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1.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
2.
Biofouling ; 37(7): 791-807, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34455871

RESUMO

Antibacterial screenings are most commonly targeted at planktonic bacteria but less effort is dedicated to the exploration of agents acting on biofilms. Here, a natural compounds library was screened against Staphylococcus aureus using a 384-well plate platform to identify compounds preventing biofilm formation. Five structurally diverse hits were selected for follow-up studies: honokiol, tschimganidin, ferutinin, oridonin and deoxyshikonin. The compounds were evaluated against different bacterial species for their capacity to prevent and disrupt biofilms. The development of resistance and cytotoxicity were also investigated. Ferutinin displayed the best antibacterial activity, with a minimum inhibitory, bactericidal and biofilm preventive concentration of 25 µM against S. aureus. It efficiently disrupted pre-formed biofilms (over 5-log reduction of viable cells) and reduced biofilm formation on a catheter in the presence of neutrophils. This work provides new information on the antibacterial activity of five natural compounds and identified ferutinin as a promising candidate against S. aureus biofilms.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacologia , Benzoatos , Biofilmes , Compostos Bicíclicos com Pontes , Cicloeptanos , Humanos , Testes de Sensibilidade Microbiana , Sesquiterpenos
3.
Molecules ; 26(11)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071603

RESUMO

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-ß-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.


Assuntos
Oligopeptídeos/genética , Peptídeos Opioides/química , Receptores Opioides mu/metabolismo , Dor Aguda/tratamento farmacológico , Analgésicos , Animais , Comportamento Animal , Células CHO , Cricetinae , Cricetulus , Cicloeptanos/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Morfina/química , Morfina/farmacologia , Movimento/efeitos dos fármacos , Naloxona/farmacologia , Naltrexona/farmacologia , Manejo da Dor , Piperidinas/farmacologia
4.
Cochrane Database Syst Rev ; 5: CD009289, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34033120

RESUMO

BACKGROUND: Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used. OBJECTIVES: To evaluate the benefits and harms of topical azole treatments for otomycosis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow-up of two weeks was required. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution). A. Topical azoles versus placebo None of the studies assessed this comparison. B. Topical azoles versus no treatment None of the studies assessed this comparison. C. One type of topical azole versus another type of topical azole i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole) Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low-certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles. One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low-certainty evidence). Clotrimazole may result in little or no difference in mycological resolution at two weeks follow-up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low-certainty evidence) or in other (less serious) adverse events at two weeks follow-up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low-certainty evidence). ii) Bifonazole cream versus bifonazole solution One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow-up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low-certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low-certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low-certainty evidence). AUTHORS' CONCLUSIONS: We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non-serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.


Assuntos
Antifúngicos/administração & dosagem , Otomicose/tratamento farmacológico , Administração Tópica , Adulto , Antifúngicos/efeitos adversos , Viés , Criança , Clotrimazol/administração & dosagem , Clotrimazol/efeitos adversos , Cicloeptanos/administração & dosagem , Cicloeptanos/efeitos adversos , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Miconazol/administração & dosagem , Miconazol/efeitos adversos , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
5.
J Biochem Mol Toxicol ; 35(4): e22713, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33501774

RESUMO

This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Benzoatos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cicloeptanos/farmacologia , Ferula/química , Fitoestrógenos/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Benzoatos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cicloeptanos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fitoestrógenos/química , Sesquiterpenos/química
6.
Molecules ; 25(23)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297504

RESUMO

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Benzoatos/farmacologia , Cicloeptanos/farmacologia , Ferula/química , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Benzoatos/química , Benzoatos/uso terapêutico , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Cicloeptanos/química , Cicloeptanos/uso terapêutico , Relação Dose-Resposta a Droga , Transporte de Elétrons/efeitos dos fármacos , Terapia de Reposição Hormonal , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Fitoestrógenos/química , Fitoestrógenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico
7.
Psychopharmacology (Berl) ; 237(10): 2943-2958, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32588078

RESUMO

RATIONALE: Evaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD. OBJECTIVES: First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2). METHODS: Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0-20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0-3 mg/kg, i.p.) prior to fear memory expression tests. RESULTS: J-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure. CONCLUSIONS: NOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders.


Assuntos
Benzimidazóis/administração & dosagem , Cicloeptanos/administração & dosagem , Medo/psicologia , Peptídeos Opioides/antagonistas & inibidores , Piperidinas/administração & dosagem , Receptores Opioides , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Peptídeos Opioides/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia
8.
Org Lett ; 22(11): 4500-4504, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437158

RESUMO

Transient strained cyclic intermediates have become valuable intermediates in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates are most often employed, the instability of some silyl triflates warrants the development of alternative precursors. We report the syntheses of silyl tosylate precursors to cyclohexyne, 1,2-cyclohexadiene, and 1,2-cycloheptadiene. The resultant strained intermediates undergo trapping in situ to give cycloaddition products. Additionally, the results of competition experiments between silyl triflates and silyl tosylates are reported.


Assuntos
Cicloeptanos/síntese química , Cicloexenos/síntese química , Silanos/química , Compostos de Tosil/química , Reação de Cicloadição , Cicloeptanos/química , Cicloexenos/química , Estrutura Molecular , Estereoisomerismo
9.
Bioorg Chem ; 98: 103750, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32182520

RESUMO

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.


Assuntos
Aminopeptidases/antagonistas & inibidores , Anisóis/farmacologia , Antimaláricos/farmacologia , Cicloeptanos/farmacologia , Inibidores Enzimáticos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Aminopeptidases/metabolismo , Anisóis/síntese química , Anisóis/química , Antimaláricos/síntese química , Antimaláricos/química , Cicloeptanos/síntese química , Cicloeptanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/enzimologia , Relação Estrutura-Atividade
10.
Psychopharmacology (Berl) ; 237(6): 1633-1642, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32095915

RESUMO

RATIONALE: Depression and anxiety frequently co-occur, and this has important clinical implications. Previous studies showed that activation of the nociceptin/orphanin FQ receptor (NOP) elicits anxiolytic effects, while its blockade promotes consistent antidepressant actions. NOP antagonists are effective in reversing footshock-induced depressive-like behaviors, but their effects on stress-induced anxiety are still unclear. OBJECTIVE: This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors. METHODS: Male Swiss mice were exposed to inescapable electric footshock stress, and behavioral phenotype was screened based on the ability to escape from footshock (i.e., helpless or non-helpless). Animals were then treated with diazepam (1 mg/kg) and SB-612111 (0.1-10 mg/kg), and their behavior was assessed in the elevated plus-maze (EPM) and open field test. RESULTS: When compared with non-stressed mice, helpless, but not non-helpless, animals displayed significant reductions in the time spent in and entries into open arms in the EPM. Diazepam significantly increased open arms exploration in helpless, non-helpless, and non-stressed mice. However, treatment with the NOP antagonist SB-612111 was inactive in naive mice, while it reversed anxiogenic-related behaviors in helpless mice and increased anxiety states in non-helpless mice. No effects on locomotion were observed. CONCLUSION: Helpless mice displayed increased anxiety compared to non-stressed and non-helpless animals, thus supporting use of this approach as an animal model to investigate anxiety/depression comorbidity. Additionally, SB-612111 modulated anxiety-like behaviors in male mice depending on individual stress susceptibility. Ultimately, NOP antagonists could be useful for treating anxiety in depressed patients.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Cicloeptanos/uso terapêutico , Piperidinas/uso terapêutico , Receptores Opioides/fisiologia , Estresse Psicológico/tratamento farmacológico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/psicologia , Depressão/tratamento farmacológico , Depressão/psicologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Masculino , Camundongos , Estresse Psicológico/psicologia
11.
Cell Calcium ; 86: 102127, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954928

RESUMO

Mitochondrial free calcium is critically linked to the regulation of cellular metabolism. Free ionic calcium concentration within these organelles is determined by the interplay between two processes: exchange across the mitochondrial inner membrane and calcium-buffering within the matrix. During stimulated calcium uptake, calcium is primarily buffered by orthophosphate, preventing calcium toxicity while allowing for well-regulated yet elevated calcium loads. However, if limited to orthophosphates only, this buffering system is expected to lead to the irreversible formation of insoluble precipitates, which are not observed in living cells, under physiological conditions. Here, we demonstrate that the regulation of free mitochondrial calcium requires the presence of free inorganic polyphosphate (polyP) within the organelle. We found that the overexpression of a mitochondrial-targeted enzyme hydrolyzing polyP leads to the loss of the cellular ability to maintain elevated calcium concentrations within the organelle, following stimulated cytoplasmic signal. We hypothesize that the presence of polyP prevents the formation of calcium-phosphate insoluble clusters, allowing for the maintenance of elevated free calcium levels, during stimulated calcium uptake.


Assuntos
Cálcio/metabolismo , Mitocôndrias/metabolismo , Polifosfatos/farmacologia , Trifosfato de Adenosina/farmacologia , Benzoatos/metabolismo , Compostos Bicíclicos com Pontes/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cicloeptanos/metabolismo , Células HEK293 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Rutênio Vermelho/metabolismo , Sesquiterpenos/metabolismo
12.
Biochim Biophys Acta Mol Basis Dis ; 1866(4): 165314, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30412793

RESUMO

Osteoporosis is a silent systemic disease that causes bone deterioration, and affects over 10 million people in the US alone. This study was undertaken to develop a potential stem cell therapy for osteoporosis. We have isolated and expanded human dental pulp-derived stem cells (DPSCs), characterized them, and confirmed their multipotential differentiation abilities. Stem cells often remain quiescent and require activation to differentiate and function. Herein, we show that ferutinin activates DPSCs by modulating the Wnt/ß-catenin signaling pathway and key osteoblast-secreted proteins osteocalcin and collagen 1A1 both mRNA and protein levels. To confirm that ferutinin modulates the Wnt pathway, we inhibited glycogen synthase kinase 3 (GSK3) and found that protein expression patterns were similar to those found in ferutinin-treated DPSCs. To evaluate the role of ferutinin in epigenetic regulation of canonical Wnt signaling, the pathway molecules Wnt3a and Dvl3 were analyzed using chromatin immunoprecipitation (ChIP)-quantitative PCR approaches. We confirmed that active marks of both H3K9 acetylation and H3K4 trimethylation were significantly enhanced in the promoter sites of the WNT3A and DVL3 genes in DPSCs after addition of ferutinin. These data provide evidence that ferutinin activates and promotes osteogenic differentiation of DPSCs, and could be used as an inducer as a potentially effective stem cell therapy for osteoporosis.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Polpa Dentária/metabolismo , Epigênese Genética/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células-Tronco/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Compostos Bicíclicos com Pontes/farmacologia , Polpa Dentária/citologia , Humanos , Células-Tronco/citologia
13.
Curr Drug Targets ; 21(5): 499-508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31663476

RESUMO

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as "shilsh Elzallouh". It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant's extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Ferula/química , Fitoestrógenos/farmacologia , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Animais , Benzoatos/química , Benzoatos/uso terapêutico , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Cicloeptanos/química , Cicloeptanos/uso terapêutico , Ésteres/química , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Fitoestrógenos/química , Fitoestrógenos/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico
14.
Addict Biol ; 25(6): e12844, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31709687

RESUMO

Developing new medications for the treatment of cocaine dependence continues to be a research priority. Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT-312 (0, 1, 3 mg/kg) could reduce operant cocaine self-administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1-hour), as well as long (6-hour) access sessions. When tested on an economic-demand reinforcement schedule, AT-312 reduced Q0 , the parameter that describes the amount of drug consumed at zero price, while leaving the parameter α, a measure of motivation for drug consumption, unaltered. Furthermore, AT-312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self-administration. Blockade of the NOP receptor with the antagonist SB-612111 prevented the effect of AT-312 in decreasing cocaine-reinforced responding under a 2-hour fixed ratio 1 schedule, suggesting a NOP receptor-mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Receptores Opioides/agonistas , Animais , Buprenorfina , Cicloeptanos/metabolismo , Indóis/metabolismo , Masculino , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Autoadministração
15.
Alcohol Clin Exp Res ; 43(10): 2167-2178, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31386211

RESUMO

BACKGROUND: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. METHODS: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice. RESULTS: We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. CONCLUSIONS: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.


Assuntos
Dissuasores de Álcool/uso terapêutico , Consumo de Bebidas Alcoólicas/prevenção & controle , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Consumo Excessivo de Bebidas Alcoólicas/genética , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Depressores do Sistema Nervoso Central/sangue , Cicloeptanos/farmacologia , Escuridão , Relação Dose-Resposta a Droga , Etanol/sangue , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Receptores Opioides/agonistas , Receptores Opioides/genética
16.
J Am Chem Soc ; 141(33): 13038-13042, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31389237

RESUMO

A rhodium-catalyzed direct insertion of ethylene into a relatively unstrained carbon-carbon bond in 1-indanones is reported, which provides a two-carbon ring expansion strategy for preparing seven-membered cyclic ketones. As many 1-indanones are commercially available and ethylene is inexpensive, this strategy simplifies synthesis of benzocycloheptenones that are valuable synthetic intermediates for bioactive compounds but challenging to prepare otherwise. In addition, the reaction is byproduct-free, redox neutral, and tolerant of a wide range of functional groups, which may have implications on unconventional strategic bond disconnections for preparing complex cyclic molecules.


Assuntos
Benzocicloeptenos/síntese química , Etilenos/química , Indanos/química , Benzocicloeptenos/química , Carbono/química , Catálise , Cicloeptanos/síntese química , Cicloeptanos/química , Etilenos/síntese química , Indanos/síntese química , Ródio/química
17.
J Psychopharmacol ; 33(12): 1540-1549, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31337258

RESUMO

BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.


Assuntos
Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Resiliência Psicológica/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Cicloeptanos/administração & dosagem , Cicloeptanos/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Nortriptilina/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/genética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologia , Estresse Psicológico/fisiopatologia
18.
J Med Chem ; 62(15): 6972-6984, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283227

RESUMO

4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).


Assuntos
Compostos Bicíclicos com Pontes/química , Cicloeptanos/química , Morfolinas/química , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Compostos Bicíclicos com Pontes/farmacologia , Cicloeptanos/farmacologia , Descoberta de Drogas/métodos , Humanos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo
19.
J Pharm Biomed Anal ; 172: 120-125, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31035093

RESUMO

Ferula ovina (Boiss.) Boiss is one of the most important endemic medicinal plants in Iran, which has three main terpenoid compounds including ferutinin, stylosin and tschimgine. Ferutinin is the strongest natural phytoestrogen that has agonistic activity on estrogen receptors, particularly α-receptors. To determine the amount of ferutinin in F. ovina roots, we firstly used HPLC-UV method. In the HPLC method, the resolution of ferutinin from the two other compounds, stylosin and tshimgine, was poor. Therefore, we decided to use qHNMR method for simultaneous quantification of ferutinin, stylosin and tshimgine in the plant roots. Quantitative 1H-NMR (qHNMR) was carried out based on the relative ratio of signal integration of each compound [(H-1 for tschimgine (δH 4.94-5.03), OCH3 for stylosin (δH 3.8), and H-9 for ferutinin (δH 5.58)] to certain amount of the internal standard dimethyl sulfone (DMSO2). The qHNMR method showed good precision (intra-day RSD ≤ 2.31%, inter-day RSD ≤ 2.72%), linearity (in the ranges of 1.3-10.41, 1.2-9.7 and 1.1-9.02 mg/mL with correlation coefficients at 0.9991), repeatability (RSD ≤ 2.99%) and stability (RSD ≤ 2.4%) for the quantification of the compounds. This work confirmed that qHNMR represents a feasible alternative to high-performance liquid chromatography based methods for simultaneous quantification of ingredients in plant extracts.


Assuntos
Ferula/química , Extratos Vegetais/química , Espectroscopia de Prótons por Ressonância Magnética/métodos , Benzoatos/análise , Compostos Bicíclicos com Pontes/análise , Cicloeptanos/análise , Composição de Medicamentos/normas , Estudos de Viabilidade , Hidroxibenzoatos/análise , Monoterpenos/análise , Extratos Vegetais/normas , Raízes de Plantas/química , Controle de Qualidade , Sesquiterpenos/análise
20.
Int J Mol Sci ; 20(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917511

RESUMO

There is an urgent need to develop novel drugs for osteoporosis which occurs due to estrogen deficiency. Phytoestrogens derived from medicinal plants would be the best alternative to chemical drugs with harmful side effects. The main purpose of the present study was to investigate the effect of ferutinin compared to 17ß-estradiol (E2) on bone mineralization of zebrafish larvae. Regarding the lack of publications, the histology analysis was performed after exposure to E2 to find effective treatment on bone mineralization of developing zebrafish larvae. Then, the larvae were exposed to four concentrations of ferutinin at three time points to assess the mortality, the expression of some related genes and histology of the ceratohyal and hyomandibular of treated larvae. The RT-PCR result of the treatment groups demonstrated the similar expression pattern in the larvae which were exposed to 1.25 µg/mL of ferutinin and 2 µM of E2 at 2 dpf, which confirmed the result of histology analysis. In addition, RT-qPCR of high concentration of ferutinin and E2 demonstrated that bmp2a/b and esr1 were downregulated and upregulated when the larvae were exposed to 5 µg/mL of ferutinin and 10 µM of E2, respectively.


Assuntos
Benzoatos/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Cicloeptanos/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Sesquiterpenos/farmacologia , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Compostos Bicíclicos com Pontes/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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