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1.
J Diet Suppl ; 17(1): 81-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30325249

RESUMO

Hedychium coronarium Koen., commonly known as ginger lily, is considered an endemic medicinal plant. In the present study, the antidiabetic action of its rhizomes was investigated by α-amylase and α-glucosidase inhibition assay, and the active compounds were identified through bioactivity guided isolation technique. Among the six different extracts, the EA extract has shown highest inhibition, and the subfractions from active EA extract were separated by silica gel column chromatography. The subfraction showing highest inhibition was investigated for its chemical composition by high-resolution liquid chromatography-mass spectroscopy (HRLC-MS/MS). The fatty acids such as suberic acid and terpenes such as triparanol, ginkgolide C, and swietenine were found to be the major compounds in the subfractions. The present work revealed that H. coronarium rhizome extract and its active constituent could be used as a natural inhibitor of these two carbohydrate-metabolizing enzymes and may play a key role in the management of diabetes.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Zingiberaceae/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Caprilatos/análise , Caprilatos/farmacologia , Caprilatos/uso terapêutico , Diabetes Mellitus , Ácidos Dicarboxílicos/análise , Ácidos Dicarboxílicos/farmacologia , Ácidos Dicarboxílicos/uso terapêutico , Ginkgolídeos/análise , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Inibidores de Glicosídeo Hidrolases/análise , Hipoglicemiantes/análise , Lactonas/análise , Lactonas/farmacologia , Lactonas/uso terapêutico , Limoninas/análise , Limoninas/farmacologia , Limoninas/uso terapêutico , Fitoterapia , Extratos Vegetais/química , Rizoma/química , Terpenos/análise , Terpenos/farmacologia , Terpenos/uso terapêutico , Triparanol/análise , Triparanol/farmacologia , Triparanol/uso terapêutico
3.
Toxins (Basel) ; 7(8): 3359-71, 2015 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-26305256

RESUMO

The cholesterol synthesis inhibitor Triparanol has been shown to trigger apoptosis in several malignancies. Similar to the apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress which may activate erythrocytic Ca(2+) permeable unselective cation channels with subsequent Ca(2+) entry and increase of cytosolic Ca(2+) activity ([Ca(2+)]i). The present study explored whether and how Triparanol induces eryptosis. To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo3-fluorescence, and ROS formation from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence. As a result, a 48 h exposure of human erythrocytes to Triparanol (20 µM) significantly increased DCFDA fluorescence and significantly increased Fluo3-fluorescence. Triparanol (15 µM) significantly increased the percentage of annexin-V-binding cells, and significantly decreased the forward scatter. The effect of Triparanol on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca(2+). In conclusion, Triparanol leads to eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane. Triparanol is at least in part effective by stimulating ROS formation and Ca(2+) entry.


Assuntos
Eritrócitos/efeitos dos fármacos , Hipolipemiantes/toxicidade , Triparanol/toxicidade , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Glutationa/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Fosfatidilserinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Neoplasia ; 15(7): 712-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23814483

RESUMO

Desmoid tumor (also called aggressive fibromatosis) is a lesion of mesenchymal origin that can occur as a sporadic tumor or a manifestation of the preneoplastic syndrome, familial adenomatous polyposis caused by a mutation in adenomatous polyposis coli (APC). This tumor type is characterized by the stabilization of ß-catenin and activation of Tcf-mediated transcription. Cell transplantation data suggest that desmoid tumors are derived from mesenchymal progenitor cells (MSCs). As such, modulating cell signaling pathways that regulate MSC differentiation or proliferation, such as hedgehog (Hh) signaling, could alter the tumor phenotype. Here, we found that Hh signaling is activated in human and murine desmoid tumors. Inhibiting Hh signaling in human cell cultures decreased cell proliferation and ß-catenin protein levels. Apc(+)/Apc(1638N) mice, which develop desmoid tumors, develop smaller and fewer tumors when Hh signaling was inhibited either genetically (by crossing Apc(+)/Apc(1638N) mice with mice lacking one copy of a Hh-activated transcription factor, Gli2 (+/-) mice) or using a pharmacologic inhibitor. Both in mice and in human tumor cell cultures, ß-catenin and Hh-mediated signaling positively regulate each other's activity. These data show that targeting a pathway that regulates MSC differentiation influences desmoid tumor behavior, providing functional evidence supporting the notion that these tumors are derived from mesenchymal progenitors. It also suggests Hh blockade as a therapeutic approach for this tumor type.


Assuntos
Fibromatose Agressiva/metabolismo , Proteínas Hedgehog/metabolismo , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais , Animais , Proliferação de Células , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , Genes APC , Proteínas Hedgehog/antagonistas & inibidores , Xenoenxertos , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Triparanol/farmacologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Gli2 com Dedos de Zinco , beta Catenina/metabolismo
5.
PLoS One ; 8(3): e58833, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23554937

RESUMO

The cell cycle is a ubiquitous, multi-step process that is essential for growth and proliferation of cells. The role of membrane lipids in cell cycle regulation is not explored well, although a large number of cytoplasmic and nuclear regulators have been identified. We focus in this work on the role of membrane cholesterol in cell cycle regulation. In particular, we have explored the stringency of the requirement of cholesterol in the regulation of cell cycle progression. For this purpose, we utilized distal and proximal inhibitors of cholesterol biosynthesis, and monitored their effect on cell cycle progression. We show that cholesterol content increases in S phase and inhibition of cholesterol biosynthesis results in cell cycle arrest in G1 phase under certain conditions. Interestingly, G1 arrest mediated by cholesterol biosynthesis inhibitors could be reversed upon metabolic replenishment of cholesterol. Importantly, our results show that the requirement of cholesterol for G1 to S transition is absolute, and even immediate biosynthetic precursors of cholesterol, differing with cholesterol merely in a double bond, could not replace cholesterol for reversing the cell cycle arrest. These results are useful in the context of diseases, such as cancer and Alzheimer's disease, that are associated with impaired cholesterol biosynthesis and homeostasis.


Assuntos
Ciclo Celular/fisiologia , Colesterol/biossíntese , Homeostase , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lovastatina/farmacologia , Ratos , Triparanol/farmacologia
6.
Hum Exp Toxicol ; 32(10): 1028-37, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23424208

RESUMO

Channels responsible for slowly activating delayed-rectifier potassium current (I(Ks)) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the I(Ks) after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3ß-hydroxysterol-▵24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (I KCNQ1), and the I(Ks) to clarify the differences in the modes of action of these agents on the I(Ks). Probucol did not inhibit cholesterol synthesis and had no effect on I KCNQ1, while I(Ks) decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased I KCNQ1 and I(Ks). Additionally, the activation kinetics of I(Ks) became faster, compared with that of control I(Ks). Triparanol inhibited cholesterol synthesis but did not reduce I KCNQ1 and I(Ks). However, the activation kinetics of I(Ks) became faster. Our data indicated that the mechanism by which probucol inhibits I(Ks) was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of I(ks).


Assuntos
Anticolesterolemiantes/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Probucol/farmacologia , Sinvastatina/farmacologia , Triparanol/farmacologia , Animais , Células CHO , Colesterol/metabolismo , Cricetulus
7.
Biochem Biophys Res Commun ; 425(3): 613-8, 2012 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-22877755

RESUMO

Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Hipolipemiantes/uso terapêutico , Neoplasias/tratamento farmacológico , Triparanol/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Camundongos , Camundongos Nus , Triparanol/química , Triparanol/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Res ; 72(4): 1013-22, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22232736

RESUMO

Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.


Assuntos
Proteínas Hedgehog/metabolismo , Histiocitoma Fibroso Maligno/metabolismo , Histiocitoma Fibroso Maligno/patologia , Receptores Notch/metabolismo , Animais , Proliferação de Células , Transformação Celular Neoplásica , Perfilação da Expressão Gênica , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/fisiologia , Triparanol/farmacologia
9.
Biochim Biophys Acta ; 1788(9): 1731-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19433058

RESUMO

Lipid rafts are plasma membrane microdomains that are highly enriched with cholesterol and sphingolipids and in which various receptors and other proteins involved in signal transduction reside. In the present work, we analyzed the effect of cholesterol biosynthesis inhibition on lipid raft/caveolae composition and functionality and assessed whether sterol precursors of cholesterol could substitute for cholesterol in lipid rafts/caveolae. 3T3-L1 preadipocytes were treated with distal inhibitors of cholesterol biosynthesis or vehicle (control) and then membrane rafts were isolated by sucrose density gradient centrifugation. Inhibition of cholesterol biosynthesis with either SKF 104976, AY 9944, 5,22-cholestadien-3beta-ol or triparanol, which inhibit different enzymes on the pathway, led to a marked reduction in cholesterol content and accumulation of different sterol intermediates in both lipid rafts and non-raft domains. These changes in sterol composition were accompanied by disruption of lipid rafts, with redistribution of caveolin-1 and Fyn, impairment of insulin-Akt signaling and the inhibition of insulin-stimulated glucose transport. Cholesterol repletion abrogated the effects of cholesterol biosynthesis inhibitors, reflecting they were specific. Our results show that cholesterol is required for functional raft-dependent insulin signaling.


Assuntos
Cavéolas/efeitos dos fármacos , Membrana Celular/metabolismo , Colesterol/biossíntese , Microdomínios da Membrana/efeitos dos fármacos , Células 3T3-L1 , Animais , Cavéolas/metabolismo , Caveolina 1/metabolismo , Desidrocolesteróis/farmacologia , Inibidores Enzimáticos/farmacologia , Gangliosídeo G(M1)/metabolismo , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Camundongos , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo , Triparanol/farmacologia , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/farmacologia
10.
Am J Pathol ; 168(1): 321-30, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16400033

RESUMO

Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.


Assuntos
Neoplasias Ósseas/metabolismo , Proliferação de Células , Condrossarcoma/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Análise Mutacional de DNA , Proteínas Hedgehog , Humanos , Hipolipemiantes/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Oncogênicas/biossíntese , Técnicas de Cultura de Órgãos , Proteína Relacionada ao Hormônio Paratireóideo/genética , Receptores Patched , Receptor Patched-1 , Polimorfismo Conformacional de Fita Simples , Receptores de Superfície Celular/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Fatores de Transcrição/biossíntese , Triparanol/farmacologia , Regulação para Cima , Proteína GLI1 em Dedos de Zinco
11.
J Pathol ; 206(2): 143-50, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15834844

RESUMO

Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.


Assuntos
Proteínas de Transporte/fisiologia , Condromatose Sinovial/fisiopatologia , Glicoproteínas de Membrana/fisiologia , Animais , Proteínas de Transporte/antagonistas & inibidores , Condromatose Sinovial/genética , Condromatose Sinovial/metabolismo , Condromatose Sinovial/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Mutantes , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Fusão Oncogênica , Proteínas Tirosina Quinases , Transdução de Sinais , Transativadores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Ativação Transcricional , Triparanol/farmacologia , Proteína GLI1 em Dedos de Zinco , Proteína Gli3 com Dedos de Zinco
12.
Hum Mol Genet ; 12(10): 1187-98, 2003 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12719383

RESUMO

Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis. Recently, it has been demonstrated that cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs. To provide insight in the functions of cholesterol during limb development and in the potential role of Hedgehog signaling in the genesis of limb defects, we developed an in vivo rat model of cholesterol deficiency. We show here that treatment with Triparanol, a distal inhibitor of cholesterol biosynthesis, induced patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, thus reproducing limb anomalies frequently observed in humans. Using in situ hybridization, we show that these malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. Our study thus unravels the molecular mechanisms underlying the genesis of limb defects associated with cholesterol deficiency in rodents, and most probably in humans.


Assuntos
Colesterol/deficiência , Deformidades Congênitas dos Membros/etiologia , Transdução de Sinais/fisiologia , Transativadores/fisiologia , Animais , Osso e Ossos/anormalidades , Relação Dose-Resposta a Droga , Proteínas Hedgehog , Hipolipemiantes/farmacologia , Botões de Extremidades , Ratos , Ratos Wistar , Teratógenos/farmacologia , Triparanol/farmacologia
13.
J Lipid Res ; 43(8): 1192-200, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12177163

RESUMO

Triparanol, an inhibitor of desmosterol Delta24 reductase, produces a high rate of limb malformations in rat fetuses exposed at gestational day 10 (gd 10) to a single oral dose (150-200 mg/kg) given to the pregnant dam. AY9944, another efficient distal inhibitor of cholesterol biosynthesis that blocks dehydrocholesterol Delta7 reductase, produces a similar degree of cholesterol depletion but fewer malformations. Gas liquid chromatography-mass spectrometry (GC-MS) profiling of the sterols in the serum of the dams and in extracted embryos shows that in addition to desmosterol Delta24 reductase inhibition the conversion of Delta8 to Delta7 unsaturated sterols is also blocked by Triparanol. Therefore, the inhibitor induces the accumulation of desmosterol (Delta8 cholesten-3beta-ol, 8-dehydrocholesterol) and zymosterol (Delta8, Delta24 cholestadien-3beta-ol) in embryo tissues. The high concentration of the teratogenic drug assayed in the embryos at three successive gestational days (10-30 micro g/g) is thought to cause the blockade in both Delta24 reductase and Delta8-Delta7 isomerase, which results in the particular profile of aberrant sterols. Comparison of the animal model with human syndromes, including limb osseous and skeleton perturbations, suggests a combination of desmosterol and Delta8 unsaturated sterols as being involved in the deleterious influence on limb bone formation.


Assuntos
Colesterol/biossíntese , Inibidores Enzimáticos/toxicidade , Deformidades Congênitas dos Membros/induzido quimicamente , Teratógenos/toxicidade , Triparanol/toxicidade , Animais , Desmosterol/sangue , Desmosterol/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Oxirredutases/antagonistas & inibidores , Gravidez , Ratos , Ratos Wistar
14.
Am J Clin Nutr ; 71(5 Suppl): 1270S-9S, 2000 05.
Artigo em Inglês | MEDLINE | ID: mdl-10799401

RESUMO

We showed previously that 3 distal inhibitors of cholesterol synthesis are highly teratogenic in rats. AY 9944 and BM 15766 inhibit 7-dehydrocholesterol reductase, which catalyzes the last step of cholesterol synthesis, and triparanol inhibits Delta(24)-dehydrocholesterol reductase, which catalyzes the last step in another pathway. These molecules cause holoprosencephalic brain anomalies. Under certain experimental conditions, other anomalies (of the limbs and male genitalia) are also observed. Assays performed by gas chromatography-mass spectrometry (GC-MS) show hypocholesterolemia and an accumulation of precursors. These data indicate that this animal model can be considered a model of Smith-Lemli-Opitz syndrome. Smith-Lemli-Opitz syndrome is a recessive autosomal genetic disease characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive. The syndrome has been attributed to a deficit in 7-dehydrocholesterol reductase. As assayed by GC-MS, the sterol status of these patients indicates severe hypocholesterolemia and an accumulation of precursors: 7-dehydrocholesterol, 8-dehydrocholesterol, and oxidized derivatives. The presence of 7-dehydrocholesterol in the serum of patients is pathognomonic of the disease. The developmental gene Shh (sonic hedgehog) plays a key role in brain, limb, and genital development; it was shown recently that the Shh protein has to be covalently linked to cholesterol to be active. This is the first time that a posttranslational function has been attributed to cholesterol. There is an obvious relation between Shh dysfunction and the malformations observed in our experiments and in patients with Smith-Lemli-Opitz syndrome. However, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account.


Assuntos
Anticolesterolemiantes/toxicidade , Colesterol/fisiologia , Desidrocolesteróis/antagonistas & inibidores , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Feto/metabolismo , Síndrome de Smith-Lemli-Opitz/embriologia , Animais , Modelos Animais de Doenças , Piperazinas/toxicidade , Ratos , Síndrome de Smith-Lemli-Opitz/induzido quimicamente , Síndrome de Smith-Lemli-Opitz/metabolismo , Triparanol/toxicidade , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/toxicidade
15.
Neurosci Lett ; 272(2): 87-90, 1999 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-10507548

RESUMO

Triparanol (Trp) is known to cause clinical features similar to those seen in myotonic dystrophy, including myotonia, cataract and baldness. To explore the pathophysiological mechanism of myotonic dystrophy, we examined the effect of Trp on intracellular calcium in cultured skeletal myoblasts and myotubes as well as cardiac myocytes by using a fluorescent indicator. Trp preferentially induced increase of intracellular calcium in myotubes of skeletal muscles. Since the increase of calcium was inhibited by thapsigargin pretreatment but not by extracellular calcium elimination, it appears that triparanol might act mostly on intracellular calcium stores. Trp also inhibited the increase of calcium in myotubes induced by acetylcholine. Trp might cause myotonia possibly through the increase of intracellular calcium from intracellular stores.


Assuntos
Cálcio/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Distrofia Miotônica/induzido quimicamente , Triparanol/farmacologia , Acetilcolina/farmacologia , Animais , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Coração/efeitos dos fármacos , Hipolipemiantes/farmacologia , Camundongos , Miocárdio/metabolismo , Tapsigargina/farmacologia
16.
Science ; 280(5369): 1603-7, 1998 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-9616123

RESUMO

Veratrum alkaloids and distal inhibitors of cholesterol biosynthesis have been studied for more than 30 years as potent teratogens capable of inducing cyclopia and other birth defects. Here, it is shown that these compounds specifically block the Sonic hedgehog (Shh) signaling pathway. These teratogens did not prevent the sterol modification of Shh during autoprocessing but rather inhibited the response of target tissues to Shh, possibly acting through the sterol sensing domain within the Patched protein regulator of Shh response.


Assuntos
Sistema Nervoso Central/embriologia , Colesterol/metabolismo , Proteínas/metabolismo , Teratógenos/farmacologia , Transativadores , Fatores de Transcrição , Alcaloides de Veratrum/farmacologia , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Membrana Celular/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Embrião de Galinha , Colesterol/biossíntese , Técnicas de Cultura , Proteínas de Ligação a DNA/biossíntese , Retículo Endoplasmático/metabolismo , Proteínas Hedgehog , Fator 3-beta Nuclear de Hepatócito , Holoprosencefalia/induzido quimicamente , Proteínas de Homeodomínio/biossíntese , Proteínas com Homeodomínio LIM , Proteínas de Membrana/metabolismo , Proteínas Musculares/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Proteínas Nucleares/biossíntese , Fator de Transcrição PAX7 , Receptores Patched , Receptores de Superfície Celular , Transdução de Sinais/efeitos dos fármacos , Tomatina/análogos & derivados , Tomatina/farmacologia , Triparanol/farmacologia , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/farmacologia
17.
Br J Pharmacol ; 121(1): 1-6, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9146879

RESUMO

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C8-C7 isomerase (ERG2 protein). Pharmacologically-but not structurally-the sigma 1-site is also related to the emopamil binding protein, the mammalian sterol C8-C7 isomerase. We therefore investigated if sterol C8-C7 isomerase inhibitors are high affinity ligands for the (+)-[3H]-pentazocine labelled sigma 1-binding site. 2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma 1-binding sites were the agricultural fungicide fenpropimorph (Ki 0.005 nM), the antihypocholesterinaemic drugs triparanol (Ki 7.0 nM), AY-9944 (Ki, 0.46 nM) and MDL28,815 (Ki 0.16 nM), the enantiomers of the ovulation inducer clomiphene (Ki 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (Ki 26 nM). 3. Except for tamoxifen these affinities are essentially identical with those for the [3H]-ifenprodil labelled sterol C8-C7 isomerase of S. cerevisiae. This demonstrates that sigma 1-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma 1-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.


Assuntos
Encéfalo/metabolismo , Microssomos Hepáticos/metabolismo , Receptores sigma/metabolismo , Esteroide Isomerases/metabolismo , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/metabolismo , Clomifeno/metabolismo , Clomifeno/farmacologia , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Antagonistas de Aminoácidos Excitatórios/metabolismo , Fármacos para a Fertilidade Feminina/metabolismo , Fármacos para a Fertilidade Feminina/farmacologia , Fungicidas Industriais/metabolismo , Fungicidas Industriais/toxicidade , Cobaias , Hipolipemiantes/metabolismo , Hipolipemiantes/farmacologia , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Marcação por Isótopo , Microssomos/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Morfolinas/metabolismo , Morfolinas/toxicidade , Pentazocina/metabolismo , Piperidinas/metabolismo , Receptores sigma/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo , Estereoisomerismo , Esteroide Isomerases/antagonistas & inibidores , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Triparanol/metabolismo , Triparanol/farmacologia , Verapamil/análogos & derivados , Verapamil/metabolismo , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/metabolismo , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/farmacologia
18.
Ann Nutr Metab ; 36(1): 55-60, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1590673

RESUMO

The serum total bile acid concentration was measured in rhesus monkeys fed diets practically free of cholesterol and with added cholesterol at two levels. Also, the effects of inhibiting cholesterol absorption by feeding plant sterols and inhibiting cholesterol synthesis by feeding triparanol upon the serum total bile acid levels were studied. Cholesterol feeding significantly increased the serum bile acid concentration. The serum bile acid level was decreased in the high responders fed plant sterols but only when the diet contained the highest level of cholesterol. In both groups serum bile acid levels were not altered when cholesterol biosynthesis was inhibited by feeding triparanol. It is suggested that cholesterol feeding increases the serum bile acid level probably due to an increase in the intestinal pool of bile acids as a result of increased production of bile acids in the liver and their excretion into the bile.


Assuntos
Ácidos e Sais Biliares/sangue , Colesterol na Dieta/administração & dosagem , Colesterol/farmacocinética , Animais , Colesterol/biossíntese , Macaca mulatta , Masculino , Fitosteróis/farmacologia , Triparanol/farmacologia
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