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1.
Hum Gene Ther ; 31(1-2): 70-79, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650869

RESUMO

Cocaine addiction continues to impose major burdens on affected individuals and broader society but is highly resistant to medical treatment or psychotherapy. This study was undertaken with the goal of Food and Drug Administration (FDA) permission for a first-in-human clinical trial of a gene therapy for treatment-seeking cocaine users to become and remain abstinent. The approach was based on intravenous administration of AAV8-hCocH, an adeno-associated viral vector encoding a modified plasma enzyme that metabolizes cocaine into harmless by-products. To assess systemic safety, we conducted "Good Laboratory Practice" (GLP) studies in cocaine-experienced and cocaine-naive mice at doses of 5E12 and 5E13 vector genomes/kg. Results showed total lack of viral vector-related adverse effects in all tests performed. Instead, mice given one injection of AAV8-hCocH and regular daily injections of cocaine had far less tissue pathology than cocaine-injected mice with no vector treatment. Biodistribution analysis showed the vector located almost exclusively in the liver. These results indicate that a liver-directed AAV8-hCocH gene transfer at reasonable dosage is safe, well tolerated, and effective. Thus, gene transfer therapy emerges as a radically new approach to treat compulsive cocaine abuse. In fact, based on these positive findings, the FDA recently accepted our latest request for investigational new drug application (IND 18579).

2.
Int J Nanomedicine ; 13: 5887-5907, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319255

RESUMO

Background: Bruceine D (BD) is a major bioactive component isolated from the traditional Chinese medicinal plant Brucea javanica which has been widely utilized to treat dysentery (also known as ulcerative colitis [UC]). Methods: To improve the water solubility and absolute bioavailability of BD, we developed a self-nanoemulsifying drug delivery system (SNEDDS) composing of MCT (oil), Solutol HS-15 (surfactant), propylene glycol (co-surfactant) and BD. The physicochemical properties and pharmacokinetics of BD-SNEDDS were characterized, and its anti-UC activity and potential mechanism were evaluated in TNBS-induced UC rat model. Results: The prepared nanoemulsion has multiple beneficial aspects including small mean droplet size, low polydispersity index (PDI), high zeta potential (ZP) and excellent stability. Transmission electron microscopy showed that nanoemulsion droplets contained uniform shape and size of globules. Pharmacokinetic studies demonstrated that BD-SNEDDS exhibited enhanced pharmacokinetic parameters as compared with BD-suspension. Moreover, BD-SNEDDS significantly restored the colon length and body weight, reduced disease activity index (DAI) and colon pathology, decreased histological scores, diminished oxidative stress, and suppressed TLR4, MyD88, TRAF6, NF-κB p65 protein expressions in TNBS-induced UC rat model. Conclusion: These results demonstrated that BD-SNEDDS exhibited highly improved oral bioavailability and advanced anti-UC efficacy. In conclusion, our current results provided a foundation for further research of BD-SNEDDS as a potential complementary therapeutic agent for UC treatment.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Quassinas/uso terapêutico , Animais , Disponibilidade Biológica , Colite Ulcerativa/patologia , Liberação Controlada de Fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Nanopartículas/química , Nanopartículas/ultraestrutura , Óleos/química , Tamanho da Partícula , Transição de Fase , Quassinas/química , Quassinas/farmacocinética , Quassinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Solubilidade
4.
Aging Cell ; 17(1)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29168299

RESUMO

Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age-related disease. We previously reported that 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α-E2 acts through pro-opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α-E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently.


Assuntos
Estradiol/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Pró-Opiomelanocortina/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Comportamento Animal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/metabolismo , Leptina/metabolismo , Camundongos Transgênicos , Neurônios/metabolismo , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo
5.
Proc Natl Acad Sci U S A ; 114(41): 10960-10965, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28973869

RESUMO

The worldwide prevalence of obesity is increasing at an alarming rate but treatment options remain limited. Despite initial success, weight loss by calorie restriction (CR) often fails because of rebound weight gain. Postdieting hyperphagia along with altered hypothalamic neuro-architecture appears to be one direct cause of this undesirable outcome. In response to calorie deficiency the circulating levels of the appetite-promoting hormone, acyl-ghrelin, rise sharply. We hypothesize that proper modulation of acyl-ghrelin and its receptor's sensitivity will favorably impact energy intake and reprogram the body weight set point. Here we applied viral gene transfer of the acyl-ghrelin hydrolyzing enzyme, butyrylcholinesterase (BChE), in a mouse model of diet-induced obesity. Our results confirmed that BChE overexpression decreased circulating acyl-ghrelin levels, suppressed CR-provoked ghrelin signaling, and restored central ghrelin sensitivity. In addition to maintaining healthy body weights, BChE treated mice had modest postdieting food intake and showed normal glucose homeostasis. Spontaneous activity and energy expenditure did not differ significantly between treated and untreated mice after body weight rebound, suggesting that BChE gene transfer did not alter energy expenditure in the long term. These findings indicate that combining BChE treatment with CR could be an effective approach in treating human obesity and aiding lifelong weight management.


Assuntos
Butirilcolinesterase/metabolismo , Restrição Calórica , Grelina/antagonistas & inibidores , Hiperfagia/prevenção & controle , Obesidade/prevenção & controle , Animais , Apetite , Peso Corporal , Ingestão de Alimentos , Grelina/metabolismo , Hiperfagia/metabolismo , Hiperfagia/patologia , Masculino , Camundongos , Camundongos Obesos , Obesidade/metabolismo , Obesidade/patologia , Transdução de Sinais , Ganho de Peso , Perda de Peso
6.
Molecules ; 22(7)2017 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-28698452

RESUMO

Recent research shows that butyrylcholinesterase (BChE) is not simply a liver enzyme that detoxifies bioactive esters in food and medications. In fact, in pursuing other goals, we recently found that it has an equally important role in regulating the peptide hormone ghrelin and its impact on hunger, obesity, and emotions. Here, we present and examine means of manipulating brain BChE levels by viral gene transfer, either regionally or globally, to modulate ghrelin signaling for long-term therapeutic purposes and to set the stage for exploring the neurophysiological impact of such an intervention.


Assuntos
Butirilcolinesterase/genética , Técnicas de Transferência de Genes , Grelina/genética , Obesidade/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Butirilcolinesterase/uso terapêutico , Emoções/fisiologia , Terapia Genética , Vetores Genéticos , Humanos , Camundongos , Obesidade/patologia , Obesidade/terapia
7.
Endocrinology ; 157(8): 3086-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27300766

RESUMO

Despite numerous reports of relationships between weight gain and butyrylcholinesterase (BChE), this enzyme's role in the genesis of obesity remains unclear, but recent research points to strong links with ghrelin, the "hunger hormone." The availability of BChE knockout (KO) mice provides an opportunity to clarify the causal relationship between BChE and obesity onset. We now find that young KO mice have abnormally high plasma ghrelin levels that slowly decline during long-term high-fat feeding and ultimately drop below those in wild-type mice. On such a diet, the KO mice gained notably more weight, more white fat, and more hepatic fat than wild-type animals. In addition to a greater burden of hepatic triglycerides, the livers of these KO mice show distinctly higher levels of inflammatory markers. Finally, their energy expenditure proved to be lower than in wild-type mice despite similar activity levels and increased caloric intake. A gene transfer of mouse BChE with adeno-associated virus vector restored nearly all aspects of the normal phenotype. Our results indicate that BChE strongly affects fat metabolism, has an important impact on fat accumulation, and may be a promising tool for combating obesity.


Assuntos
Tecido Adiposo/metabolismo , Apneia/metabolismo , Butirilcolinesterase/deficiência , Butirilcolinesterase/genética , Dieta Hiperlipídica , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Erros Inatos do Metabolismo/metabolismo , Tecido Adiposo/patologia , Adiposidade/genética , Animais , Apneia/patologia , Butirilcolinesterase/metabolismo , Células HEK293 , Humanos , Fígado/patologia , Masculino , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão , Regulação para Cima/genética
8.
Chem Biol Interact ; 259(Pt B): 271-275, 2016 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26915976

RESUMO

Butyrylcholinesterase (BChE) has long been regarded as an "orphan enzyme" with no specific physiological role other than to metabolize exogenous bioactive esters in the diet or in medicines. Human beings with genetic mutations that eliminate all BChE activity appear completely normal, and BChE-knockout mice have been described as "lacking a phenotype" except for faster weight gain on high-fat diets. However, our recent studies with viral gene transfer of BChE in mice reveal that BChE hydrolyzes the so-called "hunger hormone," ghrelin, at a rate which strongly affects the circulating levels of this peptide hormone. This action has important consequences for weight gain and fat metabolism. Surprisingly, it also impacts emotional behaviors such as aggression. Overexpression of BChE leads to low ghrelin levels in the blood stream and reduces aggression and social stress in mice. Under certain circumstances these combined effects contribute to increased life-span in group-housed animals. These findings may generalize to humans, as recent clinical studies by multiple investigators indicate that, among patients with severe cardiovascular disease, longevity correlates with increasing levels of plasma BChE activity.


Assuntos
Comportamento , Butirilcolinesterase/metabolismo , Emoções , Grelina/metabolismo , Transdução de Sinais , Animais , Humanos , Modelos Biológicos
9.
Biochem Pharmacol ; 98(4): 732-9, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26514871

RESUMO

A high-throughput radiometric assay was developed to characterize enzymatic hydrolysis of ghrelin and to track the peptide's fate in vivo. The assay is based on solvent partitioning of [(3)H]-octanoic acid liberated from [(3)H]-octanoyl ghrelin during enzymatic hydrolysis. This simple and cost-effective method facilitates kinetic analysis of ghrelin hydrolase activity of native and mutated butyrylcholinesterases or carboxylesterases from multiple species. In addition, the assay's high sensitivity facilitates ready evaluation of ghrelin's pharmacokinetics and tissue distribution in mice after i.v. bolus administration of radiolabeled peptide.


Assuntos
Grelina/metabolismo , Hidrolases/metabolismo , Trítio/metabolismo , Animais , Ativação Enzimática/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Radiometria/métodos , Distribuição Tecidual/fisiologia
10.
Proc Natl Acad Sci U S A ; 112(7): 2251-6, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25646463

RESUMO

Ongoing mouse studies of a proposed therapy for cocaine abuse based on viral gene transfer of butyrylcholinesterase (BChE) mutated for accelerated cocaine hydrolysis have yielded surprising effects on aggression. Further investigation has linked these effects to a reduction in circulating ghrelin, driven by BChE at levels ∼ 100-fold above normal. Tests with human BChE showed ready ghrelin hydrolysis at physiologic concentrations, and multiple low-mass molecular dynamics simulations revealed that ghrelin's first five residues fit sterically and electrostatically into BChE's active site. Consistent with in vitro results, male BALB/c mice with high plasma BChE after gene transfer exhibited sharply reduced plasma ghrelin. Unexpectedly, such animals fought less, both spontaneously and in a resident/intruder provocation model. One mutant BChE was found to be deficient in ghrelin hydrolysis. BALB/c mice transduced with this variant retained normal plasma ghrelin levels and did not differ from untreated controls in the aggression model. In contrast, C57BL/6 mice with BChE gene deletion exhibited increased ghrelin and fought more readily than wild-type animals. Collectively, these findings indicate that BChE-catalyzed ghrelin hydrolysis influences mouse aggression and social stress, with potential implications for humans.


Assuntos
Agressão , Butirilcolinesterase/sangue , Grelina/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C
11.
J Mol Neurosci ; 53(3): 424-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24217797

RESUMO

Cholinesterases (ChEs) have been identified in vertebrates and invertebrates. Inhibition of ChE activity in invertebrates, such as bivalve molluscs, has been used to evaluate the exposure of organophosphates, carbamate pesticides, and heavy metals in the marine system. The golden apple snail (Pomacea canaliculata) is considered as one of the worst invasive alien species harmful to rice and other crops. The ChE(s) in this animal, which has been found recently, but poorly characterized thus far, could serve as biomarker(s) for environmental surveillance as well as a potential target for the pest control. In this study, the tissue distribution, substrate preference, sensitivity to ChE inhibitors, and molecular species of ChEs in P. canaliculata were investigated. It was found that the activities of both AChE and BChE were present in all test tissues. The intestine had the most abundant ChE activities. Both enzymes had fair activities in the head, kidney, and gills. The BChE activity was more sensitive to tetra-isopropylpyrophosphoramide (iso-OMPA) than the AChE. Only one BChE molecular species, 5.8S, was found in the intestine and head, whereas two AChE species, 5.8S and 11.6S, were found there. We propose that intestine ChEs of this snail may be potential biomarkers for manipulating pollutions.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Caramujos/enzimologia , Animais , Intestinos/enzimologia , Especificidade de Órgãos
12.
Chin Med ; 7: 10, 2012 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-22546174

RESUMO

BACKGROUND: Flavonoids, a group of compounds mainly derived from vegetables and herbal medicines, chemically resemble estrogen and some have been used as estrogen substitutes. Kaempferol, a flavonol derived from the rhizome of Kaempferia galanga L., is a well-known phytoestrogen possessing osteogenic effects that is also found in a large number of plant foods.The herb K. galanga is a popular traditional aromatic medicinal plant that is widely used as food spice and in medicinal industries. In the present study, both the estrogenic and osteogenic properties of kaempferol are evaluated. METHODS: Kaempferol was first evaluated for its estrogenic properties, including its effects on estrogen receptors. The osteogenic properties of kaempferol were further determined its induction effects on specific osteogenic enzymes and genes as well as the mineralization process in cultured rat osteoblasts. RESULTS: Kaempferol activated the transcriptional activity of pERE-Luc (3.98 ± 0.31 folds at 50 µM) and induced estrogen receptor α (ERα) phosphorylation in cultured rat osteoblasts, and this ER activation was correlated with induction and associated with osteoblast differentiation biomarkers, including alkaline phosphatase activity and transcription of osteoblastic genes, e.g., type I collagen, osteonectin, osteocalcin, Runx2 and osterix. Kaempferol also promoted the mineralization process of osteoblasts (4.02 ± 0.41 folds at 50 µM). ER mediation of the kaempferol-induced effects was confirmed by pretreatment of the osteoblasts with an ER antagonist, ICI 182,780, which fully blocked the induction effect. CONCLUSION: Our results showed that kaempferol stimulates osteogenic differentiation of cultured osteoblasts by acting through the estrogen receptor signaling.

13.
Planta Med ; 76(14): 1525-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20309798

RESUMO

Fo Shou San (FSS) is an ancient herbal decoction comprised of Rhizoma Chuanxiong (RC; Chuanxiong) and Radix Angelicae Sinensis (RAS; Danggui) in a ratio of 2 : 3. It is mainly prescribed for patients having a blood deficiency. This combination is considered the most popular herb pair among Chinese medicines; however, the rationale of having these two chemically similar herbs within the decoction has historically not been made clear. Here, we attempted to reveal the chemical and biological properties of this decoction as a means to deduce its mechanism of action. The effects of FSS were determined in different cell culture models. With respect to stimulation of blood circulation, FSS inhibited ADP-mediated platelet aggregation in a dose-dependent manner. In order to reveal the hematopoietic effect of this decoction, FSS was applied onto cultured K562 human leukemia cells and Hep3B human hepatocellular carcinoma cells. Application of FSS in cultured K562 cells inhibited cell proliferation and subsequently induced the production of hemoglobin. Additionally, the mRNA expression of erythropoietin (EPO) was induced in a dose-dependent manner when FSS was applied to Hep3B cells. The current results reveal the effects of FSS in different cell models, paving a direction for mechanistic studies.


Assuntos
Angelica sinensis/química , Medicamentos de Ervas Chinesas/farmacologia , Eritropoetina/biossíntese , Hemoglobinas/biossíntese , Movimento Celular , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Eritropoese/efeitos dos fármacos , Hemoglobinas/efeitos dos fármacos , Humanos , Células K562 , Agregação Plaquetária/efeitos dos fármacos
14.
Planta Med ; 76(5): 439-43, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19847742

RESUMO

Danggui Buxue Tang (DBT), a herbal decoction composed of Radix Astragali (RA) and Radix Angelica sinensis (RAS), has been used for treating menopausal irregularity in women for more than 800 years in China. According to the old tradition, RAS had to be processed with yellow wine before DBT preparation, which markedly reduced the amount of ligustilide in RAS and DBT, as well as enhanced the bioactivities of DBT. Here, we hypothesized that ligustilide would be an ingredient that possessed suppressive effects on DBT's functions. In the presence of ligustilide, the amount of astragaloside IV, calycosin, formononetin, and total polysaccharides extracted from RA were decreased. An increase of ligustilide caused a decrease of DBT's osteogenic activity in stimulating proliferation and differentiation of cultured bone cells. In addition, in the presence of a high level of ligustilide, DBT caused a side effect inducing the proliferation of breast MCF-7 cells. The current results strongly suggest that ligustilide is a negative regulator that hinders DBT to achieve its biological efficacy, which supports the traditional practice of preparing DBT using the ethanol-treated RAS.


Assuntos
4-Butirolactona/análogos & derivados , Medicamentos de Ervas Chinesas/química , 4-Butirolactona/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Antagonismo de Drogas , Humanos , Isoflavonas/isolamento & purificação , Medicina Tradicional Chinesa , Polissacarídeos/isolamento & purificação , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação
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