RESUMEN
Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor ß1 (TGFß1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl4) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)2D3, did not cause hypercalcemia that is toxic to nerve, heart, and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.
Asunto(s)
Diseño de Fármacos , Cirrosis Hepática/tratamiento farmacológico , Pentanos/síntesis química , Pentanos/farmacología , Pirroles/química , Receptores de Calcitriol/agonistas , Animales , Línea Celular , Técnicas de Química Sintética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Pentanos/química , Pentanos/uso terapéutico , Conformación Proteica , Receptores de Calcitriol/químicaRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-ß (Aß) deposition and neurofibrillary tangles. Dl-PHPB [potassium 2-(1-hydroxypentyl)-benzoate], has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia, and Aß-induced animal models by inhibiting oxidative injury, neuronal apoptosis, and glial activation. The aim of the present study was to examine the effect of dl-PHPB on learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic AD mouse models (APP/PS1) and the mechanisms of dl-PHPB in reducing Aß accumulation and τ phosphorylation. Twelve-month-old APP/PS1 mice were given 30 mg/kg dl-PHPB by oral gavage for 3 months. Dl-PHPB treatment significantly improved the spatial learning and memory deficits compared with the vehicle-treated APP/PS1 mice. In the meantime, dl-PHPB obviously reduced τ hyperphosphorylation at Ser199, Thr205, and Ser396 sites in APP/PS1 mice. This reduction was accompanied by APP phosphorylation reduction and protein kinase C activation. In addition, expression of cyclin-dependent kinase and glycogen synthase kinase 3ß, the most important kinases involved in τ phosphorylation, was markedly decreased by dl-PHPB treatment. Phosphorylated protein kinase B and phosphoinositide 3-kinase levels of APP/PS1 mice were significantly reduced compared with levels in wild-type mice, and dl-PHPB reversed the reduction. The effects of dl-PHPB effecting a decrease in τ phosphorylation and kinase activation were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. These data raised the possibility that dl-PHPB might be a promising multitarget neuronal protective agent for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Benzoatos/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Pentanos/uso terapéutico , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Animales , Células Cultivadas , Quinasa 5 Dependiente de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Ratones , Neuroglía/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/fisiología , Fosforilación , Proteína Quinasa C/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiologíaRESUMEN
Daucus carota (DC) is a herb used in folklore medicine in Lebanon to treat numerous diseases including cancer. Recent studies in our laboratory on DC oil and its fractions revealed potent anticancer activities in vitro and in vivo. The present study aims to investigate the effect of the most potent DC fraction, pentane/diethyl ether (50:50), on lung, skin, breast and glioblastoma cancer cell motility and invasion. Upon treatment, a pronounced decrease in cancer cell motility was observed in the 4 cell lines. The treatment also led to a decrease in cancer cell invasion and an increased cell adhesion. Additionally, the DC fraction caused a decrease in the activation of the ρ-GTPases Rac and CDC42, a finding that may partially explain the treatment-induced decrease in cell motility. The current study demonstrates a crucial effect of the DC pentane/diethyl ether fraction on cancer cell motility and metastasis, making it a potential candidate for cancer therapy specifically targeting cancer motility and metastasis.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Daucus carota , Éter/uso terapéutico , Invasividad Neoplásica/prevención & control , Pentanos/uso terapéutico , Extractos Vegetales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Éter/aislamiento & purificación , Éter/farmacología , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Melanoma Experimental , Invasividad Neoplásica/patología , Pentanos/aislamiento & purificación , Pentanos/farmacología , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Aceites de Plantas/aislamiento & purificación , Aceites de Plantas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and ß- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.
Asunto(s)
Antineoplásicos/uso terapéutico , Butadienos/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Dieta , Hemiterpenos/uso terapéutico , Neoplasias Hepáticas/prevención & control , Terapia Molecular Dirigida , Pentanos/uso terapéutico , Animales , Butadienos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Hemiterpenos/química , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Pentanos/químicaRESUMEN
PURPOSE: To compare the effects of a new gel-to-foam dentifrice to two standard fluoride control dentifrices on foam generation, levels of total viable anaerobes and total viable volatile sulfur compound (VSC)-producing bacteria in expectorate after brushing. METHODS: 36 subjects participated in this investigator-blind, randomized, crossover study. After a 1-week wash-out period prior to each product use, participants reported to the test site having refrained from oral hygiene, eating and drinking on the morning prior to the visit. Subjects brushed with a full ribbon of assigned dentifrice (Aquafresh Iso-active, Aquafresh Extreme Clean or Aquafresh Fresh & Minty), then expectorated the slurry into a collection vessel after 30 and 60 seconds of supervised brushing. Total foam volume was immediately measured. Subjects then rinsed with sterile water for 10 seconds and expectorated into the same vessel, which was processed for microbiological analysis. Total viable anaerobes and total viable VSC-producing bacteria were enumerated using appropriate selective media. RESULTS: No statistically significant difference was indicated between the gel-to-foam dentifrice and either of the control dentifrices with respect to the level of total viable anaerobes (P > 0.05). The level of total viable VSC-producing bacteria was statistically significantly lower for the gel-to-foam dentifrice (Aquafresh Iso-active) than for one of the control dentifrices (Aquafresh Fresh & Minty) (P < 0.05), and numerically lower for the gel-to-foam dentifrice than for the other control dentifrice (Aquafresh Extreme Clean) (P = 0.0526). Use of the gel-to-foam dentifrice resulted in statistically significantly greater (P < 0.05) foam generation than the two control dentifrices.
Asunto(s)
Bacterias/efectos de los fármacos , Cariostáticos/uso terapéutico , Dentífricos/uso terapéutico , Fluoruros/uso terapéutico , Saliva/microbiología , Cepillado Dental/métodos , Adolescente , Adulto , Anciano , Bacterias Anaerobias/efectos de los fármacos , Recuento de Colonia Microbiana , Estudios Cruzados , Dentífricos/administración & dosificación , Detergentes/administración & dosificación , Detergentes/uso terapéutico , Formas de Dosificación , Geles , Humanos , Persona de Mediana Edad , Pentanos/administración & dosificación , Pentanos/uso terapéutico , Método Simple Ciego , Dodecil Sulfato de Sodio/administración & dosificación , Dodecil Sulfato de Sodio/uso terapéutico , Compuestos de Azufre/análisis , Adulto JovenRESUMEN
2-(1-Hydroxypentyl)-benzoate (dl-PHPB), a derivate of 3-n-butylphthalide (dl-NBP), is a novel drug candidate used for treatment of cerebral ischemia. The goal of the present study was to investigate the effects of dl-PHPB on infarct volume, neurological function, and cerebral blood flow (CBF) in transient focal cerebral ischemia. Therefore, an animal model of 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion was used. Rats received dl-PHPB (1.3, 3.9, or 12.9 mg/kg) intravenously 10 min after the onset of MCAO. Compared with the vehicle control group (37.4%), infarct volume in dl-PHPB-treated groups was reduced significantly and dose-dependently to 25.4, 17.4, and 13.7%, respectively. The changes in neurological deficient were also observed in neurobehavioral test in a dose-dependent manner, and the neuronal score was improved significantly from the vehicle control of 3.2 to 2.7, 2.1, and 1.8, respectively. At the highest dose, the potency of dl-PHPB was similar to those of dl-NBP. CBF was quantified by using laser-Doppler flowmetry. During the ischemia, the regional CBF values of dl-PHPB groups were significantly higher than that of vehicle group. In addition, our study showed that dl-PHPB converted into dl-NBP very quickly in blood in vitro. Approximately 70% of dl-PHPB converted into dl-NBP in 5 min when dl-PHPB was added into plasma at final concentrations of 6, 30, and 60 mug/ml. This result demonstrated that the neuronal protection effects of dl-PHPB were mainly induced by dl-NBP, an active compound converted from its precursor, dl-PHPB. In conclusion, dl-PHPB can reduce infarct volume and improve neurobehavioral deficits in a rat model of transient MCAO. Those effects may partially be due to an increase in CBF by the active metabolite (dl-NBP) of dl-PHPB. Therefore, our results suggest that dl-PHPB may be useful for treatment of ischemia stroke.
Asunto(s)
Benzoatos/uso terapéutico , Benzofuranos/uso terapéutico , Circulación Cerebrovascular/efectos de los fármacos , Infarto de la Arteria Cerebral Media/prevención & control , Ataque Isquémico Transitorio , Fármacos Neuroprotectores/uso terapéutico , Pentanos/uso terapéutico , Profármacos/uso terapéutico , Animales , Benzoatos/administración & dosificación , Benzoatos/farmacología , Benzofuranos/administración & dosificación , Benzofuranos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Infarto de la Arteria Cerebral Media/etiología , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/fisiopatología , Flujometría por Láser-Doppler , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Pentanos/administración & dosificación , Pentanos/farmacología , Profármacos/administración & dosificación , Profármacos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.