levels of inflammatory factors in serum and striatum. RH inhibited the activation of TLR/NLRP3/NF-κB signaling proteins in the striatum of TS rats. In BV2 cells, DOI-induced inflammation mediated through TLR/NLRP3/NF-κB was significantly inhibited following RH administration. The therapeutic effect of RH in TS was studied and its mechanism of action mediated via the TLR/NLRP3/NF-κB pathway was clarified in vitro and in vivo.


Assuntos
Anfetaminas/toxicidade , Corpo Estriado/efeitos dos fármacos , Oxindois/administração & dosagem , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Encefalite/induzido quimicamente , Encefalite/metabolismo , Masculino , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
18.
J Pharm Biomed Anal ; 170: 102-111, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30909055

RESUMO

Incubation of oxindole derivatives containing an arylpiperazine pharmacophore in rat liver microsomes in vitro formed several metabolites hydroxylated at various positions of the aromatic rings of the oxindole carbocycle or the arylpiperazine moiety. In order to substitute the sites of metabolic attack on these positional isomers, the exact structure of the molecules had to be identified. As polarities of the compounds depend on the site of hydroxylation, we measured retention times of the metabolites using reversed-phase HPLC. It was noted that the relative retention times (RRT, the ratio of the retention time of the metabolite and the parent compound) fell into distinct narrow ranges for metabolites identified by MS spectra as positional isomers. These RRT ranges correlated with the positions of hydroxylation. The hypothesis was validated by synthesis of hydroxy compounds of known structure and by determination of their RRT values. Change in the chromatographic parameters such as column type, eluent, gradient time and temperature did not impede the identification of the sites of hydroxylation as the RRT pattern remained similar to the original one. The new empirical method proposed in our study can be used for tentative identification of hydroxy metabolites and orient the direction of efforts to synthesize metabolically stable compounds.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Oxindois/química , Hidroxilação , Isomerismo
19.
Bioorg Med Chem ; 27(9): 1804-1817, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902399

RESUMO

Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Oxindois/química , Inibidores de Proteínas Quinases/síntese química , Células A549 , Animais , Sítios de Ligação , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Teste de Tolerância a Glucose , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Oxindois/farmacologia , Oxindois/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Relação Estrutura-Atividade
20.
J Exp Clin Cancer Res ; 38(1): 134, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898152

RESUMO

BACKGROUND: The transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFß/BMP pathways and further studying its anti-proliferative/-metastatic effects as well as the underlying mechanisms in multiple tumor models. METHODS: Multiple in vitro cell-based assays are used to examine the compound's inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFß/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170's effects on TNBC growth and metastasis potentials in vivo. RESULTS: ZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFß/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFß/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells. CONCLUSIONS: ZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Oxindois/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Feminino , Humanos , Camundongos , Camundongos Nus , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Oxindois/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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