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1.
Gene ; 809: 145992, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34648917

RESUMO

Renal cell carcinoma (RCC) is a common type of urological cancer and is often diagnosed at an advanced stage. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is used as second-line therapy for sorafenib- or sunitinib-refractory metastatic RCC. However, the clinical benefits of Everolimus are often hampered by drug resistance. Ferroptosis is a novel form of regulated cell death that has recently been implicated in the development and therapeutic responses to different cancers. RSL3 ((1S,3R)-RSL3) and Erastin are two experimental compounds that can induce ferroptosis. In the present study, we evaluated the anti-tumor effects of Everolimus in combination with RSL3 or Erastin in RCC. Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in RCC cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Moreover, the forced expression of GPX4 abrogated ferroptosis induced by the combined treatment of Everolimus and RSL3/Erastin. Taken together, these results demonstrated that Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment and it may also help to overcome the limitation in clinical applicability of Everolimus.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Carbolinas/administração & dosagem , Carbolinas/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Everolimo/administração & dosagem , Everolimo/farmacologia , Ferroptose/fisiologia , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
2.
Int J Mol Sci ; 22(24)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34948361

RESUMO

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Carbolinas/síntese química , Linhagem Celular , Desenho de Fármacos , Humanos , Malária Falciparum/tratamento farmacológico , Simulação de Acoplamento Molecular , Plasmodium falciparum/enzimologia , Plasmodium falciparum/metabolismo
3.
Molecules ; 26(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576998

RESUMO

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer's disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure-activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced ß-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.


Assuntos
Amantadina/química , Amantadina/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Amantadina/análogos & derivados , Animais , Butirilcolinesterase/química , Carboxilesterase/química , Domínio Catalítico , Linhagem Celular , Inibidores da Colinesterase/síntese química , Cavalos , Humanos , Cinética , Ligantes , Memantina/química , Memantina/farmacologia , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/efeitos dos fármacos , Simulação de Acoplamento Molecular , Propídio/química , Ratos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Suínos , Tubulina (Proteína)/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
4.
Molecules ; 26(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34443633

RESUMO

Pseudostellaria heterophylla is used in China not only as a functional food but also as an herb to tonify the spleen, enhance immunity, and treat palpitation. Our previous investigation showed that a fraction enriched in glycosides obtained from the roots of P. heterophylla possessed pronounced protective effects on H9c2 cells against CoCl2-induced hypoxic injury. However, the active compounds responsible for the observed effects were still unknown. In the current investigation, pseudosterins A-C (1-3), three new alkaloids with a 1-ethyl-3-formyl-ß-carboline skeleton, together with polydatin, have been isolated from the active fraction. Their structures were elucidated on the basis of spectroscopic analysis and quantum chemical calculations. The four compounds showed cardioprotective effects against sodium hydrosulfite-induced hypoxia-reoxygenation injury in H9c2 cells, with the three alkaloids being more potent. This is also the first report of alkaloids with a ß-carboline skeleton isolated from P. heterophylla as cardioprotective agents.


Assuntos
Alcaloides/farmacologia , Carbolinas/farmacologia , Cardiotônicos/farmacologia , Caryophyllaceae/química , Extratos Vegetais/farmacologia , Alcaloides/química , Animais , Carbolinas/química , Cardiotônicos/química , Linhagem Celular , China , Glicosídeos/química , Glicosídeos/farmacologia , Hipóxia/tratamento farmacológico , Extratos Vegetais/química , Raízes de Plantas/química , Ratos
5.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34296310

RESUMO

Ferroptosis is critically involved in the pathophysiology of diabetic nephropathy (DN). As a bioactive peptide, salusin­ß is abundantly expressed in the kidneys. However, it is unclear whether salusin­ß participates in the pathologies of diabetic kidney damage by regulating ferroptosis. The present study found that high glucose (HG) treatment upregulated the protein expressions of salusin­ß in a dose­ and time­dependent manner. Genetic knockdown of salusin­ß retarded, whereas overexpression of salusin­ß aggravated, HG­triggered iron overload, antioxidant capability reduction, massive reactive oxygen species production and lipid peroxidation in HK­2 cells. Mechanistically, salusin­ß inactivated nuclear factor erythroid­derived 2­like 2 (Nrf­2) signaling, thus contributing to HG­induced ferroptosis­related changes in HK­2 cells. Notably, the protein expression of salusin­ß was upregulated by ferroptosis activators, such as erastin, RSL3, FIN56 and buthionine sulfoximine. Pretreatment with ferrostatin­1 (a ferroptosis inhibitor) prevented the upregulated protein expression of salusin­ß in HK­2 cells exposed to HG. Taken together, these results suggested that a positive feedback loop between salusin­ß and ferroptosis primes renal tubular cells for injury in diabetes.


Assuntos
Ferroptose/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Butionina Sulfoximina/farmacologia , Carbolinas/farmacologia , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Ferroptose/efeitos dos fármacos , Glucose/toxicidade , Humanos , Peroxidação de Lipídeos/genética , Oximas/farmacologia , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacos
6.
J Med Chem ; 64(13): 9166-9181, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34132541

RESUMO

Timely myocardial reperfusion salvages ischemic myocardium from infarction, whereas reperfusion itself induces cardiomyocyte death, which is called myocardial ischemia/reperfusion (MI/R) injury. Herein, ß-carboline derivative 17c was designed and synthesized with obvious myocardial protective activity for the first time. Pretreatment of 17c effectively protected the cardiomyocyte H9c2 cells from H2O2-induced lactate dehydrogenase leakage and restored the endogenous antioxidants, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Besides, 17c effectively protected the mitochondria through decreasing the reactive oxygen species overproduction and enhancing the mitochondrial membrane potential. As a result, 17c significantly reduced the necrosis of cardiomyocytes in H2O2-induced oxidative stress, which was more potent than polydatin. In MI/R injury rats, 17c pretreatment obviously increased the levels of SOD and GSH-Px and inhibited the apoptosis of cardiomyocytes. Through this way, the size of myocardial infarction was significantly reduced after MI/R injury in vivo, better than that of polydatin, suggesting that 17c is a promising cardioprotectant for the prevention of MI/R injury.


Assuntos
Carbolinas/farmacologia , Descoberta de Drogas , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Masculino , Estrutura Molecular , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismo
7.
Eur J Med Chem ; 222: 113563, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118721

RESUMO

Natural ß-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted ß-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 µM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 µM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl ß-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.


Assuntos
Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Carbolinas/farmacologia , Descoberta de Drogas , Fusarium/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Carbolinas/síntese química , Carbolinas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
8.
J Alzheimers Dis ; 82(2): 541-560, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34057079

RESUMO

BACKGROUND: The roles of amyloid-ß and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-ß and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. OBJECTIVE: Examine the impact of amyloid-ß and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. METHODS: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. RESULTS: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. CONCLUSION: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-ß in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva , Conectoma/métodos , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Carbolinas/farmacologia , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Meios de Contraste/farmacologia , Correlação de Dados , Imagem de Tensor de Difusão/métodos , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Testes de Estado Mental e Demência , Tomografia por Emissão de Pósitrons
9.
Drug Des Devel Ther ; 15: 1705-1716, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935493

RESUMO

Objective: Flavopereirine has been identified to be a potential anti-cancer agent in several types of human cancer. This study aimed to investigate the anti-cancer activity of flavopereirine in oral cancer. Methods: The effect of flavopereirine on cell viability of human oral cancer cell lines (BcaCD885 and Tca8113) was evaluated by MTT assay and colony formation assay. Cell apoptosis and cell cycle distribution were detected by flow cytometry. Cell invasion and migration were evaluated by Transwell assay. The expression of LASP1, JAK2, p-JAK2, STST3, p-STST3, STST5 and p-STST5 was evaluated by qRT-PCR and Western blot. In addition, the xenograft mouse model was constructed to determine the anti-cancer role of flavopereirine in vivo. Results: Flavopereirine significantly inhibited cell proliferation, invasion, migration and EMT process of BcaCD885 and Tca8113 cells, while promoted cell apoptosis in vitro. Flavopereirine markedly decreased the expression levels of p-JAK2, p-STST3 and p-STST5, while increased the expression levels of LASP1. In addition, downregulation of LASP1 significantly increased the expression levels of p-JAK2, p-STAT3 and p-STAT5 compared with si-NC in BcaCD885 cells. Moreover, flavopereirine was found to decrease tumor weight and volume of xenograft tumors in vivo. Conclusion: Flavopereirine inhibited the progression of oral cancer through inactivating the JAK/STAT signaling pathway by upregulating LASP1, suggesting that flavopereirine might be a potential anti-cancer agent for oral cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbolinas/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Proteínas com Domínio LIM/antagonistas & inibidores , Neoplasias Bucais/tratamento farmacológico , Fatores de Transcrição STAT/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Janus Quinase 2/metabolismo , Proteínas com Domínio LIM/metabolismo , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
J Med Chem ; 64(11): 7667-7690, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34044539

RESUMO

The activation of cyclic GMP-AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound 5 (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one with cellular IC50 values of 1.38 and 11.4 µM for h- and m-cGAS, respectively. Mechanistic studies confirmed its direct targeting of cGAS. Further, compound 25 showed superior in vivo anti-inflammatory effects in the lipopolysaccharide-induced mouse model. The encouraging result of compound 25 provides solid evidence for further pursuit of cGAS-targeting inhibitors as a new anti-inflammatory treatment.


Assuntos
Anti-Inflamatórios/síntese química , Carbolinas/química , Nucleotidiltransferases/antagonistas & inibidores , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Sítios de Ligação , Carbolinas/metabolismo , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Simulação de Acoplamento Molecular , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
11.
Bioorg Chem ; 111: 104846, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33813149

RESUMO

A series of ß-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC50 values of 5.58 ± 0.56 and 2.81 ± 0.07 µM, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca2+ levels ([Ca2+]i) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca2+]i in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Bibenzilas/farmacologia , Carbolinas/farmacologia , Desenho de Fármacos , Inflamação/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Bibenzilas/química , Carbolinas/química , Relação Dose-Resposta a Droga , Humanos , Inflamação/metabolismo , Estrutura Molecular , Neutrófilos/metabolismo , Relação Estrutura-Atividade
12.
Molecules ; 26(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799355

RESUMO

Biocompatible tryptophan-derived copper (1) and zinc (2) complexes with norharmane (ß-carboline) were designed, synthesized, characterized, and evaluated for the potential anticancer activity in vitro and in vivo. The in vitro cytotoxicity of both complexes 1 and 2 were assessed against two cancerous cells: (human breast cancer) MCF7 and (liver hepatocellular cancer) HepG2 cells with a non-tumorigenic: (human embryonic kidney) HEK293 cells. The results exhibited a potentially decent selectivity of 1 against MCF7 cells with an IC50 value of 7.8 ± 0.4 µM compared to 2 (less active, IC50 ~ 20 µM). Furthermore, we analyzed the level of glutathione, lipid peroxidation, and visualized ROS generation to get an insight into the mechanistic pathway and witnessed oxidative stress. These in vitro results were ascertained by in vivo experiments, which also supported the free radical-mediated oxidative stress. The comet assay confirmed the oxidative stress that leads to DNA damage. The histopathology of the liver also ascertained the low toxicity of 1.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbolinas/farmacologia , Cobre/farmacologia , Triptofano/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Ensaio Cometa/métodos , Dano ao DNA/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Zinco/farmacologia
13.
Nat Med ; 27(5): 871-881, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33927414

RESUMO

Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.


Assuntos
Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Disfunção Cognitiva/patologia , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/classificação , Carbolinas/farmacologia , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Masculino , Neuroimagem/métodos , Fenótipo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Análise Espaço-Temporal
14.
PLoS One ; 16(4): e0250712, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891670

RESUMO

Canthin-6-one, one of the main alkaloid compounds extracted from Ailanthus altissima, has recently attracted increasing interest for its antifungal activity. To evaluate the potential of canthin-6-one in controlling plant fungal diseases, we investigated the antifungal activity of canthin-6-one isolated from A. altissima against Fusarium oxysporum f. sp. cucumerinum (Foc) in vitro. The mycelial growth rate and micro-broth dilution were used to test antifungal activity. Furthermore, label-free quantitative proteomics and parallel reaction monitoring (PRM) techniques were applied to analyze the antifungal mechanism. It was found that canthin-6-one significantly inhibited the growth of Foc, and had higher inhibitory action than chlorothalonil at the same concentration. Proteomic analysis showed that the expression of 203 proteins altered significantly after canthin-6-one treatment. These differentially expressed proteins were mainly involved in amino acid biosynthesis and nitrogen metabolism pathways. These results suggest that canthin-6-one significantly interferes with the metabolism of amino acids. Therefore, it affects nitrogen nutrients and disturbs the normal physiological processes of fungi, and ultimately leads to the death of pathogens. This study provides a natural plant antifungal agent and a new perspective for the study of antifungal mechanisms.


Assuntos
Ailanthus/química , Antifúngicos/farmacologia , Carbolinas/química , Dendrobium/microbiologia , Fusarium/efeitos dos fármacos , Alcaloides Indólicos/química , Ailanthus/metabolismo , Aminoácidos/biossíntese , Antifúngicos/química , Antifúngicos/isolamento & purificação , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , Análise por Conglomerados , Estabilidade de Medicamentos , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Testes de Sensibilidade Microbiana , Nitrogênio/metabolismo , Caules de Planta/química , Caules de Planta/metabolismo , Proteômica/métodos , Esporos Fúngicos/efeitos dos fármacos
15.
Biofouling ; 37(2): 145-160, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33682541

RESUMO

Serratia marcescens NJ01, a Gram-negative bacterium, can infect tomato leaves and cause chlorosis and wilting. The present study evaluated the quorum sensing (QS) and biofilm inhibitory effects of seven carboline compounds against S. marcescens NJ01 at 20 µg ml-1, and subsequently focused the study on norharmane as this had the best inhibitory activity. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed the down-regulation of QS and biofilm related genes bsmA, bsmB, fimA, fimC, flhD, pigA, pigC and shlA on exposure to norharmane. Fourier-Transform Infrared Spectroscopy (FT-IR) analysis showed a reduction in the major components of the exopolysaccharide (EPS) matrix such as nucleic acids, proteins and fatty acids, which are involved in forming the tertiary structure of biofilms. Norharmane exposure also enhanced the susceptibility of the biofilm to ofloxacin. Hence, norharmane has the potential for use as an antibiotic adjuvant to enhance the efficacy of conventional antibiotics to reduce pathogenic bacterial infections.


Assuntos
Percepção de Quorum , Serratia marcescens , Antibacterianos/farmacologia , Biofilmes , Carbolinas/farmacologia , Serratia marcescens/genética , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Virulência/genética
16.
Bioorg Med Chem Lett ; 40: 127954, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33744440

RESUMO

Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-ß-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.


Assuntos
Antineoplásicos/uso terapêutico , Carbolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/uso terapêutico , Inibidores da Topoisomerase II/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Carbolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos Nus , Estrutura Molecular , Estudo de Prova de Conceito , Quinazolinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 40: 127952, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33744443

RESUMO

The cytotoxicity properties of the ß-carboline alkaloids have been broadly investigated. However, the potential application of ß-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty ß-carboline-(phenylsulfonyl)furoxan hybrids (11a-j, 12a-j and 13a-j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 µM) and MDA-MB-231 (IC50 = 0.62 µM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbolinas/farmacologia , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Sulfonas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Carbolinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Doadores de Óxido Nítrico/síntese química , Oxidiazóis/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química
18.
Biochem Pharmacol ; 186: 114490, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647259

RESUMO

Canthin-6-one (Cant) is an indole alkaloid found in several botanical drugs used as medicines, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of colitis using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1ß and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone. Glutathione concentration was reduced in rats administered with TNBS alone (50.00% of sham group) but restored to 72.73% (of sham group) with Cant treatment. TNF-α, IL-1ß, IL-12p70 and VEGF were reduced, and anti-inflammatory IL-10 was increased following Cant administration compared to rats administered TNBS alone. Docking ligation results for MAPK14 (p38α) and TLR8 with Cant, confirmed that these proteins are feasible putative targets. Cant has an anti-inflammatory effect in the intestine by down-regulating molecular immune mediators and decreasing oxidative stress. Therefore, Cant could have therapeutic potential for the treatment of inflammatory bowel disease and related syndromes.


Assuntos
Carbolinas/uso terapêutico , Colite/metabolismo , Simulação por Computador , Alcaloides Indólicos/uso terapêutico , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carbolinas/química , Carbolinas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/uso terapêutico , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Estresse Oxidativo/fisiologia , Estrutura Secundária de Proteína , Ratos , Ratos Wistar
19.
Neurotox Res ; 39(3): 588-597, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33713301

RESUMO

Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1-1000 µM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 µM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Carbolinas/farmacologia , Inibidores Enzimáticos/farmacologia , Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Rodanina/análogos & derivados , Tiazolidinas/farmacologia , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Carbolinas/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Indóis/química , Indóis/farmacologia , Camundongos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Células PC12 , Piridonas/química , Piridonas/farmacologia , Ratos , Rodanina/química , Rodanina/farmacologia , Tiazolidinas/química
20.
Angew Chem Int Ed Engl ; 60(21): 11784-11788, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33684237

RESUMO

Peroxidized phosphatidylethanolamine (PEox) species have been identified by liquid chromatography mass spectrometry (LC-MS) as predictive biomarkers of ferroptosis, a new program of regulated cell death. However, the presence and subcellular distribution of PEox in specific cell types and tissues have not been directly detected by imaging protocols. By applying gas cluster ion beam secondary ion mass spectrometry (GCIB-SIMS) imaging with a 70 keV (H2 O)n + (n>28 000) cluster ion beam, we were able to map PEox with 1.2 µm spatial resolution at the single cell/subcellular level in ferroptotic H9c2 cardiomyocytes and cortical/hippocampal neurons after traumatic brain injury. Application of this protocol affords visualization of physiologically relevant levels of very low abundance (20 pmol µmol-1 lipid) peroxidized lipids in subcellular compartments and their accumulation in disease conditions.


Assuntos
Ferroptose/fisiologia , Peroxidação de Lipídeos/fisiologia , Fosfatidiletanolaminas/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Carbolinas/farmacologia , Linhagem Celular , Ferroptose/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Espectrometria de Massa de Íon Secundário/métodos
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