RESUMO
OSW-1 is a plant-derived natural product proposed to selectively kill cancer cells by binding to members of the oxysterol binding protein family, thereby disrupting lipid/sterol homeostasis. However, how these protein-ligand interactions mediate cell death signaling has remained elusive. Here, we discovered that OSW-1 selectively activates the Golgi stress response leading to apoptosis, providing a mechanistic basis for the anticancer activity of OSW-1.
Assuntos
Antineoplásicos/uso terapêutico , Colestenonas/uso terapêutico , Complexo de Golgi/efeitos dos fármacos , Saponinas/uso terapêutico , Antineoplásicos/farmacologia , Colestenonas/farmacologia , Humanos , Saponinas/farmacologiaRESUMO
INTRODUCTION: We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the 3 domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function. METHODS: Nonlinear mixed-effects modeling was applied to data from 2 observational studies and 1 prospective clinical efficacy study comprising 190 healthy participants and 277 patients with type 2/3 SMA. RESULTS: The model evidenced correlations between parameter estimates for different MFM domains. Slower development in MFM domain D1 (standing and transfers) was associated with faster deterioration for MFM domains D2 (proximal and axial motricity) and D3 (distal motor function). DISCUSSION: The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug-effect model that could differentiate between symptomatic and disease modifying effects. Muscle Nerve 58: 528-535, 2018.
Assuntos
Atrofias Musculares Espinais da Infância/fisiopatologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Colestenonas/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Dinâmica não Linear , Estudos Observacionais como Assunto , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Adulto JovemRESUMO
Frequent local recurrence and metastasis are generally involved in human liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human liposarcoma SW872-S cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S cells, indicating that OSBP may be involved in malignant liposarcoma cell survival. Cancer cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human liposarcoma.
Assuntos
Antineoplásicos/farmacologia , Colestenonas/farmacologia , Lipossarcoma/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Saponinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenonas/uso terapêutico , Feminino , Humanos , Lipossarcoma/tratamento farmacológico , Lipossarcoma/genética , Lipossarcoma/patologia , Camundongos Nus , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Saponinas/uso terapêuticoRESUMO
Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy. The overhaul of the landscape for all those involved in SMA extends to the design of further drug trials and the necessity of multidisciplinary supportive care to potentiate the effects of disease modifying medications. The impact of respiratory complications in SMA is central to management in the current era of emerging novel therapies. These fundamental changes in our knowledge and management approach to those with SMA are explored further in this review.
Assuntos
Colestenonas/uso terapêutico , Terapia Genética/métodos , Imidazóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Oligonucleotídeos/uso terapêutico , Modalidades de Fisioterapia , Pirazinas/uso terapêutico , Atrofias Musculares Espinais da Infância/terapia , Humanos , Respiração Artificial , Atrofias Musculares Espinais da Infância/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Studies on the lipid-regulating effects of alisol compounds are reported that include alisol B, alisol A 24-acetate (24A), alisol A and an alisol B - 24A - alisol A mixture (content ratioâ¯=â¯1:1:1). The effects on the activity of lipoprotein lipase (LPL), a key lipid-modulating enzyme, were studied to investigate the molecular mechanism of lipid-regulating activity of alisols. The effects of alisols on regulating blood lipids and the activities of LPL were determined using a reagent kit method. The structure of LPL was obtained by homology modeling and the interactive mechanism of alisol monomers and the mixture with LPL was investigated by molecular simulation. The alisol monomer and mixture were shown to regulate blood lipids, suggesting that alisols may decrease the level of triglyceride (TG) by improving the activity of LPL. The order of intensity was: mixtureâ¯>â¯alisol Aâ¯>â¯alisol Bâ¯>â¯24A, indicating that alisols of alismatis rhizoma feature a synergistic effect on LPL. The N- and C-terminus of LPL both represented the catalytic active domains of this lipid-regulating effect. Cys306, Gln129 and Ser166 were the key amino acid residues resulting in the lipid-regulating effect of the alisol monomer while Ser166 and Arg18 were found to be responsible for the lipid-regulating effect of the mixture. The C-terminus of LPL was indirectly involved in the enzymatic process. A folded side chain of alisols or the parent ring was found to bind somewhat weaker to LPL than an open side chain or parent ring. The hydroxyl groups on the C14-, C22-, C28-, C30- and C31-terminus in the side chain, the ring ether structure in C23-position, and the acetyl group in C29-position represented the key sites for the lipid-regulating action of alisols. Meanwhile, the C30-site hydroxyl group played an important role in the synergistic effect of the alisol mixture.
Assuntos
Colestenonas/metabolismo , Lipase Lipoproteica/metabolismo , Animais , Sítios de Ligação , Colestenonas/química , Colestenonas/uso terapêutico , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/veterinária , Lipídeos/sangue , Lipase Lipoproteica/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Eletricidade EstáticaRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic disorders including hepatic lipid accumulation and inflammation. Alisol A 24-acetate, a triterpene from Alismatis rhizome, has multiple biologic activities such as hypolipidemic, anti-inflammatory and anti-diabetic. Thus we hypothesized that Alisol A 24 -acetate would have effect on NAFLD. The present study was conducted to investigate the therapeutic effects and potential mechanisms of Alisol A 24-acetate against hepatic steatosis in a free fatty acids (FFAs) induced NAFLD cell model. METHODS: This study was divided into four groups including Control group, Model group (FFA group), Alisol A 24-acetate (FFA+A) group, Fenofibrate (FFA+F) group. Preventive role of Alisol A 24-acetate was evaluated using 10µM Alisol A 24-acetate plus 1 mM FFA (oleate:palmitate=2:1) incubated with HepG2 cells for 24 h, which was determined by Oil Red O Staining, Oil Red O based colorimetric assay and intracellular triglyceride (TG) content. Besides, the inflammatory cytokines tumor necrosis factor (TNF)- α, interleukin (IL)-6 levels as well as the protein and mRNA expressions that were involved in fatty acid synthesis and oxidation including Adiponectin, AMP-activated protein kinase (AMPK) α, peroxisome proliferator-activated receptor (PPAR) α, sterol regulatory element binding protein 1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), carnitine palmitoyltransferase 1 (CPT1) and acyl coenzyme A oxidase 1 (ACOX1) were detected. RESULTS: Alisol A 24-acetate significantly decreased the numbers of lipid droplets, Oil Red O lipid content, and intracellular TG content. Besides, inflammatory cytokines TNF-α, IL-6 levels were markedly inhibited by Alisol A 24-acetate. Furthermore, Alisol A 24-acetate effectively increased the protein and mRNA expressions of Adiponectin, the phosphorylation of AMPKα, CPT1 and ACOX1, whereas decreased SREBP-1c, the phosphorylation of ACC and FAS at both protein and mRNA levels. However, there was no significant effect on the protein and mRNA expressions of PPARα by Alisol A 24-acetate. CONCLUSIONS: These results demonstrated that Alisol A 24-acetate effectively ameliorated hepatic steatosis likely through Adiponectin, which activated AMPKα signaling pathways via down-regulating SREBP-1c, ACC, FAS and up-regulating CPT1 and ACOX1, and inhibited inflammation. Thereby, Alisol A 24-acetate could be a promising candidate for the treatment of NAFLD.
Assuntos
Colestenonas/uso terapêutico , Doenças Metabólicas/complicações , Doenças Metabólicas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/química , Colestenonas/farmacologia , Citocinas/metabolismo , Ácido Graxo Sintases/metabolismo , Ácidos Graxos , Células Hep G2 , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of olesoxime. Our findings suggest that olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of olesoxime as a therapeutic for Huntington's disease.
Assuntos
Calpaína/metabolismo , Colestenonas/farmacologia , Colestenonas/uso terapêutico , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Proteínas Mutantes/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Proteólise/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Calpaína/antagonistas & inibidores , Colestenonas/sangue , Colestenonas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Proteína Huntingtina , Doença de Huntington/enzimologia , Doença de Huntington/genética , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Ratos , Ratos TransgênicosRESUMO
OBJECTIVE: The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)-1ß processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH. METHODS: ICH was induced by injecting autologous arterial blood (30µl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated. RESULTS: ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloperoxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO. INTERPRETATION: The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1ß and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.ANN NEUROL 2014;75:209-219.
Assuntos
Proteínas de Transporte/metabolismo , Hemorragia Cerebral/complicações , Inflamação/etiologia , Animais , Antioxidantes/uso terapêutico , Edema Encefálico/etiologia , Edema Encefálico/terapia , Proteínas de Transporte/genética , Hemorragia Cerebral/prevenção & controle , Colestenonas/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hematoma/tratamento farmacológico , Hematoma/etiologia , Injeções Intraventriculares , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/genética , Compostos Organofosforados/uso terapêutico , Piperidinas/uso terapêutico , RNA Interferente Pequeno/uso terapêuticoRESUMO
PURPOSE: To investigate protective effects of alisol B 23-acetate (AB23A) against hepatotoxity and cholestasis induced by 17α-ethinylestradiol (EE) in association with farnesoid X receptor (FXR) activation in vivo and in vitro. METHODS: The cholestatic liver injury model was established by subcutaneous injections of EE in C57BL/6 mice. Serum biomarkers, bile flow assay and H&E staining were used to identify the amelioration of cholestasis after AB23A treatment. Mice primary hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. RESULTS: AB23A treatment protected against liver injury induced by EE through increasing hepatic efflux and reducing uptake of bile acid via an induction in efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) expression. AB23A also reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrated that the changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo and were abrogated after FXR was silenced in vitro. CONCLUSIONS: AB23A produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colestase/induzido quimicamente , Colestenonas/uso terapêutico , Proteínas de Membrana Transportadoras/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colestase/complicações , Colestase/patologia , Colestenonas/administração & dosagem , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Modelos Animais de Doenças , Etinilestradiol/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Testes de Função Hepática , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos Endogâmicos C57BL , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Cultura Primária de Células , Esteroide 12-alfa-Hidroxilase/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Simportadores/genética , Simportadores/metabolismoRESUMO
BACKGROUND AND PURPOSE: To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole. METHODS: A double-blind, randomized, placebo-controlled, multicenter trial of 18 months' duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) ≥70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months' survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed. RESULTS: At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan-Meier analysis was 67.5% (95% CI 61.0%-73.1%) in the placebo group and 69.4% (95% CI 63.0%-74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months' treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns. CONCLUSIONS: Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Colestenonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo. METHODS: The effect of olesoxime on oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC-neuron cocultures. Using naive animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo. RESULTS: Olesoxime accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naive animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, olesoxime favored the repair process, promoting myelin formation with consequent functional improvement. INTERPRETATION: Our observations support the strategy of promoting oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide proof of concept that olesoxime could be useful for the treatment of demyelinating diseases.
Assuntos
Colestenonas/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Many viral infections are associated with the development of immunopathologies and autoimmune diseases, which are of difficult treatment and for which no vaccines are yet available. Obtaining compounds that conjugate both antiviral and immunomodulatory activities in the same molecule would be very useful for the prevention and/or treatment of these immunopathologies. The compound (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays anti-Herpes simplex virus type 1 activity in vitro and reduces the incidence of herpetic stromal keratitis (HSK) in mice, a chronic inflammatory syndrome induced by ocular HSV-1 infection. In the present study, compound 1 showed opposite immunomodulatory properties in vitro. It induced the release of pro-inflammatory cytokines in HSV-1-infected epithelial cells of ocular origin, and significantly reduced the production of these cytokines in LPS-activated macrophages. RNA microarrays revealed various overexpressed and repressed genes in compound 1 treated infected epithelial cells and activated macrophages, many of which are associated with innate immune responses and inflammatory processes. These immunomodulatory properties of compound 1, together with its previously reported antiviral activity, make it a potential drug for the treatment of HSK and many other immunopathologies of viral and non-viral origin.
Assuntos
Antivirais/farmacologia , Colestenonas/química , Herpesvirus Humano 1/efeitos dos fármacos , Fatores Imunológicos/química , Estigmasterol/análogos & derivados , Animais , Antivirais/química , Antivirais/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/farmacologia , Colestenonas/uso terapêutico , Substância Própria/citologia , Substância Própria/virologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Perfilação da Expressão Gênica , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Ceratite Herpética/tratamento farmacológico , Ceratite Herpética/imunologia , Ceratite Herpética/veterinária , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Estigmasterol/química , Estigmasterol/farmacologia , Estigmasterol/uso terapêutico , Ativação Transcricional/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Multiple sclerosis is a neurodegenerative autoimmune disease characterized by diffuse oligodendrocyte injury, axonal loss and multifocal demyelination of myelin sheaths in the central nervous system. TRO19622 is a small cholesterol-like compound, which displays remarkable neuroprotective and neuroregenerative properties in neural cell culture and rodent models of nerve trauma. Therefore, the aim of the present study is to evaluate the pharmacological action of TRO19622 on the demyelination/remyelination processes by using a rat model of cuprizone-induced demyelination. METHODS: Using Female Sprague-Dawley rats models of demyelination, we morphologically and functionally assessed the effect of TRO19622 on myelination in vivo. RESULTS: In this study, we first provided in vivo proof that cuprizone intoxication contributed to spatial learning and memory ability injury and that TRO19622 restored neurological function. The structure of myelin injury and repair in cuprizone intoxication rats was then measured by T2-weighted magnetic resonance imaging. These magnetic resonance imaging-based results and trends were confirmed by histological, immunohistochemistry and electron microscopy analyses. CONCLUSIONS: The results clearly showed that TRO19622 promoted myelin formation with consequent functional improvement.
Assuntos
Colestenonas/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Animais , Doenças Desmielinizantes/patologia , Feminino , Ratos , Ratos Sprague-DawleyRESUMO
As a global epidemic disease, obesity causes dysfunction of glucose and lipid metabolism leading to persistently high morbidity and mortality. Given the difficulty to achieve and maintain weight loss through controlling diet and physical exercise, pharmacotherapy is considered an effective treatment for obesity. This investigation revealed that alisol B, a triterpene monomer isolated from the classical Chinese medicine Alisma orientale (Sam.) Juzep, functioned in suppressing adipogenesis and reducing the mass of subcutaneous adipose tissue, resulting in the reduction of weight gain, and improvements of hyperglycemia, hyperlipidemia, and insulin resistance in HFD-induced obese mice. In consistent to the results, alisol B also significantly inhibited adipocyte differentiation and maturation in vitro. Furthermore, our data revealed that the effects of alisol B on adipogenesis were mediated by LKB1-AMPK signaling pathway. In total, alisol B could be a potential lead compound which contributes to the improvement of obesity-related metabolic disorders.
Assuntos
Proteínas Quinases Ativadas por AMP , Obesidade , Camundongos , Animais , Obesidade/tratamento farmacológico , Obesidade/etiologia , Gordura Subcutânea , Colestenonas/farmacologia , Colestenonas/uso terapêutico , Adipogenia , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo , Camundongos Endogâmicos C57BLRESUMO
The 70% ethanol extract of the rhizome of Alisma orientale (Alismatis rhizome) (AOE) was prepared and found to significantly inhibit 5-lipoxygenase (5-LOX)-catalyzed leukotriene (LT) production from rat basophilic leukemia (RBL)-1 cells and ß-hexosaminidase release by antigen-stimulated RBL-2H3 cells. It also attenuated delayed-type hypersensitivity (DTH) reaction in mice. Among the three major triterpene constituents isolated (i.e., alisol B, alisol B 23-acetate, alisol C 23-acetate) as active principles, alisol B and its 23-acetate strongly and significantly inhibited LT production and ß-hexosaminidase release between 1-10 µM. On the other hand, all these alisol derivatives significantly and strongly inhibited DTH response after oral administration. In addition, AOE (200 mg/kg/d) was for the first time found to considerably alleviate hapten-induced dermatitis symptoms in NC/Nga mice, an animal model of atopic dermatitis. These results indicate that alisol derivatives possess inhibitory activities on immediate-type as well as delayed-type hypersensitivity reactions and may contribute to the anti-allergic action of AOE.
Assuntos
Alisma/química , Colestenonas/uso terapêutico , Dermatite Atópica/prevenção & controle , Hipersensibilidade Tardia/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Antígenos/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Linhagem Celular Tumoral , Colestenonas/farmacologia , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Haptenos/metabolismo , Hipersensibilidade Tardia/metabolismo , Leucemia , Leucotrienos/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos , Extratos Vegetais/farmacologia , Rizoma/química , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.
Assuntos
Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/tratamento farmacológico , Estudos Observacionais como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Colestenonas/uso terapêutico , Humanos , Oligonucleotídeos/uso terapêutico , Prognóstico , Resultado do TratamentoRESUMO
Alismatis rhizoma (AR) is the dried rhizome of Alisma orientale (Sam.) Juz. (Alismataceae). This traditional Chinese formula is diuretic, hypoglycemic, and hypolipidemic. Alisol C 23-acetate (AC23A) from AR is anti-inflammatory and ameliorates certain metabolic diseases. However, the mechanism by which AC23A mitigates osteoporosis is unknown. The present study investigated the anti-osteoporotic effects of AC23A in vivo and in vitro. In an ovariectomized (OVX) rat model, AC23A ameliorated OVX-induced organ coefficients and trabecular bone loss. In OVX rats, AC23A treatment lowered serum TRAP5b, CTK, ß-CTX, TNF-α, IL-6, and IL-1ß, raised serum E2, and did not significantly change serum OCN or BALP. AC23A inhibited osteoclast formation in a rat co-culture system without affecting osteoblast activity. RANK (receptor activator of nuclear factor kappaB) signaling channels are vital osteoclastogenesis transcription elements. AC23A inhibited RANK ligand (RANKL)-induced TRAP, c-Fos, MMP9, NFATc1, and CTK expression and JNK phosphorylation. Therefore, AC23A is anti-osteoclastogenic in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function. Moreover, AC23A could help prevent or limit osteoclast-mediated bone diseases by inhibiting osteoclastogenesis.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Colestenonas/uso terapêutico , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , Alisma/química , Animais , Osso e Ossos/patologia , Células Cultivadas , Técnicas de Cocultura , Medicamentos de Ervas Chinesas , Feminino , Osteoporose/patologia , Ovariectomia , Ligante RANK/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Malha Trabecular/efeitos dos fármacosRESUMO
Alchornea floribunda (Euphorbiaceae) leaves are widely used in African ethnomedicine for the management of acute and chronic inflammatory disorders. In the present study, bioactivity-guided fractionation led to the isolation of two known (1 and 3) and one new (2) stigmastane steroids from the hexane extract of Alchornea floribunda leaves. The anti-inflammatory activities of these compounds were evaluated using IN VITRO and IN VIVO animal models. The compounds 1, 2, and 3 at 50 and 100 microg/ear significantly (p < 0.05) inhibited xylene-induced ear edema in mice in a dose-dependent manner. The topical anti-inflammatory effect of 1 and 2 are significantly (p < 0.05) higher than that of indomethacin and prednisolone. At 20 mg/kg (i. p.), all the compounds significantly (p < 0.05) inhibited acute inflammation induced by subplantar injection of egg albumen in rats. Compound 1 exhibited an anti-inflammatory effect (50.9 % edema inhibition) comparable (p < 0.05) to that of prednisolone (48.0 % edema inhibition) at 3 h. Compounds 1, 2, and 3 (50 microg/mL) significantly (p < 0.05) inhibited heat-induced haemolysis of human erythrocytes in vitro, but had no effect on hypotonicity-induced hemolysis. The compounds were elucidated as (24R)-5alpha-stigmast-3,6-dione ( 1), 5alpha-stigmast - 23-ene-3,6-dione ( 2), and 3beta-hydroxy-5alpha-stigmast-24-ene ( 3) by spectral analysis. The results of this study show that these compounds may, in part, account for the anti-inflammatory effect of Alchornea floribunda leaves. This is the first report on the isolation and structure elucidation of these anti-inflammatory steroids from Alchornea floribunda leaves.
Assuntos
Anti-Inflamatórios/uso terapêutico , Membrana Celular/efeitos dos fármacos , Colestenonas/uso terapêutico , Edema/tratamento farmacológico , Euphorbiaceae/química , Fitosteróis/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Colestenonas/isolamento & purificação , Colestenonas/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Fitosteróis/isolamento & purificação , Fitosteróis/farmacologia , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta , Ratos , Ratos Wistar , XilenosRESUMO
In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA.
Assuntos
Colestenonas/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Atividade Motora/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AßPP) and mitochondrial dysfunction. METHODS: Three months old Thy-1-AßPPSL (tg) and wild type mice (wt) received TRO19622 (100â¯mg/kg b.w.) in supplemented food pellets for 15â¯weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aß1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aß1-40 levels were also determined in HEK-AßPPsw-cells. RESULTS: Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2⯵g/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aß1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells. CONCLUSIONS: TRO19622 improves mitochondrial dysfunction but enhances Aß levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aß, which could be harmful.