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1.
J Med Microbiol ; 69(5): 670-675, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32186482

RESUMO

Introduction. Biocide-induced cross-resistance to antimicrobials in bacteria has been described and is a concern for regulators. We have recently reported on a new protocol to predict the propensity of biocide to induce phenotypic resistance in bacteria.Aim. To measure bacterial propensity to develop antimicrobial resistance following exposure to a new cosmetic preservative developed by L'Oréal R and I.Methodology. Well-established antimicrobials including triclosan (TRI) and benzalkonium chloride (BZC) and a new molecule hydroxyethoxy phenyl butanone (HEPB) were investigated for their antimicrobial efficacy, effect on bacterial growth, and their potential to induce resistance to chemotherapeutic antibiotics using a new predictive protocol.Results. The use of this predictive protocol with Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa showed that TRI and BZC significantly affected bacterial growth, MICs and minimum bactericidal concentrations (MBCs). There was no change in antibiotic susceptibility profile following exposure to BZC, but E. coli became intermediate resistant to tobramycin following treatment with TRI (0.00002 % w/v). HEPB did not change the antimicrobial susceptibility profile in P. aeruginosa and S. aureus but E. coli became susceptible to gentamicin. TRI exposure resulted in bacterial susceptibility profile alteration consistent with the literature and confirmed the use of TRI as a positive control in such a test.Conclusion. Data produced on the propensity of a molecule to induce bacterial resistance is useful and appropriate when launching a new preservative.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Butanonas/farmacologia , Farmacorresistência Bacteriana , Conservantes Farmacêuticos/farmacologia , Butanonas/química , Interações Medicamentosas , Humanos , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Conservantes Farmacêuticos/química , Reprodutibilidade dos Testes
2.
Molecules ; 25(3)2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32050419

RESUMO

Root-knot nematode diseases cause severe yield and economic losses each year in global agricultural production. Virgibacillus dokdonensis MCCC 1A00493, a deep-sea bacterium, shows a significant nematicidal activity against Meloidogyne incognita in vitro. However, information about the active substances of V. dokdonensis MCCC 1A00493 is limited. In this study, volatile organic compounds (VOCs) from V. dokdonensis MCCC 1A00493 were isolated and analyzed through solid-phase microextraction and gas chromatography-mass spectrometry. Four VOCs, namely, acetaldehyde, dimethyl disulfide, ethylbenzene, and 2-butanone, were identified, and their nematicidal activities were evaluated. The four VOCs had a variety of active modes on M. incognita juveniles. Acetaldehyde had direct contact killing, fumigation, and attraction activities; dimethyl disulfide had direct contact killing and attraction activities; ethylbenzene had an attraction activity; and 2-butanone had a repellent activity. Only acetaldehyde had a fumigant activity to inhibit egg hatching. Combining this fumigant activity against eggs and juveniles could be an effective strategy to control the different developmental stages of M. incognita. The combination of direct contact and attraction activities could also establish trapping and killing strategies against root-knot nematodes. Considering all nematicidal modes or strategies, we could use V. dokdonensis MCCC 1A00493 to set up an integrated strategy to control root-knot nematodes.


Assuntos
Antinematódeos/isolamento & purificação , Doenças das Plantas/prevenção & controle , Tylenchoidea/efeitos dos fármacos , Virgibacillus/química , Compostos Orgânicos Voláteis/isolamento & purificação , Acetaldeído/isolamento & purificação , Acetaldeído/farmacologia , Animais , Antinematódeos/farmacologia , Organismos Aquáticos , Derivados de Benzeno/isolamento & purificação , Derivados de Benzeno/farmacologia , Butanonas/isolamento & purificação , Butanonas/farmacologia , Quimiotaxia/efeitos dos fármacos , Dissulfetos/isolamento & purificação , Dissulfetos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/parasitologia , Contagem de Ovos de Parasitas , Doenças das Plantas/parasitologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/parasitologia , Microextração em Fase Sólida , Tylenchoidea/crescimento & desenvolvimento , Compostos Orgânicos Voláteis/farmacologia
3.
Trop Anim Health Prod ; 51(7): 1823-1827, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30945154

RESUMO

Zebu bulls are a shy breeder and they exhibit optimum libido in the presence of females with estrus phase. Continuous semen collection with the use of male dummy leads to lack of adequate sexual stimulation. Therefore, the present study was designed to test the effect of estrus-specific molecule(s) for effective sexual preparation of donor bulls. The bulls were divided into normal and poor libido group, five bulls in each group by taking 1-month control study data after collecting the information of individual bull's sexual behaviour during semen collection by regular semen collector. The bulls were never being exposed to female animals and semen was collected by an artificial vagina. The ten animals were exposed to a glycerol-water solution (50/50 v:v) as control and then exposed to estrus-specific molecules one by one. The estrus-specific molecules like squalene, 1-iodoundecane, acetic acid, coumarin, propionic acid, oleic acid, and 2-butanone were purchased from Sigma-Aldrich Company, USA, and the molecules were solubilised individually in a non-pressurised aerosol dispenser as 1.0% concentration in glycerol-water solution (50/50, v:v). Identical bulls were used as the control and exposed to each molecule one by one by giving a refractory period of 14 days. A nasal spray of acetic acid or 2-butanone significantly (p < 0.05) reduced reaction time (RT) and total time taken to ejaculate (TTTE) in normal libido bull group. Semen volume, sperm concentration, and the total number of sperm per ejaculation obtained did not show significant improvement in the normal libido group of bulls after the application of estrus-specific molecules as compared to the control. In poor libido group, acetic acid, oleic acid, and 2-butanone application showed significant (p < 0.01) improvement in RT and TTTE as compared to the control group, whereas semen production variables like sperm concentration and total sperm output per ejaculation increased significantly (p < 0.05) except semen volume. There was significant (p < 0.01) reduction in RT (%) and TTTE (%) after the application of acetic acid followed by 2-butanone and oleic acid. The sperm concentration and total sperm output per ejaculation were more after the application of each molecule but significant increase (p < 0.05) in sperm concentration was observed with 2-butanone (11.42%), acetic acid (11.42%), and oleic acid (10.13%), whereas total sperm output per ejaculation increased significantly (p < 0.05) only after the application of acetic acid and 2-butanone (24.75% and 26.84%). Hence, it can be concluded that acetic acid, 2-butanone, and oleic acid are effective for better sexual preparation of Sahiwal bulls and total sperm output per ejaculation.


Assuntos
Bovinos/fisiologia , Libido/fisiologia , Sêmen/fisiologia , Ácido Acético/farmacologia , Animais , Butanonas/farmacologia , Cumarínicos/farmacologia , Estro/fisiologia , Índia , Masculino , Ácido Oleico/farmacologia , Propionatos/farmacologia , Espermatogênese/efeitos dos fármacos , Esqualeno/farmacologia , Clima Tropical
4.
FEBS J ; 286(4): 678-687, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30653821

RESUMO

The involvement of superoxide-generating NADPH oxidase (NOX) in the cytotoxic effects of cigarette smoke extracts has been documented. However, the underlying molecular mechanisms and NOX isoform involved have not been fully clarified. Among the different NADPH oxidase isoforms identified so far, NOX1 and NOX4 were found to be expressed in rat H9c2 cardiomyocytes. When H9c2 cells were exposed to acrolein or methyl vinyl ketone (MVK), major toxic components of cigarette smoke extracts, a dose-dependent decline in cell viability was observed. Unexpectedly, disruption of Nox1 as well as Nox4 significantly exacerbated cytotoxicity induced by acrolein or MVK. Compared with Nox4-disrupted cells, Nox1-disrupted cells were more vulnerable to acrolein and MVK at lower concentrations. Disruption of Nox1 markedly attenuated the levels of total and reduced glutathione (GSH) in H9c2 clones. Reduction in the cystine level in the culture medium to deplete intracellular GSH significantly exacerbated acrolein or MVK-induced cytotoxicity. Nox1 disruption neither attenuated the level of glutamate-cystine antiporter protein nor the activity of glutamate-cysteine ligase, both rate-limiting factors for GSH synthesis. On the other hand, increased expression of multidrug resistance-associated protein 1 (MRP1), which mediates glutathione efflux, was demonstrated in Nox1-disrupted cells. The augmented toxicity of acrolein and MVK in these cells was partially but significantly blunted in the presence of an MRP1 inhibitor, reversan. Taken together, these results show that NOX1/NADPH oxidase regulates the expression of MRP1 to maintain intracellular GSH levels in cardiomyocytes and protect against cytotoxic components of cigarette smoke extracts. A novel crosstalk between NOX1 and MRP1 was demonstrated in this study.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Miócitos Cardíacos/metabolismo , NADPH Oxidase 1/metabolismo , Acroleína/farmacologia , Animais , Butanonas/farmacologia , Sistemas CRISPR-Cas , Sobrevivência Celular , Células Cultivadas , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , NADPH Oxidase 1/antagonistas & inibidores , NADPH Oxidase 1/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
5.
Biomed Pharmacother ; 110: 500-509, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530230

RESUMO

AIM: Obesity is a continually growing pandemic leading to many diseases that affect the overall quality of life. The widely marketed Garcinia cambogia (GC) and Raspberry ketone (RK) were used in this study. Despite their known dietetic effect, however, the metabolomic/signaling pathways involved in this effect are not fully elucidated. Hence, our study comprehends the possible trajectories of their combination against obesity and insulin resistance in addition to exploring their combination merit. MATERIALS AND METHODS: Adult male Wistar rats were divided into 5 groups; viz., normal diet (ND), high fat fructose diet (HFFD), HFFD+GC (600mg/kg), HFFD+RK (55mg/kg) and HFFD+GC+RK. To assess our aim, we determined their effect on body weight, IPGTT, glucose homeostasis (glucose, insulin, HOMA IR), lipid profile parameters and SREBP-1c, oxidative stress markers, insulin and leptin signaling pathways (p-IRS-1/p-AKT/GLUT-4, and leptin/STAT-3), as well as liver and adipose tissue histopathology. RESULTS: GC/RK combinationcaused weight loss, corrected the disturbed glucose and insulin homeostasis, raised serum levels of HDL anddecreased all other lipid profile parameters. They also increased Nrf-2 expression, ad GSH, as well as p-IRS-1/p-Akt/GLUT-4 cue, while they decreased MDA, leptin/STAT-3 and SREBP-1c content compared to the HFFD group. Furthermore, the GC/RK combination abolished apoptosis, fatty changes and inflammation in hepatocytes and decreased sclerotic blood vessels and congestion in adipose tissue. CONCLUSION: Our study highlights the involvement ofp-IRS-1/p-Akt/GLUT-4, leptin/STAT-3 and SREBP-1c signaling trajectories in the beneficial combination of GC and RK, besides, the efficient rebalance of the redox status, insulin resistance and tissue fat deposition confirmed histopathologically.


Assuntos
Butanonas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Garcinia cambogia , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo , Adiposidade/efeitos dos fármacos , Adiposidade/fisiologia , Animais , Butanonas/farmacologia , Leptina/antagonistas & inibidores , Masculino , Obesidade/tratamento farmacológico , Obesidade/etiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Eur J Pharmacol ; 842: 157-166, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30431010

RESUMO

The peroxisome proliferator-activated receptor-α (PPAR-α) controls the lipid and glucose metabolism and also affects inflammation, cell proliferation and apoptosis during cardiovascular disease. Raspberry ketone (RK) is a red raspberry (Rubusidaeus, Family-Rosaceae) plant constituent, which activates PPAR-α. This study was conducted to assess the cardioprotective action of RK against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups (six rats/group). Rats were orally administered with RK (50, 100 and 200 mg/kg, respectively) and fenofibrate (standard, 80 mg/kg) for 28 days and ISO was administered (85 mg/kg, subcutaneously) on 27th and 28th day. Administration of ISO in rats significantly altered hemodynamic and electrocardiogram patterns, total antioxidant capacity, PPAR-α, and apolipoprotein C-III levels. These myocardial aberrations were further confirmed during infarct size, heart weight to body weight ratio and immunohistochemical assessments (caspase-3 and nuclear factor-κB). RK pretreatment (100 and 200 mg/kg) significantly protected rats against oxidative stress, inflammation, and dyslipidemia caused by ISO as demonstrated by change in hemodynamic, biochemical and histological parameters. The results so obtained were quite comparable with fenofibrate. Moreover, RK was found to have binding affinity with PPAR-α, as confirmed by docking analysis. PPAR-α expression and concentration was also found increased in presence of RK which gave impression that RK probably showed cardioprotection via PPAR-α activation, however direct binding study of RK with PPAR-α is needed to confirm this assumption.


Assuntos
Butanonas/farmacologia , Cardiotônicos/farmacologia , Coração/efeitos dos fármacos , Isoproterenol/toxicidade , PPAR alfa/metabolismo , Animais , Apolipoproteína C-II/metabolismo , Butanonas/metabolismo , Butanonas/uso terapêutico , Cardiotônicos/metabolismo , Cardiotônicos/uso terapêutico , Caspase 3/genética , Eletrocardiografia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Coração/fisiologia , Hemodinâmica/efeitos dos fármacos , Isoproterenol/antagonistas & inibidores , Masculino , Simulação de Acoplamento Molecular , Infarto do Miocárdio/tratamento farmacológico , NF-kappa B/genética , PPAR alfa/química , PPAR alfa/genética , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
7.
Pest Manag Sci ; 75(7): 1942-1950, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30578612

RESUMO

BACKGROUND: Tephritid fruit flies are recognized as the most economically important insect pest group, causing significant losses to horticultural crops globally. The sterile insect technique (SIT) is used to suppress or eradicate pest fruit flies in many countries. The provisioning of adult dietary or olfactory supplementation pre-release is commonly used to improve the mating performance of sterile male flies in SIT. This study on a major pest species, Queensland fruit fly, Bactrocera tryoni (Froggatt), focused on improving mating performance by providing a semiochemical, raspberry ketone (RK), in the pre-release adult diet. RESULTS: Survival was numerically higher for RK-supplemented males. Sexual maturity occurred 1 day earlier (from 7 to 6 days) in RK-supplemented sterile males. The mating latency period decreased with maturation age and was lower for RK-fed males. RK-supplemented sterile males increasingly mated with fertile females as they aged (10-19 days). The mating competitiveness of both RK-supplemented sterile males and RK-denied sterile males was greater than that of wild males. CONCLUSION: The early sexual maturity and increased mating performance of RK-supplemented sterile males indicate that the effectiveness of SIT programmes can be increased through dietary supplementation with RK during the pre-release period. © 2018 Society of Chemical Industry.


Assuntos
Ração Animal/análise , Butanonas/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Tephritidae/efeitos dos fármacos , Animais , Dieta/veterinária , Feminino , Masculino , Controle Biológico de Vetores/métodos
8.
Biomed Pharmacother ; 107: 1166-1174, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257330

RESUMO

Obesity is a proven risk factor for neurodegenerative disease like Alzheimer's disease (AD). Accumulating evidences suggested that nutritional interventions provide potential for prevention and treatment of AD. The present study aimed to investigate the effect of dietary treatment of obese rats with natural Raspberry ketone (RK) and their relationship with neurodegeneration. Obesity was first induced in 40 male Wistar rats (140-160 g) by feeding high fat diet (HFD) for 16 weeks. Obese rats were then assigned into 4 groups (n = 10 each). (O-AD) is obese induced AD group maintained on HFD for another 6 weeks. OCR is obese group received calorie restricted diet for 6 weeks. OCRRK is obese group received calorie restricted diet and RK (44 mg/kg body weight, daily, orally) for 6 weeks and OCRD is obese group received calorie restricted diet and orlistate (10 mg/kg body weight, daily orally) for 6 weeks. Another 10 normal rats received normal diet were used as normal control group (NC). Body weight, visceral white adipose tissue weight (WAT), lipid profile, oxidative stress markers, adiponectin, cholinergic activity and amyloid extracellular plaques were examined. In addition to histological changes in brain tissues were evaluated.Raspberry ketone (RK) via its antioxidant properties attenuated oxidative damage and dyslipidemia in O-AD group. It inhibited acetylcholinesterase enzyme (AchE) and hence increased acetylcholine level (Ach) in brain tissues of O-AD rats. It is also impeded the upregulation of beta-secretase-1 (BACE-1) and the accumulation of amyloid beta (Aß) plaques which crucially involved in AD. The combination of CR diet with RK was more effective than CR diet with orlistate (antiobese drug) in abrogating the neurodegenerative changes induced by obesity. Results from this study suggested that concomitant supplementation of RK with calorie restricted regimen effectively modulate the neurodegenerative changes induced by obesity and delay the progression of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Butanonas/farmacologia , Obesidade/complicações , Acetilcolina/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/etiologia , Doença de Alzheimer/fisiopatologia , Animais , Restrição Calórica , Inibidores da Colinesterase/farmacologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Masculino , Obesidade/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Ratos , Ratos Wistar , Fatores de Risco
9.
Chem Pharm Bull (Tokyo) ; 66(7): 721-726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962455

RESUMO

Highly reactive α,ß-unsaturated carbonyl compounds, such as acrolein (ACR), crotonaldehyde (CA) and methyl vinyl ketone (MVK), are environmental pollutants present in high concentrations in cigarette smoke. We have previously found that these carbonyl compounds in cigarette smoke extract (CSE) react with intracellular glutathione (GSH) to produce the corresponding GSH-ACR, GSH-CA and GSH-MVK adducts via Michael addition reaction. These adducts are then further reduced to the corresponding alcohol forms by intracellular aldo-keto reductases in highly metastatic mouse melanoma (B16-BL6) cells and then excreted into the extracellular fluid. This time, we conducted a similar study using sheep erythrocytes and found analogous changes in the sheep erythrocytes after exposure to CSE as those with B16-BL6 cells. This indicates similarity of the detoxification pathways of the α,ß-unsaturated carbonyl compounds in sheep blood cells and B16-BL6 cells. Also, we found that the GSH-MVK adduct was reduced by aldose reductase in a cell-free solution to generate its alcohol form, and its reduction reaction was completely suppressed by pretreatment with epalrestat, an aldose reductase inhibitor, a member of the aldo-keto reductase family. In the presence of sheep blood cells, however, reduction of the GSH-MVK adduct was partially inhibited by epalrestat. This revealed that some member of the aldo-keto reductase superfamily other than aldose reductase is involved in reduction of the GSH-MVK adduct in sheep blood. These results suggest that blood cells, mainly erythrocytes are involved in reducing the inhalation toxicity of cigarette smoke via an aldo-keto reductase pathway other than that of aldose reductase.


Assuntos
Acroleína/metabolismo , Aldeídos/metabolismo , Butanonas/metabolismo , Fumar Cigarros/metabolismo , Eritrócitos/metabolismo , Fumaça/análise , Acroleína/química , Acroleína/farmacologia , Aldeídos/química , Aldeídos/farmacologia , Animais , Butanonas/química , Butanonas/farmacologia , Eritrócitos/efeitos dos fármacos , Ovinos , Produtos do Tabaco
10.
J Insect Physiol ; 109: 41-46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29890169

RESUMO

The males of different species of Bactrocera and Zeugodacus fruit flies are commonly attracted to plant-derived phenylpropanoids (e.g. methyl eugenol (ME)) or phenylbutanoids (e.g. raspberry ketone (RK)) but almost never to both. However, one particular plant-derived phenylbutanoid, zingerone (ZN), which possesses an intermediate chemical structure between ME and RK, weakly attracts both ME- and RK-responding fruit fly species. Bactrocera jarvisi, an Australian fruit fly species, is weakly attracted to cue lure (an analogue of RK) but strongly attracted to ZN. Here, we investigated the minimum olfactory threshold and optimum sensitivity of B. jarvisi males to ZN and RK as a function of dose, time and sexual maturation. Our results show that B. jarvisi males had a marked preferential response to ZN, with a much lower olfactory threshold and faster response time to ZN than RK. Probit analysis demonstrated that ZN was at least >1600× more potent than RK as a male attractant to B. jarvisi. Although fruit fly male attraction to the phytochemicals is generally associated with sexual maturity, in B. jarvisi immature males were also attracted to ZN. Our results suggest that B. jarvisi males have a fine-tuned olfactory response to ZN, which appears to play a central role in the chemical ecology of this species.


Assuntos
Butanonas/farmacologia , Guaiacol/análogos & derivados , Limiar Sensorial , Tephritidae/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Guaiacol/farmacologia , Masculino , Feromônios/farmacologia , Maturidade Sexual/fisiologia , Olfato/fisiologia , Tephritidae/crescimento & desenvolvimento
11.
Comput Biol Chem ; 75: 178-195, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29883916

RESUMO

The present paper deals with in silico evaluation of 32 virtually designed transition metal complexes of 2-butanone thiosemicarbazone and N,S,O containing donor hetero-ligands namely py, bpy, furan, thiophene, 2-picoline, 1,10-phenanthroline, piperazine and liquid ammonia. The complexes were designed with a view to assess their potential anticancer, antioxidant and antibacterial activity. The absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the chosen ligands were calculated by admetSAR software. Metabolic sites of different ligands likely to undergo metabolism were predicted using Metaprint 2D. The proposed complexes were also evaluated for their drug-like quality based on Lipinski's, Veber, Ghose and leadlikeness filters. Druglikeness and toxicity potential were predicted by OSIRIS property explorer. The pharmacokinetic properties and bioactivity scores were calculated by Molinspiration tool. Bioactivity scores of the complexes were predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G-protein coupled receptor ligands and ion channel modulators. Molecular docking of selected Fe(II) mixed-ligand complexes was performed using AutoDock version 4.2.6 and i-GEMDOCK version 2.1 with two target proteins namely Ribonucleotide reductase (RR) and Topoisomerase II (Topo II). The results were compared with three standard reference drugs viz. Doxorubicin HCl, Letrozole (anticancer) and Tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA) for visualization and projection as scatter and 3D plots. Positive results obtained for hetero-ligands using admetSAR version 1.0 indicated good absorption and transport kinetics of the hetero-ligand complexes through the human intestine and blood-brain barrier. The hetero-ligands were predicted to have no associated mutagenic effect(s) also. However, none of the hetero-ligands was predicted to be Caco-2 (human colon cancer cell line) permeable. Most of the hetero-ligands and the parent ligand (2-butanone thiosemicarbazone) were predicted to undergo Phase-I metabolism prior to excretion using MetaPrint2D software. Pharmacokinetic evaluation of the proposed complexes revealed that all complexes displayed drug-like character and were predicted to have no apparent toxic side-effects. All the proposed complexes showed moderate to good biological activity scores (-5.0 to 0.0). Mixed complexes with bpy, 2-picoline and 1,10-phenanthroline showed significant bioactivity scores (as enzyme inhibitors) in the range 0.02-0.13. Likewise, good docking scores were obtained for Fe (II) complexes with the same ligands. [FeL(2-pic)2] displayed the lowest binding energy (-6.47 kcal/mol) with respect to Topo II followed by [FeL(py)2] (-6.14 kcal/mol) as calculated by AutoDock version 4.2.6. With respect to binding with RR, [FeL(2--pic)2] again displayed the lowest binding energy (-7.21 kcal/mol) followed by [FeL(py)2] (-5.96 kcal/mol). On the basis of docking predictions and various other computational evaluations, four mixed-ligand complexes of Fe in +2 oxidation state with py, bpy, 2--picoline and 1,10-phenanthroline were synthesized with 2-butanone thiosemicarbazone. All the synthesized Fe complexes were characterized using various spectroscopic techniques and tested for their potential anticancer activity in vitro against human breast carcinoma cell line MDA-MB 231 and human lung carcinoma cell line A549 cell line using MTT assay. [FeL(2-pic)2], [FeL(bpy)], and [FeL(py)2] were found to exhibit significant antiproliferative activity with IC50 values in the range of 80-100 µM against breast and lung cancer cells. The synthesized Fe complexes also displayed mild antioxidant activities. The synthesized and studied Fe complexes have the potential for development into future anticancer agents if analyzed and modified further for improvement of their ADMET, solubility and permeability criteria set for potential drug-candidates.


Assuntos
Antineoplásicos/farmacologia , Técnicas de Química Combinatória , Desenho Assistido por Computador , Desenho de Fármacos , Compostos Organometálicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Butanonas/química , Butanonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Solubilidade , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Elementos de Transição/química , Elementos de Transição/farmacologia
12.
Eur J Pharmacol ; 832: 81-89, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-29787773

RESUMO

Obesity constitutes a major worldwide problem in which hyperlipidemia and insulin resistance represents adverse metabolic consequences of it. The present study was conducted to elucidate the role of raspberry ketones (RKs) in controlling body weight gain, hyperlipidemia and insulin resistance in male obese rats through affecting the expression of various adipocytokines. As Aquaporin-7 is co-related with the expression of various adipocytokines and has recently emerged as a modulator of adipocyte metabolism, the present study evaluated the effect of RKs on adipose tissue expression of aquaporin-7(AQP7) in high-fat (HF) diet-fed rats. Groups of male rats were assigned to normal, HF diet-fed control rats and RKs-treated (250 and 500 mg/kg) groups. RKs administration effectively abrogated hyperlipidemia and oxidative burden and enhanced insulin sensitivity. In addition, treatment with RKs ameliorated adipose tissue and liver indices and the reduced adipocyte diameters. Moreover, administration of the low dose of RKs ameliorated the expression of apelin and its receptor, and visfatin with upregulating adiponectin expression compared to HF diet control rats. However, both doses effectively downregulated leptin expression. It was obvious that both RKs doses revealed effectiveness in upregulating the AQP7 expression. The present data suggest the promising therapeutic role of RKs in HF diet-induced obesity that is likely attributable, at least in part, to upregulation of AQP7 expression.


Assuntos
Adipocinas/genética , Tecido Adiposo/efeitos dos fármacos , Aquaporinas/genética , Butanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Butanonas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Hiperlipidemias/complicações , Hiperlipidemias/genética , Hiperlipidemias/patologia , Masculino , Obesidade/induzido quimicamente , Obesidade/complicações , Ratos , Ratos Wistar
13.
Chem Commun (Camb) ; 54(47): 6000-6003, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29796466
14.
J Toxicol Sci ; 43(4): 257-266, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29618714

RESUMO

The increased ratio of longer amyloid-ß (Aß1-42)/shorter amyloid-ß (Aß1-40) peptides, generated from amyloid precursor protein (APP), is known to promote the development of Alzheimer's disease (AD). To investigate the role of smoking in Aß production, we determined the production of Aß species in the presence of nicotine or methyl vinyl ketone (MVK), major components of cigarette smoke extracts, in Flp-In™ T-REx™-293 (T-REx293) cells harboring a single copy of human APP. While treatment with nicotine or MVK did not affect the amount of APP, the levels of Aß1-40 in the culture media were significantly increased. On the other hand, the levels of Aß1-42 were unaltered by nicotine or MVK treatment. The Aß1-42/Aß1-40 ratio was therefore attenuated by cigarette smoke extracts. Similar results were obtained in T-REx293 cells harboring APP of Swedish- or London-type mutation linked to familial AD. T-REx293 cells expressed the nicotinic acetylcholine receptor (nAchR) and tubocurarine, an nAChR antagonist, completely blocked the effects of nicotine. Treatment with nicotine significantly elevated cellular levels of ß-secretase that cleaves APP prior to Aß generation. Taken together, a protective role of nicotine against AD pathology was suggested by enhanced extracellular Aß1-40 production, which may suppress Aß fibrillogenesis.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Butanonas/farmacologia , Fumar Cigarros/metabolismo , Nicotina/farmacologia , Produtos do Tabaco/análise , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/metabolismo , Butanonas/isolamento & purificação , Células Cultivadas , Depressão Química , Humanos , Nicotina/isolamento & purificação
15.
In Vivo ; 32(3): 493-497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29695551

RESUMO

We investigated the anti-metastatic action of nicotine- and tar-removed cigarette smoke extract (CSE) on highly metastatic mouse Colon-26 cells using syngeneic BALB/c mice. Colon-26 cells were injected into the spleen of mice, cells were grown in the spleen as the primary lesion, and some metastasized from the spleen to liver and established a metastatic lesion. CSE (10, 30, and 100%) was intraperitoneally administered daily to the mice for 14 days after tumor inoculation. As a result, the relative spleen weights of CSE-administered mice did not differ significantly from those of the control mice. However, the relative liver weights of CSE 30%-administered mice significantly decreased compared to control mice. In order to identify the active component in CSE, we examined the action of methyl vinyl ketone (MVK) on the invasiveness of Colon-26 cells. MVK significantly reduced the invasiveness of cells. MVK may be a candidate active component of CSE.


Assuntos
Fumaça/efeitos adversos , Fumar , Alcatrões/química , Alcatrões/farmacologia , Animais , Butanonas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Camundongos , Nicotina/farmacologia , Neoplasias Retais
16.
Exp Mol Med ; 50(2): e446, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29504608

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and its prevalence is increasing. AD usually elicits skin barrier dysfunction, dry skin and itching. As the mechanisms of AD remain unknown, there is an urgent need to find effective therapies. Because of the diversity and complexity of marine environments, the discovery of drugs from marine organisms as novel therapeutic agents for human diseases has seen renewed interest. Dihydroaustrasulfone alcohol (WA-25), the synthetic precursor of austrasulfone, which is a natural product isolated from a Formosan soft coral, has been shown to possess many therapeutic effects in our previous studies. However, the detailed mechanisms and therapeutic effects of WA-25 on AD are incompletely understood. We performed in vitro and in vivo studies to examine the effects of WA-25 on AD. We showed that WA-25 blocks inflammation and oxidative stress. Simultaneously, we also found that WA-25 reduces the AD scores and AD-induced transepidermal water loss (TEWL), scratching behavior, and alloknesis. WA-25 is more effective in cases of AD than are the drugs that are currently used clinically. Importantly, we also found that when nucleophosmin (NPM) was inhibited or when its expression was reduced, the anti-inflammatory and anti-AD effects of WA-25 were blocked. These data suggest that NPM plays dual roles in inflammation and AD. Overall, these results suggest that WA-25 is a potential anti-inflammatory and AD therapeutic agent that is modulated by NPM.


Assuntos
Organismos Aquáticos , Produtos Biológicos/farmacologia , Butanonas/farmacologia , Dermatite Atópica/metabolismo , Proteínas Nucleares/metabolismo , Sulfonas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/química , Butanonas/química , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/química
17.
J Nutr Biochem ; 56: 116-125, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29525531

RESUMO

Promoting white adipose tissue (WAT) to acquire brown-like characteristics is a promising approach for obesity treatment. Although raspberry ketone (RK) has been reported to possess antiobesity activity, its effects on the formation of brown-like adipocytes remain unclear. Therefore, we investigated the effects and underlying mechanism of RK on WAT browning in 3T3-L1 adipocytes and rats with ovariectomy (Ovx)-induced obesity. RK (100 µM) significantly induced browning of 3T3-L1 cells by increasing mitochondrial biogenesis and the expression of browning-specific proteins (PR domain containing 16, PRDM16; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α; uncoupling protein-1, UCP-1) and lipolytic enzymes (hormone-sensitive lipase and adipose triglyceride lipase). RK significantly reduced the expression of the autophagy-related protein Atg12 and increased the expression of p62 and heme oxygenase 1 (HO-1). Additionally, these effects of RK were reversed by the HO-1 inhibitor SnPP (20 µM). In addition, RK (160 mg/kg, gavage, for 8 weeks) significantly reduced body weight gain (Ovx+RK, 191.8 ± 4.6 g vs. Ovx, 223.6 ± 5.9; P < .05), food intake, the amount of inguinal adipose tissue (Ovx+RK, 9.05 ± 1.1 g vs Ovx, 12.9 ± 0.92 g; P < .05) and the size of white adipocytes in Ovx rats. Moreover, compared to expression in the Ovx group, the levels of browning-specific proteins were significantly higher and the levels of autophagy-related proteins were significantly lower in the Ovx+RK group. Therefore, this study elucidated the mechanism associated with RK-induced WAT browning and thus provides evidence to support the clinical use of RK for obesity treatment.


Assuntos
Adipócitos/citologia , Tecido Adiposo Marrom/citologia , Autofagia/efeitos dos fármacos , Butanonas/farmacologia , Células 3T3-L1 , Animais , Proteína 12 Relacionada à Autofagia/metabolismo , Peso Corporal , Sobrevivência Celular , Feminino , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Metabolismo dos Lipídeos , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/metabolismo
18.
Int J Biol Macromol ; 113: 212-218, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29477543

RESUMO

Inhibition of α-glucosidase is directly associated with treatment of type 2 diabetes. In this regard, we conducted enzyme kinetics integrated with computational docking simulation to assess the inhibitory effect of raspberry ketone (RK) on α-glucosidase. RK bound to the active site of α-glucosidase and interacted with several key residues such as ASP68, TYR71, HIS111, PHE157, PHE158, PHE177, GLN181, ASP214, THR215, ASP349, ASP408, and ARG439, as detected by protein-ligand docking simulation. Subsequently, we confirmed the action of RK on α-glucosidase as the non-competitive type of inhibition in a reversible and rapidly binding manner. The relevant kinetic parameters were IC50=6.17±0.46mM and Ki=7.939±0.211mM. Regarding the structure-activity relationship, the higher concentration of RK induced slight modulation of the shape of the active site as monitored by hydrophobic exposure. The tertiary conformational change was linked to RK inhibition, and mostly involved regional changes of the active site. Our study provides insight into the functional role of RK due to its structural property of a hydroxyphenyl ring that interacts with the active site of α-glucosidase. We suggest that similar hydroxyphenyl ring compounds targeting the key residues of the active site might be potential α-glucosidase inhibitors.


Assuntos
Butanonas/metabolismo , Butanonas/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Cinética , Conformação Proteica , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/química
19.
Stem Cell Res Ther ; 8(1): 245, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096702

RESUMO

BACKGROUND: Because the lack of an induced pluripotent stem cell (iPSC) induction system with optimal safety and efficiency limits the application of these cells, development of such a system is important. METHODS: To create such an induction system, we screened a variety of reprogrammed plasmid combinations and multiple compounds and then verified the system's feasibility using urine cells from different individuals. We also compared large-scale iPSC chromosomal variations and expression of genes associated with genomic stability between this system and the traditional episomal system using karyotype and quantitative reverse transcription polymerase chain reaction analyses. RESULTS: We developed a high-efficiency episomal system, the 6F/BM1-4C system, lacking tumorigenic factors for human urine-derived cell (hUC) reprogramming. This system includes six low-risk factors (6F), Oct4, Glis1, Klf4, Sox2, L-Myc, and the miR-302 cluster. Transfected hUCs were treated with four compounds (4C), inhibitor of lysine-demethylase1, methyl ethyl ketone, glycogen synthase kinase 3 beta, and histone deacetylase, within a short time period. Comparative analysis revealed significantly decreased chromosomal variation in iPSCs and significantly increased Sirt1 expression compared with iPSCs induced using the traditional episomal system. CONCLUSION: The 6F/BM1-4C system effectively induces reprogramming of urine cells in samples obtained from different individuals. iPSCs induced using the 6F/BM1-4C system are more stable at the cytogenetic level and have potential value for clinical application.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/metabolismo , Plasmídeos/metabolismo , Urina/citologia , Adulto , Butanonas/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Expressão Gênica , Glicogênio Sintase Quinase 3 beta/farmacologia , Histona Desacetilases/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Plasmídeos/química , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Risco , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção
20.
PLoS One ; 12(8): e0184086, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28859132

RESUMO

Tephritid fruit flies are amongst the most damaging insect pests of horticulture globally. Some of the key fruit fly species are managed using the sterile insect technique (SIT), whereby millions of sterile males are released to suppress reproduction of pest populations. Male annihilation technique (MAT), whereby sex specific lures are used to attract and kill males, is often used to reduce wild male numbers before SIT programs commence, providing released sterile males an increased numerical advantage. Overall program efficacy might be improved if MAT could be deployed simultaneously with SIT, continuously depleting fertile males from pest populations and replacing them with sterile males. However, such 'male replacement' requires a means of suppressing attraction of released sterile males to lures used in MAT. Previous studies have found that exposure of some fruit flies to lure compounds as mature adults can suppress subsequent response to those lures, raising the possibility of pre-release treatments. However, this approach requires holding flies until after maturation for treatment and then release. The present study takes a novel approach of exposing immature adult male Queensland fruit flies (Bactrocera tryoni, or 'Qfly') to raspberry ketone (RK) mixed in food, forcing these flies to ingest RK at ages far younger than they would naturally. After feeding on RK-supplemented food for two days after emergence, male Qflies exhibited a reduction in attraction to cuelure traps that lasted more than 20 days. This approach to RK exposure is compatible with current practises, in which Qflies are released as immature adults, and also yields advantages of accelerated reproductive development and increased mating propensity at young ages.


Assuntos
Butanonas/farmacologia , Controle Biológico de Vetores , Reprodução/genética , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Suplementos Nutricionais , Feminino , Infertilidade Masculina/genética , Controle de Insetos , Masculino , Feromônios/farmacologia , Reprodução/efeitos dos fármacos , Tephritidae/genética , Tephritidae/crescimento & desenvolvimento , Tephritidae/patogenicidade
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