RESUMO
Mesenchymal stem cells (MSCs) are multipotent cells characterized by self-renewal and cellular differentiation capabilities. Oxysterols comprise a very heterogeneous group derived from cholesterol through enzymatic and non-enzymatic oxidation. Potent effects in cell death processes, including cytoxicity and apoptosis induction, were described in several cell lines. Very little is known about the effects of oxysterols in MSCs. 7-ketocholesterol (7-KC), one of the most important oxysterols, was shown to be cytotoxic to human adipose tissue-derived MSCs. Here, we describe the short-term (24h) cytotoxic effects of cholestan-3α-5ß-6α-triol, 3,5 cholestan-7-one, (3α-5ß-6α)- cholestane-3,6-diol, 7-oxocholest-5-en-3ß-yl acetate, and 5ß-6ß epoxy-cholesterol, on MSCs derived from human adipose tissue. MSCs were isolated from adipose tissue obtained from three young, healthy women. Oxysterols, with the exception of 3,5 cholestan-7-one and 7-oxocholest-5-en-3ß-yl acetate, led to a complex mode of cell death that include apoptosis, necrosis and autophagy, depending on the type of oxysterol and concentration, being cholestan-3α-5ß-6α-triol the most effective. Inhibition of proliferation was also promoted by these oxysterols, but no changes in cell cycle were observed.
Assuntos
Tecido Adiposo/citologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Oxisteróis/farmacologia , Actinas/metabolismo , Adulto , Apoptose , Autofagia , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular , Proliferação de Células , Sobrevivência Celular , Colestanos/farmacologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Cetocolesteróis/farmacologia , Potenciais da Membrana , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Necrose , OxirreduçãoRESUMO
Twelve polyhydroxylated sulfated steroids synthesized from a 5α-cholestane skeleton with different substitutions in C-2, C-3 and C-6 were evaluated for cytotoxicity and antiviral activity against herpes simplex virus (HSV) by a virus plaque reduction assay. Four compounds elicited a selective inhibitory effect against HSV. The disodium salt of 2ß,3α-dihydroxy-6E-hydroximine-5α-cholestane-2,3-disulfate, named compound 7, was the most effective inhibitor of HSV-1, HSV-2 and pseudorabies virus (PrV) strains, including acyclovir-resistant variants, in human and monkey cell lines. Preliminary mechanistic studies demonstrated that compound 7 did not affect the initial steps of virus entry but inhibited a subsequent event in the infection process of HSV.
Assuntos
Antivirais/farmacologia , Colestanos/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Esteroides/farmacologia , Animais , Antivirais/química , Linhagem Celular , Colestanos/química , Herpes Genital/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/fisiologia , Humanos , Estrutura Molecular , Esteroides/química , Relação Estrutura-Atividade , Internalização do Vírus/efeitos dos fármacosRESUMO
The spirostanic steroidal side-chain of diosgenin and hecogenin was modified to produce 22-oxocholestane derivatives. This type of side-chain was obtained in good yields through a straightforward four-step pathway. These compounds show potent brassinosteroid-like growth promoting activity evaluated via the rice lamina joint inclination bioassay. This is the first report of steroidal skeletons bearing the 22-oxocholestane side-chain and preserving the basic structure (A-D rings) from their corresponding parent compounds acting as plant growth promoters.
Assuntos
Colestanos , Oryza/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas , Colestanos/síntese química , Colestanos/química , Colestanos/farmacologia , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologiaRESUMO
The synthesis and biological evaluation of three new cholestane frameworks of the type: (25R)-3ß,16ß-Diacetoxy-23-ethylidene-26-hydroxy-22-oxocholestane, starting from spirostanic sapogenins of the 25R series, is described. The compounds were obtained by the reductive cleavage of the F ring of 22-oxo-23(1),26-epoxycholestane derivatives using 9-BBN. These modified derivatives exhibit cytotoxic activity against CEM and MCF7 cells and are able to induce apoptosis in them. Its effect on the cell cycle was determined.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Colestanos/síntese química , Colestanos/farmacologia , Sapogeninas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Colestanos/química , HumanosRESUMO
In a previous work our group showed that some synthetic stigmastanes may play a role in immune-mediated inflammation. In this paper we report the syntheses of a series of new steroidal compounds derived from dehydroepiandrosterone and stigmasterol, and the evaluation of their in vitro inhibitory activity of the TNF-alpha production by macrophages. A preliminary qualitative structure-activity relationship was established.
Assuntos
Androstanos/síntese química , Androstanos/farmacologia , Colestanos/síntese química , Colestanos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Androstanos/química , Animais , Linhagem Celular , Colestanos/química , Desidroepiandrosterona/química , Avaliação Pré-Clínica de Medicamentos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Camundongos , Estrutura Molecular , Estigmasterol/química , Relação Estrutura-AtividadeRESUMO
A phytochemical investigation of the stems of the South Brazilian endemic species Raulinoa echinata has led to the isolation of two new methoxylated protolimonoid epimers (1 and 2) together with the known melianone and melianodiol. The leaves afforded three glabretal-type triterpene derivatives esterified by N-methylanthranilic acid (3-5). Compounds 1 and 2 displayed weak inhibitory activity when assayed in vitro against trypomastigote forms of Trypanosoma cruzi. Compounds 1-5 were inactive in a brine shrimp (Artemia salina) lethality test.