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1.
Viruses ; 13(4)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808275

RESUMO

Porcine epidemic diarrhea virus (PEDV), an enteropathogenic coronavirus, has catastrophic impacts on the global pig industry. Owing to the lack of effective vaccines and specific therapeutic options for PEDV, it is pertinent to develop new and available antivirals. This study identified, for the first time, a salinomycin that actively inhibited PEDV replication in Vero cells in a dose-dependent manner. Furthermore, salinomycin significantly inhibited PEDV infection by suppressing the entry and post-entry of PEDV in Vero cells. It did not directly interact with or inactivate PEDV particles, but it significantly ameliorated the activation of Erk1/2, JNK and p38MAPK signaling pathways that are associated with PEDV infection. This implied that salinomycin inhibits PEDV replication by altering MAPK pathway activation. Notably, the PEDV induced increase in reactive oxidative species (ROS) was not decreased, indicating that salinomycin suppresses PEDV replication through a pathway that is an independent pathway of viral-induced ROS. Therefore, salinomycin is a potential drug that can be used for treating PEDV infection.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/veterinária , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Piranos/farmacologia , Doenças dos Suínos/virologia , Animais , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Sistema de Sinalização das MAP Quinases , Vírus da Diarreia Epidêmica Suína/genética , Vírus da Diarreia Epidêmica Suína/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/genética , Doenças dos Suínos/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Molecules ; 26(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670784

RESUMO

The fungus strain SCSIO 40433 was isolated from an Arctic-derived glacier sediment sample and characterized as Tolypocladium cylindrosporum. A new compound, cylindromicin (1), and seven known secondary metabolites (2-8) were isolated from this strain. The chemical structures of these compounds were elucidated by comprehensive spectroscopic analyses. Cylindromicin (1) featured a 3,4-dihydro-2H-pyran skeleton. The absolute configuration of compound 1 was assigned via interpretation of key Nuclear Overhauser Effect Spectroscopy (NOESY) correlations and Electronic Circular Dichroism (ECD) calculation. Cylindromicin (1) exhibited significant tyrosinase inhibition activity. This study highlights Polar fungi as a potential resource for new bioactive natural products.


Assuntos
Hypocreales/química , Piranos/isolamento & purificação , Regiões Árticas , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Piranos/química , Piranos/farmacologia , Pironas/química , Pironas/farmacologia , Relação Estrutura-Atividade
3.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672072

RESUMO

Calcium (Ca2+) dependent signaling circuit plays a critical role in influenza A virus (IAV) infection. The 8-O-(E-p-methoxycinnamoyl)harpagide (MCH) exhibits pharmacological activities that exert neuroprotective, hepatoprotective, anti-inflammatory and other biological effects. However, not have reports of antiviral effects. To investigate the antiviral activity of MCH on IAV-infected human lung cells mediated by calcium regulation. We examined the inhibitory effect of MCH on IAV infections and measured the level of viral proteins upon MCH treatment using Western blotting. We also performed molecular docking simulation with MCH and IAV M2 protein. Finally, we analyzed MCH's suppression of intracellular calcium and ROS (reactive oxygen species) in IAV-infected human lung cells using a flow cytometer. The results shown that MCH inhibited the infection of IAV and increased the survival of the infected human lung cells. The levels of IAV protein M1, M2, NS1 and PA were inhibited in MCH-treated human lung cells compared to that in infected and untreated cells. Also, docking simulation suggest that MCH interacted with M2 on its hydrophobic wall (L40 and I42) and polar amino acids (D44 and R45), which formed intermolecular contacts and were a crucial part of the channel gate along with W41. Lastly, MCH inhibited IAV infection by reducing intracellular calcium and mitochondrial Ca2+/ROS levels in infected human lung cells. Taken together, these data suggest that MCH inhibits IAV infection and increases the survival of infected human lung cells by suppressing calcium levels. These results indicate that MCH is useful for developing IAV treatments.


Assuntos
Antivirais/farmacologia , Cálcio/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Espaço Intracelular/metabolismo , Glicosídeos Iridoides/farmacologia , Piranos/farmacologia , Células A549 , Antivirais/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Canais Iônicos/metabolismo , Glicosídeos Iridoides/química , Glicosídeos Iridoides/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Simulação de Acoplamento Molecular , Piranos/química , Piranos/uso terapêutico , Proteínas da Matriz Viral
4.
Poult Sci ; 100(3): 100840, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33531152

RESUMO

This study was conducted to evaluate the effects of 3 rearing systems (FL: flooring litter rearing, MC: multilayer cage rearing, PN: plastic net rearing) with or without supplemental narasin on growth performance, gastrointestine development and health of broilers. A total of 2,400 one-day-old Ross 308 mixed-sex broilers (1:1 ratio of males and females) were used in a completely randomized design utilizing a 3 × 2 factorial arrangement of treatments, with 12 replicates per treatment. Each replicate for FL, MC, and PN consisted of 34 birds per floor pen, 30 birds per cage, and 36 birds per net pen, respectively, ensuring the same stocking density (12 birds/m2) across the 3 systems. Results showed that lower ADG (average daily gain), ADFI (average daily feed intake), and FCR (feed conversation ratio) observed in the MC group than those of the other 2 systems from 1 to 36 d of age (P < 0.05). Narasin inclusion in the diets decreased ADFI and FCR significantly (P < 0.05). Multilayer cage and PN rearing systems reduced the relative weight of the gizzard significantly (P < 0.05). Compared with FL, MC reduced the relative weight of the duodenum, jejunum, and ileum (P < 0.05). The mRNA expression levels of the ileal IL-1ß and IFN-γ in FL were higher than those in PN and MC (P < 0.05). Narasin decreased the ileal mRNA expression of TNF-α (P < 0.05). Different rearing systems changed the ileal microflora structure of broilers. The FL system increased the ileal microbial diversity of broilers and the relative abundance of Actinobacteria. Narasin combined with MC increased the relative abundance of Proteobacteria. In conclusion, birds reared in PN had a higher body weight. The MC birds had poorer intestinal development and health condition, higher abundance of Proteobacteria, but better FCR. The FL rearing appeared to be propitious for gastrointestinal development and health. Narasin inclusion in the diets improved FCR and changed the relative abundance Proteobacteria of broilers.


Assuntos
Criação de Animais Domésticos , Galinhas , Suplementos Nutricionais , Microbioma Gastrointestinal , Trato Gastrointestinal , Piranos , Ração Animal/análise , Criação de Animais Domésticos/métodos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antibacterianos/farmacologia , Biodiversidade , Dieta/veterinária , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Moela das Aves/efeitos dos fármacos , Masculino , Piranos/farmacologia , Distribuição Aleatória
5.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513799

RESUMO

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Iridoides/farmacologia , Neoplasias/prevenção & controle , Azeite de Oliva/análise , Aldeídos/química , Aldeídos/farmacologia , Aldeídos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Monoterpenos Ciclopentânicos/uso terapêutico , Dieta Mediterrânea , Glucosídeos/química , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Iridoides/química , Iridoides/isolamento & purificação , Iridoides/uso terapêutico , Neoplasias/dietoterapia , Azeite de Oliva/farmacologia , Fenóis/química , Fenóis/farmacologia , Fenóis/uso terapêutico , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Piranos/química , Piranos/farmacologia , Piranos/uso terapêutico
6.
Exp Parasitol ; 218: 107978, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32853633

RESUMO

One hundred and twenty one-day-old chukar partridges were randomly divided into eight groups which received diets with different supplementations. There were four unchallenged groups. One group received salinomycin (50 ppm), two groups received cinnamaldehyde (CINN) (100 and 200 mg/kg of diet), and another one received only the basal diet from the 1st to the 31st day. There were also four corresponding groups orally challenged by 3 × 105Eimeria kofoidi sporulated oocysts at the 21st day. Three samplings were done at the 24th, 26th, and 31st days of rearing for pathological and biochemical assessments. Fecal samples were daily taken to check the pattern of oocyst shedding from the 26th to 31st day. The body weight of birds was measured at 21st and 31st days. Along with the in vivo experiment, an in vitro sporulation inhibition test was carried out. The in vitro results showed that CINN decreased sporulation rate at 1 and 0.5 mg/ml. In vivo, it was found that CINN did not prevent the oocyst shedding. Furthermore, the histopathological findings revealed that CINN and salinomycin had no effect on infection establishment. However, our findings showed that CINN (200 mg/kg of diet) could enhance the body weight and improve antioxidant status. Although our results did not support the in vivo anticoccidial activity of CINN, it had a promising potential to improve antioxidant status and body weight in the chukar partridge.


Assuntos
Acroleína/análogos & derivados , Doenças das Aves/parasitologia , Coccidiose/veterinária , Eimeria/efeitos dos fármacos , Galliformes/parasitologia , Acroleína/farmacologia , Acroleína/uso terapêutico , Ração Animal/análise , Animais , Antioxidantes/metabolismo , Doenças das Aves/tratamento farmacológico , Peso Corporal , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Coccidiostáticos/farmacologia , Coccidiostáticos/uso terapêutico , Fezes/parasitologia , Galliformes/crescimento & desenvolvimento , Intestinos/parasitologia , Intestinos/patologia , Contagem de Ovos de Parasitas/veterinária , Piranos/farmacologia , Piranos/uso terapêutico , Distribuição Aleatória , Esporos de Protozoários/efeitos dos fármacos , Esporos de Protozoários/fisiologia , Ganho de Peso/efeitos dos fármacos
7.
Chemosphere ; 261: 127728, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32731022

RESUMO

Current study was performed to explore the effect of butanolide (KAR1) in mitigation of cadmium (Cd) induced toxicity in Brussels sprout (Brassica oleracea L.). Brussels sprout seeds, treated with 10-5 M, 10-7 M and 10-10 M solution of KAR1 were allowed to grow in Cd-contaminated (5 mg L-1) regimes for 25 d. Cadmium toxicity decreased seed germination and growth in B. oleracea seedlings. Elevated intensity of electrolyte leakage (EL), malondialdehyde (MDA) and hydrogen peroxide (H2O2) were observed in Cd-stressed seedlings. Additionally, reduced level of stomatal conductivity, transpiration rate, photosynthesis rate, intercellular carbon dioxide concentration, and leaf relative water content (LRWC) was also observed in Cd-stressed seedlings. Nevertheless, KAR1 improved seed germination, seedling growth and biomass production in Cd stressed plants. KAR1 application showed elevated LRWC, osmotic potential, and higher membranous stability index (MSI) in seedlings under Cd regime. Furthermore, seedlings developed by KAR1 treatment exhibited higher stomatal conductivity, and intercellular carbon dioxide concentration together with improved rate of transpiration and photosynthetic rate in B. oleracea under Cd stress. These findings elucidate that the reduced level of MDA, EL and H2O2, as well as improvement in antioxidative machinery increased growth and alleviated Cd toxicity in KAR1 treated seedlings under Cd stress.


Assuntos
Antioxidantes/metabolismo , Brassica/efeitos dos fármacos , Cádmio/toxicidade , Furanos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Piranos/farmacologia , Poluentes do Solo/toxicidade , Brassica/crescimento & desenvolvimento , Brassica/metabolismo , Peróxido de Hidrogênio/metabolismo , Malondialdeído/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/metabolismo
8.
Viruses ; 12(6)2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32545799

RESUMO

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Testes de Neutralização/métodos , Pneumonia Viral/tratamento farmacológico , Amodiaquina/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/terapia , Quimioterapia Combinada , Emetina/farmacologia , Células HEK293 , Células HT29 , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Soros Imunes/imunologia , Imunização Passiva/métodos , Nelfinavir/farmacologia , Pandemias , Piranos/farmacologia , Pirróis/farmacologia , Células Vero
9.
J Cancer Res Clin Oncol ; 146(7): 1801-1811, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32435894

RESUMO

PURPOSE: Oral mucositis is a debilitating inflammatory disorder observed in patients undergoing active cancer treatment, particularly cancer of the head and neck region. A key pathway believed to be involved in the pathogenesis of oral mucositis is the formation of reactive oxygen species (ROS). The identification of compounds that can inhibit this pathway may therefore be of benefit in treating this disorder. The kava plant (Piper methysticum) contains various constituents, including flavokawain A (FKA), flavokawain B (FKB), yangonin, methysticin and kavain. These constituents are known to be biologically active and possess anti-oxidative properties. This study therefore focused on examining these constituents for their effect on ROS formation in an in vitro oral mucositis model. METHODS: Cell proliferation was assessed in normal oral keratinocytes (OKF6) treated with and without kava constituents, namely FKA, FKB, yangonin, methysticin and kavain using an MTS in vitro assay. Oxidative stress was assessed by co-treating and pre-treating OKF6 cells with H2O2. The effects were quantified by analysis of ROS production, using a CM-H2DCFDA assay. RESULTS: Pre-treatment of cells for 24 h with 2.5 µg/ml kavain and 5 µg/ml FKA demonstrated a significant protective anti-oxidative effect. Similarly, FKB at a concentration of 2.5 µg/ml, demonstrated a trend of ROS reduction but was observed to be cytotoxic at concentrations greater than 5 µg/ml. Reduction in ROS production by methysticin and yangonin was compromised by their cell cytotoxicity. CONCLUSION: This was the first study to identify the anti-oxidative effects and safety of FKA and kavain with regard to oral keratinocytes, highlighting their potential use in the development of a preventative treatment for oral mucositis.


Assuntos
Kava/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Peróxido de Hidrogênio/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Substâncias Protetoras/química , Piranos/farmacologia , Pironas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estomatite/tratamento farmacológico , Estomatite/etiologia
10.
Curr Pharm Biotechnol ; 21(12): 1269-1277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32400328

RESUMO

BACKGROUND: Salinomycin is part of a group of ionophore antibiotics characterized by an activity towards tumor cells. To this day, the mechanism through which salinomycin induces their apoptosis is not fully known yet. The goal of this study was to assess the expression pattern of genes and the proteins coded by them connected with the process of programmed cell death in an endometrial cancer cell Ishikawa culture exposed to salinomycin and compared to the control. MATERIALS AND METHODS: Analysis of the effect of salinomycin on Ishikawa endometrial cancer cells (ECACC 99040201) included a cytotoxicity MTT test (with a concentration range of 0.1-100 µM), assessment of the induction of apoptosis and necrosis by salinomycin at a concentration of 1 µM as well the assessment of the expression of the genes chosen in the microarray experiment (microarray HG-U 133A_2) and the proteins coded by them connected with apoptosis (RTqPCR, ELISA assay). The statistical significance level for all analyses carried out as part of this study was p<0.05. RESULTS: It was observed that salinomycin causes the death of about 50% of cells treated by it (50.74±0.80% of all cells) at a concentration of 1µM. The decrease in the number of living cells was determined directly after treatment of the cells with the drug (time 0). The average percent of late apoptotic cells was 1.65±0.24% and 0.57±0.01% for necrotic cells throughout the entire observation period. DISCUSSION: Microarray analysis indicated the following number of mRNA differentiating the culture depending on the time of incubation with the drug: H_12 vs C = 114 mRNA, H_8 vs C = 84 mRNA, H_48 vs. C = 27 mRNA, whereas 5 mRNAs were expressed differently at all times. During the whole incubation period of the cells with the drug, the following dependence of the expression profile of the analyzed transcripts was observed: Bax>p53>FASL>BIRC5>BCL2L. CONCLUSION: The analysis carried out indicated that salinomycin, at a concentration of 1 µM, stopped the proliferation of 50% of endometrial cancer cells, mainly by inducing the apoptotic process of the cells. The molecular exponent of the induction of programmed cell death was an observed increase in the transcriptional activity of pro-apoptotic genes: Bax;p53;FASL and a decrease in the expression of anti-apoptotic genes: BCL2L2; BIRC5.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose/efeitos dos fármacos , Neoplasias do Endométrio/patologia , Expressão Gênica/efeitos dos fármacos , Piranos/farmacologia , Apoptose/genética , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/genética , Feminino , Humanos
11.
J Med Chem ; 63(13): 7108-7126, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32452679

RESUMO

In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Piranos/síntese química , Piranos/farmacologia , Animais , Técnicas de Química Sintética , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Macaca mulatta , Masculino , Camundongos , Piranos/química , Piranos/farmacocinética , Distribuição Tecidual
12.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276415

RESUMO

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.


Assuntos
Acetatos/uso terapêutico , Monoterpenos Ciclopentânicos/uso terapêutico , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/prevenção & controle , Álcool Feniletílico/análogos & derivados , Piranos/uso terapêutico , alfa-Sinucleína , Acetatos/farmacologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Monoterpenos Ciclopentânicos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/fisiologia , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Polifenóis/farmacologia , Piranos/farmacologia , Resultado do Tratamento
13.
Int J Nanomedicine ; 15: 1283-1295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161458

RESUMO

Background: Cervical cancer stem cells (CCSCs) represent a subpopulation of tumor cells that possess self-renewal capacity and numerous intrinsic mechanisms of resistance to conventional chemotherapy and radiotherapy. These cells play a crucial role in relapse and metastasis of cervical cancer. Therefore, eradication of CCSCs is the primary objective in cervical cancer therapy. Salinomycin (Sal) is an agent used for the elimination of cancer stem cells (CSCs); however, the occurrence of several side effects hinders its application. Nanoscale drug-delivery systems offer great promise for the diagnosis and treatment of tumors. These systems can be used to reduce the side effects of Sal and improve clinical benefit. Methods: Sal-loaded polyethylene glycol-peptide-polycaprolactone nanoparticles (Sal NPs) were fabricated under mild and non-toxic conditions. The real-time biodistribution of Sal NPs was investigated through non-invasive near-infrared fluorescent imaging. The efficacy of tumor growth inhibition by Sal NPs was evaluated using tumor xenografts in nude mice. Flow cytometry, immunohistochemistry, and Western blotting were used to detect the apoptosis of CSCs after treatment with Sal NPs. Immunohistochemistry and Western blotting were used to examine epithelial-mesenchymal transition (epithelial interstitial transformation) signal-related molecules. Results: Sal NPs exhibited antitumor efficacy against cervical cancers by inducing apoptosis of CCSCs and inhibiting the epithelial-mesenchymal transition pathway. Besides, tumor pieces resected from Sal NP-treated mice showed decreased reseeding ability and growth speed, further demonstrating the significant inhibitory ability of Sal NPs against CSCs. Moreover, owing to targeted delivery based on the gelatinase-responsive strategy, Sal NPs was more effective and tolerable than free Sal. Conclusion: To the best of our knowledge, this is the first study to show that CCSC-targeted Sal NPs provide a potential approach to selectively target and efficiently eradicate CCSCs. This renders them a promising strategy to improve the therapeutic effect against cervical cancer.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Piranos/administração & dosagem , Neoplasias do Colo do Útero/patologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Gelatinases/metabolismo , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Nanopartículas/administração & dosagem , Células-Tronco Neoplásicas/patologia , Poliésteres/química , Polietilenoglicóis/química , Piranos/farmacocinética , Piranos/farmacologia , Distribuição Tecidual , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 11(1): 1264, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152287

RESUMO

Wildfires can encourage the establishment of invasive plants by releasing potent germination stimulants, such as karrikins. Seed germination of Brassica tournefortii, a noxious weed of Mediterranean climates, is strongly stimulated by KAR1, the archetypal karrikin produced from burning vegetation. In contrast, the closely-related yet non-fire-associated ephemeral Arabidopsis thaliana is unusual because it responds preferentially to KAR2. The α/ß-hydrolase KARRIKIN INSENSITIVE 2 (KAI2) is the putative karrikin receptor identified in Arabidopsis. Here we show that B. tournefortii expresses three KAI2 homologues, and the most highly-expressed homologue is sufficient to confer enhanced responses to KAR1 relative to KAR2 when expressed in Arabidopsis. We identify two amino acid residues near the KAI2 active site that explain the ligand selectivity, and show that this combination has arisen independently multiple times within dicots. Our results suggest that duplication and diversification of KAI2 proteins could confer differential responses to chemical cues produced by environmental disturbance, including fire.


Assuntos
Arabidopsis/metabolismo , Brassica/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Furanos/farmacologia , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/metabolismo , Piranos/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis , Brassica/efeitos dos fármacos , Brassica/genética , Domínio Catalítico , Fogo , Regulação da Expressão Gênica de Plantas , Germinação/efeitos dos fármacos , Germinação/fisiologia , Hidrolases/genética , Hidrolases/metabolismo , Magnoliopsida , Proteínas de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plântula , Sementes/efeitos dos fármacos , Sementes/fisiologia , Análise de Sequência de Proteína , Transcriptoma , Incêndios Florestais
15.
Chemistry ; 26(33): 7416-7424, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32083773

RESUMO

Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20-propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20-amination, C1-esterification, C9-oxidation, and C28-dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24low /CD44high cells, a well-established model of breast CSC, and HMLER CD24high /CD44low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC50 value of 23 nm against HMLER CD24low /CD44high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Hialuronatos/química , Ferro/agonistas , Lisossomos/química , Células-Tronco Neoplásicas/química , Piranos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lisossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Piranos/química
16.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059518

RESUMO

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.


Assuntos
Antiprotozoários/farmacologia , Proliferação de Células/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Piranos/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Humanos , Leishmania/patogenicidade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piranos/síntese química , Piranos/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
17.
Biochem Biophys Res Commun ; 523(4): 874-879, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31955885

RESUMO

Drug combination is considered to be the cornerstone of cancer treatment. Simultaneous administration of two or more drugs but at lower doses not only increases cytotoxic effects on tumor cells, but also reduces side effects and possibly overcomes drug resistance. Salinomycin is a well-known cancer stem cell killer, and dichloroacetate is a pyruvate dehydrogenase kinase inhibitor that exclusively targets cells with altered mitochondrial activity, a characteristic being common to most of the cancer cells. In our recent study, we have demonstrated that salinomycin exerted a cytotoxic effect on colorectal carcinoma cells in the 2D and 3D cultures and provided evidence that the mechanism of their synergy was mediated by dichloroacetate-dependent inhibition of the activity of multidrug resistance proteins. In the current work, we confirmed the synergistic cytotoxic properties of salinomycin and dichloroacetate in the 2D and 3D cultures of Lewis lung carcinoma (LLC1) cells. To verify if a synergistic effect of these compounds persisted in vivo, we performed series of experiments using a syngeneic LLC1-C57BL/6 mouse model and demonstrated that combination therapy with salinomycin and DCA increased the survival rate of allografted mice, inhibited metastatic site formation and reduced the populations of cancer stem cells as well as cells that underwent the epithelial-to-mesenchymal transition. Our results demonstrate that a synergistic effect of salinomycin and dichloroacetate exists not only in vitro but also in vivo and suggest their benefits in the treatment of metastatic cancers.


Assuntos
Carcinoma Pulmonar de Lewis/patologia , Ácido Dicloroacético/farmacologia , Piranos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
18.
Molecules ; 25(3)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991882

RESUMO

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs-5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Piranos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Estrutura Molecular , Compostos Organoplatínicos/química , Neoplasias Ovarianas , Piranos/química
19.
Trop Anim Health Prod ; 52(4): 1985-1989, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31981055

RESUMO

The objective of the present study was to investigate the comparative efficacy of recommended dose of selected anticoccidial drugs Salinomycin, Dinitolmide, while Cocciban at three dose levels on the performance of broilers. For this purpose, 420-day-old commercial male broiler chicks were randomly divided into 7 treatment groups with 10 replications of 6 birds each and reared in battery brooders up to 42 days of age. Groups were designated as uninfected unmedicated (T1), infected unmedicated (T2), Cocciban 500 g/ton and infected (T3), Cocciban 750 g/ton and infected (T4), Cocciban 1000 g/ton and infected (T5), Salinomycin 500 g/ton and infected (T6), and Dinitolmide and infected (T7). Groups T2, T3, T4, T5, T6, and T7 were experimentally infected at 21 days old by 50,000 oocysts of Eimeria species. The broilers were fed with starter (0-21 days) and finisher diets (22-42 days). The herbal product Cocciban 1000 g/ton alone had significantly (P < 0.05) higher body weight gain and feed efficiency than all other infected groups during the overall experimental period (0-42 days), but significantly lower than healthy control. All the groups did not show significant (P > 0.05) effect on mean feed intake, percent carcass yields and percent weights of liver, heart and gizzard. Similarly there was no significant (P < 0.05) influence of treatment groups on the organoleptic characteristics of meat. Treatment groups did not have any significant (P < 0.05) influence on humeral immune response to ND vaccine and cell-mediated immune response to PHA-P. Among all the infected groups, Cocciban 1000 g/ton group (78.33%) recorded more mean percent livability than all other infected groups.


Assuntos
Galinhas , Coccidiose/veterinária , Coccidiostáticos/farmacologia , Eimeria/efeitos dos fármacos , Doenças das Aves Domésticas/prevenção & controle , Animais , Coccidiose/parasitologia , Coccidiose/prevenção & controle , Coccidiostáticos/classificação , Dinitolmida/farmacologia , Masculino , Oocistos/efeitos dos fármacos , Doenças das Aves Domésticas/parasitologia , Piranos/farmacologia
20.
J Pharmacol Exp Ther ; 373(1): 34-43, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31937563

RESUMO

The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP), which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol), a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classic opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer assay measuring NOP interaction with G proteins and ß-arrestins, the label-free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared with the standard NOP antagonist SB-612111. In all assays, BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10-fold higher potency than the standard antagonist SB-612111. BTRX-246040 is an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. SIGNIFICANCE STATEMENT: NOP antagonists may be innovative antidepressant drugs. In this research, the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent, and selective NOP antagonist.


Assuntos
Piranos/farmacologia , Receptores Opioides/fisiologia , Compostos de Espiro/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos
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