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1.
Life Sci ; 257: 118040, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622943

RESUMO

AIMS: Timosaponin AIII (TAIII), an active component with anti-tumor activity from Anemarrhena asphodeloides Bunge, can induce both autophagy and apoptosis of cancer cells. The present study aimed to reveal the promoting or inhibiting role of TAIII-induced autophagy on TAIII-induced apoptosis, to determine the respective upstream signaling pathways for TAIII-induced autophagy and apoptosis; and to observe the therapeutic potential of TAIII in human non-small cell lung cancer in vivo. METHODS AND MATERIALS: WST-1 assay was used to determine the effect of TAIII on cell growth and proliferation. Apoptosis was detected by DAPI staining and flow cytometry. Autophagy was verified by immunofluorescence and transmission electron microscopy. Western blot was used to determine the levels of protein expression. Furthermore, the anti-tumor activity of TAIII was observed in nude mice. KEY FINDINGS: TAIII at high concentrations from 10 µM to 30 µM induced both autophagy and apoptosis in human non-small cell lung cancer cells in a time- and concentration-dependent manner. TAIII at low concentration (1 µM) only induced autophagy. The AMP-activated protein kinase (AMPK) signaling pathway was identified to be responsible for TAIII-induced autophagy both at high or low concentrations. The MAPK/Erk1/2 signaling pathway was identified to be responsible for TAIII-induced apoptosis at the high concentration (20 µM). TAIII-induced autophagy protected cancer cells from apoptosis, and combination of TAIII and autophagy inhibitor showed higher anti-cancer activity.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Saponinas/farmacologia , Esteroides/farmacologia , Células A549 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Saponinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroides/metabolismo
2.
Int J Nanomedicine ; 15: 4573-4589, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606693

RESUMO

Background: Therapeutic efficiency of ceragenins against cancers may be limited by lack of their hemocompatibility when high concentrations of molecules are required to reach a desired result. Synergistic effects observed upon administration of anticancer agents and metal nanoparticles may provide an opportunity to limit toxicity of immobilized ceragenins on the surface of metal nanoparticles and to improve their therapeutic efficiency at the same time. The aim of present work is to investigate the anticancer activities and hemocompatibility of nanoformulations consisting of ceragenin CSA-131 united with aminosilane-modified iron oxide-based magnetic nanoparticles (MNP) and prepared by 1) covalent bonding (MNP@CSA-131) or 2) by combining CSA-131 with MNP in 1:1 ratio (CSA-131 + MNP). Possible synergistic interactions between CSA-131 and magnetic nanoparticles were also quantified. Methods: MNP@CSA-131 and CSA-131+MNP were tested in vitro against selected lung and colon cancer cells using colorimetric, fluorimetric and flow cytometry methods. Results: Performed analysis demonstrates that MNP-based nanosystems significantly improve the killing efficiency of tested ceragenin, decreasing the viability of extra 1.37±4.72% to 76.07±15.30% cancer cells when compared to free CSA-131. Quantification of synergistic effects indicates the favorable interactions between CSA-131 and magnetic nanoparticles (CI < 1 for all tested doses), revealing at the same time a reduction in effective doses of ceragenin from 1.17 ± 0.61 to 34.57 ± 12.78 times when combined with MNP. We demonstrate that both MNP@CSA-131 and CSA-131+MNP induce significantly apoptosis of cancer cells and prevent the division of colon cancer cells even at relatively low doses of the active compound (10 µg/mL). Importantly, combining CSA-131 with MNP decreases the hemolytic activity of free ceragenin 4.72 to 7.88 times, which indicates a considerable improvement of hemotoxicity profile. Conclusion: Comparative analyses have revealed that both developed CSA-containing nanoformulations due to the utility of synergistic interactions between MNP and CSA-131, which are effective against lung and colon cancer cells. This indicates the new directions in preparation of MNP-based therapeutics, which are relatively easy to synthetize, cost-effective and safe when intravenously administrated.


Assuntos
Compostos Férricos/uso terapêutico , Nanopartículas de Magnetita/uso terapêutico , Esteroides/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/patologia , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/ultraestrutura , Teste de Materiais
3.
CJEM ; 22(5): 591-594, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32438948

RESUMO

A 53-year-old male presents with cough, fever, and myalgias for 7 days. Vitals include temperature, 38.0°C; heart rate, 110; blood pressure, 118/70 mm Hg; respiration rate, 28; and oxygen saturation 83% on room air. His only past medical history is hypertension. Your community is in the midst of the coronavirus disease 2019 (COVID-19) pandemic. The patient is hypoxic but responds to oxygen supplementation with nasal cannula and a face mask. His chest x-ray demonstrates multifocal infiltrates. Are there any therapeutic agents currently available for COVID-19?


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Infecções por Coronavirus/tratamento farmacológico , Tratamento Farmacológico/métodos , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Alanina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacologia , Infecções por Coronavirus/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Determinação de Necessidades de Cuidados de Saúde , Pandemias , Segurança do Paciente , Pneumonia Viral/epidemiologia , Medição de Risco , Síndrome Respiratória Aguda Grave/diagnóstico , Índice de Gravidade de Doença , Esteroides/administração & dosagem , Esteroides/farmacologia , Resultado do Tratamento
5.
Leukemia ; 34(5): 1229-1240, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32242050

RESUMO

Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroid-refractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.


Assuntos
Resistência a Medicamentos , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Esteroides/farmacologia , Doença Aguda , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos
7.
Chem Pharm Bull (Tokyo) ; 68(3): 273-287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115535

RESUMO

Phytochemical analysis of the whole Helleborus foetidus plants identified 28 steroidal glycosides (1-28), including 20 novel spirostanol glycosides (1-20) and a novel furostanol glycoside (21). The structures of the newly identified compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic cleavage. Compounds 12, 13, and 15 were determined to be spirostanol trisdesmosides bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone unit. The isolated compounds were subsequently evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells. In particular, 7 showed cytotoxic activity against the HL-60 and A549 cells, with IC50 values of 5.9 and 6.6 µM, respectively, whereas 19 was selectively cytotoxic to A549 cells with an IC50 value of 5.5 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glicosídeos/farmacologia , Helleborus/química , Compostos Fitoquímicos/farmacologia , Esteroides/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Glicosídeos/isolamento & purificação , Células HL-60 , Humanos , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Esteroides/química , Esteroides/isolamento & purificação , Relação Estrutura-Atividade
8.
Br J Anaesth ; 124(5): 603-613, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151384

RESUMO

BACKGROUND: The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABAA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABAA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABAA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development. METHODS: The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups. RESULTS: CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABAA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents. CONCLUSIONS: The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.


Assuntos
Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/toxicidade , Pregnanodionas/toxicidade , Esteroides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Agonistas de Receptores de GABA-A/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Hipocampo/patologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacologia , Propofol/administração & dosagem , Propofol/farmacologia , Propofol/toxicidade , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Esteroides/administração & dosagem , Esteroides/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
9.
J Steroid Biochem Mol Biol ; 198: 105575, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31899316

RESUMO

Diabetes mellitus is a chronic and common metabolic disease that seriously endangers human health. Hyperglycemia and long-term metabolic disorders in diabetes will cause damage to the whole body tissues and organs, resulting in serious complications. Nowadays, drugs for treating diabetes on the market has strong side effects, new treatments thus are urgently needed. Natural therapy of natural ingredients is a promising avenue, this is because natural ingredients are safer and they also show strong activity in the treatment of diabetes. Diosgenin is such a very biologically active natural steroidal sapogenin. The research of diosgenin in the treatment of diabetes and its complications has been widely reported. This article reviews the effects of diosgenin through multiple targets and multiple pathways in diabetes and its complications which including diabetic nephropathy, diabetic liver disease, diabetic neuropathy, diabetic vascular disease, diabetic cardiomyopathy, diabetic reproductive dysfunction, and diabetic eye disease.


Assuntos
Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Diosgenina/farmacologia , Animais , Apoptose , Feminino , Glicolipídeos/metabolismo , Células Hep G2 , Humanos , Hipoglicemia/metabolismo , Inflamação , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Estresse Oxidativo , Plantas/química , Coelhos , Ratos , Esteroides/farmacologia
10.
J Nanobiotechnology ; 18(1): 3, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898542

RESUMO

Nanotechnology-based therapeutic approaches have attracted attention of scientists, in particular due to the special features of nanomaterials, such as adequate biocompatibility, ability to improve therapeutic efficiency of incorporated drugs and to limit their adverse effects. Among a variety of reported nanomaterials for biomedical applications, metal and metal oxide-based nanoparticles offer unique physicochemical properties allowing their use in combination with conventional antimicrobials and as magnetic field-controlled drug delivery nanocarriers. An ever-growing number of studies demonstrate that by combining magnetic nanoparticles with membrane-active, natural human cathelicidin-derived LL-37 peptide, and its synthetic mimics such as ceragenins, innovative nanoagents might be developed. Between others, they demonstrate high clinical potential as antimicrobial, anti-cancer, immunomodulatory and regenerative agents. Due to continuous research, knowledge on pleiotropic character of natural antibacterial peptides and their mimics is growing, and it is justifying to stay that the therapeutic potential of nanosystems containing membrane active compounds has not been exhausted yet.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Membrana Celular/efeitos dos fármacos , Invenções , Nanopartículas de Magnetita/química , Esteroides/farmacologia , Humanos
11.
Food Chem ; 312: 126061, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31891886

RESUMO

In the context of mRNA biomarker profiling, formalin fixed paraffin embedded (FFPE) samples represent an interesting source for retrospective analysis. However, the implementation in routine analysis of FFPE samples, following legislation demands for validated and accredited methods, often requires critical revision and optimization. In the frame of an official control program the validation study of a molecular test for detection of sex steroids administration in calves, based on quantification of progesterone-Receptor mRNA in bulbo-urethral gland samples, was performed: analyses were made on FFPE tissues sections routinary used for histological investigations and compared with RNAlater tissue preservation. To overcome the limitations of original assays several modifications were tested. Obtained results confirmed how Progesterone-Receptor assay represent a useful tool to study suspected cases of sex steroid illicit administration in veal calves, complementary to histological and/or immune histochemical investigation, overcoming the limitation of field studies, where optimal pre-analytical condition cannot always be guarantee.


Assuntos
Reação em Cadeia da Polimerase em Tempo Real/métodos , Carne Vermelha , Animais , Biomarcadores/análise , Bovinos , Feminino , Formaldeído/química , Perfilação da Expressão Gênica , Humanos , Inclusão em Parafina , RNA Mensageiro/genética , Receptores de Progesterona/genética , Estudos Retrospectivos , Esteroides/farmacologia , Fixação de Tecidos
12.
Appl Biochem Biotechnol ; 190(1): 57-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31301012

RESUMO

To address the high demand for Pueraria candollei var. mirifica (PM) used as the active ingredient in health products and its difficulty to cultivate in the field, the growth and production of deoxymiroestrol (DME) and isoflavonoid (ISF) phytoestrogens in PM cell suspensions were studied. In a 125-mL shake flask, the cell suspension produced DME [78.7 ± 8.79-116 ± 18.2 µg/g dry weight (DW)] and ISF (140 ± 6.83-548 ± 18.5 µg/g DW), which are the predominant ISF glycosides. While ISF aglycones accumulated in the PM cell suspension cultured in the airlift bioreactor. The DME content was increased to 976 ± 79.6 µg/g DW when the PM cell suspension was cultured in the 5-L scale bioreactor. The production of DME and ISF was enhanced by elicitors including methyl jasmonate (MJ), yeast extract (YE), and chitosan (CHI). MJ produced the highest induction of DME accumulation, while ISF accumulation was the highest with YE treatment. Analysis of catalase activity implied that the elicitors enhanced ROS production, which resulted in the enhancement of DME and ISF production and accumulation in PM cell suspension cultures. PM cell suspension culture is a promising source of beneficial PM phytoestrogens that exhibit bioactivity that may useful for the treatment of menopausal symptoms.


Assuntos
Reatores Biológicos , Flavonoides/biossíntese , Pueraria/metabolismo , Catalase/metabolismo , Cumarínicos/farmacologia , Flavonoides/farmacologia , Fitoestrógenos/metabolismo , Pueraria/citologia , Pueraria/crescimento & desenvolvimento , Esteroides/biossíntese , Esteroides/farmacologia
13.
Eur J Med Chem ; 187: 111909, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830636

RESUMO

Hybrid chemical compounds formed by conjugation of two or more bioactive molecules have shown wide variety of applications in biology, microelectronics as well as material sciences. In particular, the conjugates of steroid framework are known to have broad biological activity profile due to their ability to penetrate the biomembranes and bind to specific hormone receptors. Among the various conjugates of steroids, Steroid Amino Acid Conjugates (SAACs) are attractive because of the possibility of fine tuning of the amphiphilicity with position, orientation and nature of amino acids. The structural details, applications, mechanistic insights and their diverse pharmacological as well as other physicochemical properties of several SAACs are summarized in the present review. This review provides better insight for medicinal chemists to design and explore such novel conjugates which can be used as lead structures in the future drug discovery or as probes to understand the complex biological system.


Assuntos
Aminoácidos/farmacologia , Esteroides/farmacologia , Aminoácidos/química , Animais , Humanos , Conformação Molecular , Esteroides/química
14.
J Colloid Interface Sci ; 563: 207-217, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31874308

RESUMO

The present paper discusses the use of monolayers of lipid mixtures mimicking the composition of biological membranes of bacteria, erythrocyte and yeast in the context of the anti-bacterial, hemolytic and anti-fungal activity of saponins. Saponins are plant-produced glycosidic biosurfactants with either steroidal or triterpenoidal aglycone. In the present study we used digitonin as a representative steroidal saponin (extracted from Digitalis purpurea) and a mixture of triterpenoid saponins from Quillaja saponaria Molina. The effect of saponins was studied first on monolayers consisting of single lipids characteristic for the given type of biological membrane, and then - on model mixed lipid monolayers. Finally, the monolayers were formed from total lipid extracts of natural cell membranes (E. coli and S. cerevisiae) to verify the results obtained in the simplified models. The effect of saponins on monolayers was studied by a combination of surface pressure relaxation, infrared reflection - absorption spectroscopy (IRRAS) and fluorescence microscopy. In line with expectations, sterols (cholesterol and ergosterol) play a major role in the saponin-lipid interactions in monolayers, which may explain especially the hemolytic and antifungal properties of saponins. In contrast, bacterial membranes are devoid of sterols, although the presence of similar compounds may be responsible for their affinity to saponins. Nevertheless, the effect of saponins on bacterial models is less pronounced than for the erythrocyte or fungal ones.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Antibacterianos/química , Antifúngicos/química , Membrana Celular/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Microscopia de Fluorescência , Estrutura Molecular , Tamanho da Partícula , Saponinas/química , Saponinas/farmacologia , Esteroides/química , Esteroides/farmacologia , Propriedades de Superfície , Triterpenos/química , Triterpenos/farmacologia
15.
Commun Biol ; 2: 416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754646

RESUMO

In black African children with focal segmental glomerulosclerosis (FSGS) there are high rates of steroid resistance. The aim was to determine genetic associations with apolipoprotein L1 (APOL1) renal risk variants and podocin (NPHS2) variants in 30 unrelated black South African children with FSGS. Three APOL1 variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and controls. APOL1 risk alleles show a modest association with steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic syndrome (SRNS). The NPHS2 V260E variant was present in SRNS cases (V/V = 5; V/E = 4; E/E = 11), and was absent in SSNS cases. Haplotype analysis suggests a single mutation origin for V260E and it was associated with a decline in kidney function over a 60-month period (p = 0.026). The V260E variant is a good predictor of autosomal recessive SRNS in black South African children and could provide useful information in a clinical setting.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Alelos , Substituição de Aminoácidos , Glomerulosclerose Segmentar e Focal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Síndrome Nefrótica/genética , Apolipoproteína L1/genética , Criança , Pré-Escolar , Resistência a Medicamentos/genética , Feminino , Genótipo , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Haplótipos , Humanos , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Linhagem , Esteroides/farmacologia , Esteroides/uso terapêutico
16.
Chin J Nat Med ; 17(10): 778-784, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31703758

RESUMO

Thibetanosides E-H (1-4), four new steroidal constituents including three rare sulfonates (2-4), were isolated from the roots and rhizomes of Helleborus thibetanus, together with nine known steroidal compounds (5-13). Their structures were elucidated by detailed spectroscopic analysis, including 1D and 2D NMR techniques and chemical evidence. In this study, compounds 2-13 were evaluated for their cytotoxic activities against HCT116, A549 and HepG2 tumor cell lines in vitro. Among them, compound 8 (thibetanoside C) showed cytotoxicities against A549 cells(IC50 39.6 ± 1.9 µmol·L-1) and HepG2 cells(IC50 41.5 ± 1.1 µmol·L-1), respectively. Compound 9 (23S, 24S)-24-[(O-ß-D-fucopyranosyl)oxy]-3ß, 23-dihydroxy-spirosta-5, 25(27)-diene-1ß-ylO-(4-O-acetyl- α-L-rhamnopyranosyl)-(1→2)-O-[ß-D-xylopyranosyl-(1→3)]-α-L-arabinopyranoside) showed cytotoxicity against HCT116 cells(IC50 33.6 ± 2.1 µmol·L-1).


Assuntos
Citotoxinas/química , Medicamentos de Ervas Chinesas/química , Helleborus/química , Esteroides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citotoxinas/isolamento & purificação , Citotoxinas/toxicidade , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Estrutura Molecular , Raízes de Plantas/química , Esteroides/isolamento & purificação , Esteroides/farmacologia
17.
Thromb Res ; 183: 63-68, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669825

RESUMO

INTRODUCTION: Immune thrombocytopenia (ITP) is known as an immune-mediated disease and often evolves to chronic type in adult. Corticosteroids only work in around 60% of patients. This study evaluated the roles of subgroup lymphocytes from peripheral blood in ITP adults with different treatment response. METHODS: Between October 2009 and March 2017, 37 adults were newly diagnosed as ITP requiring treatment. The patients were separated into two groups: 23 patients with platelet count <50,000/µL with corticosteroid dependence or second-line treatment (Poor-responder Group), and 14 patients with platelet counts <50,000/µL with standard steroid treatment, which stopped within three months (Good-responder Group). Subgroup lymphocyte percentages of peripheral blood were determined through flow cytometry before treatment. Data analysis with Mann-Whitney test and receiver operating characteristic curves were performed using GraphPad Prism (Version 7). A p-value of <0.05 was considered significant. RESULTS: Lymphocyte percentage was significantly lower in Poor-responder Group than in Good-responder Group (p = 0.008). In subgroup lymphocytes, higher percentages of CD19+ B lymphocytes were found in Good-responder Group (p = 0.03). In Poor-responder Group, a higher CD2+ and CD56+ lymphocytes were observed (p = 0.02 and 0.03). By the cut-off value of percentage of CD56+ lymphocytes with 24.5% or CD2+ lymphocytes with 85.7%, the specificity showed 92.86%. CONCLUSIONS: This study found that newly diagnosed ITP patients with increased percentages of CD56+ or CD2+ lymphocytes in peripheral blood associated with a poorer response to steroid treatment.


Assuntos
Antígenos CD2/metabolismo , Antígeno CD56/metabolismo , Linfócitos/metabolismo , Esteroides/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esteroides/farmacologia
18.
Molecules ; 24(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614780

RESUMO

A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,ß-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI50 values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pirimidinas/farmacologia , Esteroides/farmacologia , Acetatos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Nitrogênio/química , Pregnenolona/química , Pirimidinas/síntese química , Pirimidinas/química , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade
19.
Asian Pac J Cancer Prev ; 20(10): 3057-3070, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31653155

RESUMO

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa -fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Drogas em Investigação/farmacologia , Inflamação/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Esteroides/farmacologia , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/patologia , Drogas em Investigação/química , Inflamação/patologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Neovascularização Patológica/patologia , Ratos , Ratos Wistar , Esteroides/química
20.
PLoS One ; 14(10): e0224081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622417

RESUMO

Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested. Here we show that intact cells rapidly accumulate free steroids to markedly elevated concentrations. This effect varies widely depending on steroid structure; more lipophilic steroids reach more elevated concentrations. Strong preferences exist for 3ß-OH, Δ5-steroids vs. 3-keto, Δ4-structural features and for progestogens vs. androgens. Surprisingly, steroid-structure-specific preferences do not require cell viability, implying a passive mechanism, and occur across cells derived from multiple tissue types. Physiologic relevance is suggested by structure-specific preferences in human prostate tissue compared with serum. On the other hand, the presence of serum proteins in vitro blocks much, but not all, of the passive accumulation, while still permitting a substantial amount of active accumulation for certain steroids. Our findings suggest that both passive and active uptake mechanisms make important contributions to the cellular steroid uptake process. The role of passive, lipophilicity-driven accumulation has previously been largely unappreciated, and its existence provides important context to studies on steroid transport and action both in vitro and in vivo.


Assuntos
Esteroides/metabolismo , Androgênios/análise , Androgênios/sangue , Androgênios/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Desidroepiandrosterona/análise , Desidroepiandrosterona/metabolismo , Humanos , Cinética , Pregnenolona/análise , Pregnenolona/metabolismo , Progesterona/análise , Progesterona/metabolismo , Progesterona/farmacologia , Esteroides/análise , Esteroides/farmacologia , Espectrometria de Massas em Tandem
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