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1.
Phytomedicine ; 92: 153715, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34474353

RESUMO

BACKGROUND: The regulative effects of caudatin, a C-21 steroid that is identified from Cynanchum bungee roots, on adipogenesis and obesity have not been studied. Many studies have demonstrated that the activation of hedgehog (Hh) signaling can help prevent obesity. Therefore, we hypothesized that caudatin can inhibit adipogenesis and obesity via activating the Hh signaling pathway. METHODS: To investigate the effects of caudatin on adipogenesis in 3T3-L1 preadipocytes and high-fat diet induced obesity in C57BL/6 mice, in vitro and in vivo experiments were performed. For in vitro evaluation, Oil red O staining were used to represent lipid accumulation in differentiated 3T3-L1 adipocytes. For in vivo assessment, male 5 week-old C57BL/6 mice were fed with standard chow diet, high-fat diet (HFD), HFD with 25 mg/kg caudatin, HFD with 1mg/kg purmorpharmine for 10 weeks, respectively. Hh signaling and key adipogenic marker involved in adipogenesis were evaluated by real-time PCR and western blot. The adipocyte size of white adopose tissue and lipid storage of liver were visualized by hematoxylin and eosin staining. In addition, the expression of Gli1 and peroxisome proliferator-activated receptor γ (PPARγ) in white adipose tissue were investigated by immunohistochemistry staining. RESULTS: Caudatin suppressed the accumulation of lipid droplets and downregulated the expression of key adipogenic factors, i.e., peroxisome proliferator-activated receptor γ PPARγ and CCAAT-enhancer binding protein α (C/EBPα), through activating Hh signaling in differentiated 3T3-L1 cells. Furthermore, caudatin and the Hh activator purmorpharmine significantly decreased body weight gain and white adipose tissue (WAT) weight in HFD-induced mice and affected adipogenic markers and Hh signaling mediators in WAT, which were in line with the in vitro experimental results. CONCLUSION: To our best knowledge, it is the first report to demonstrate that caudatin downregulated adipocyte differentiation and suppressed HFD-induced body weight gain through activating the Hh signaling pathway, suggesting that caudatin can potentially counteract obesity.


Assuntos
Adipogenia , Fármacos Antiobesidade , Células 3T3-L1 , Adipócitos , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica/efeitos adversos , Glicosídeos , Proteínas Hedgehog , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama , Transdução de Sinais , Esteroides/farmacologia , Ganho de Peso
2.
Biomolecules ; 11(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356650

RESUMO

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.


Assuntos
Maleato de Dizocilpina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/tratamento farmacológico , Esteroides/farmacologia , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Modelos Animais de Doenças , Teste de Labirinto em Cruz Elevado , Células HEK293 , Humanos , Masculino , Pregnenolona/metabolismo , Pregnenolona/farmacologia , Ratos Long-Evans , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/metabolismo
3.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279417

RESUMO

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds ß-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Esteroides/farmacologia , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micrometástase de Neoplasia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202717

RESUMO

Timosaponin BII is one of the most abundant Anemarrhena saponins and is in a phase II clinical trial for the treatment of dementia. However, the pharmacological activity of timosaponin BII does not match its low bioavailability. In this study, we aimed to determine the effects of gut microbiota on timosaponin BII metabolism. We found that intestinal flora had a strong metabolic effect on timosaponin BII by HPLC-MS/MS. At the same time, seven potential metabolites (M1-M7) produced by rat intestinal flora were identified using HPLC/MS-Q-TOF. Among them, three structures identified are reported in gut microbiota for the first time. A comparison of rat liver homogenate and a rat liver microsome incubation system revealed that the metabolic behavior of timosaponin BII was unique to the gut microbiota system. Finally, a quantitative method for the three representative metabolites was established by HPLC-MS/MS, and the temporal relationship among the metabolites was initially clarified. In summary, it is suggested that the metabolic characteristics of gut microbiota may be an important indicator of the pharmacological activity of timosaponin BII, which can be applied to guide its application and clinical use in the future.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Saponinas/farmacocinética , Esteroides/farmacocinética , Animais , Biotransformação , Masculino , Ratos , Ratos Sprague-Dawley , Saponinas/farmacologia , Esteroides/farmacologia
5.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281176

RESUMO

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 µM) and colon cancer HT29 (IC50 9.0 ± 0.4 µM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 µM; HT29: IC50 7.4 ± 0.6 µM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 µM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.


Assuntos
Óxidos N-Cíclicos/química , Bibliotecas de Moléculas Pequenas/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Ácido Cólico/química , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Ácido Fusídico/química , Humanos , Neoplasias/tratamento farmacológico , Triterpenos Pentacíclicos/química , Marcadores de Spin , Esteroides/farmacologia , Triterpenos/farmacologia
6.
Sci Rep ; 11(1): 12301, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112889

RESUMO

Oxidative and glycolytic muscle fibers differ in their ultrastructure, metabolism, and responses to physiological stimuli and pathological insults. We examined whether these fibers respond differentially to exogenous anabolic androgenic steroids (AASs) by comparing morphological and histological changes between the oxidative anterior latissimus dorsi (ALD) and glycolytic pectoralis major (PM) fibers in adult avian muscles. Adult female White Leghorn chickens (Gallus gallus) were randomly divided into five groups: a vehicle control and four mesterolone treatment groups (4, 8, 12, and 16 mg/kg). Mesterolone was administered orally every three days for four weeks. Immunocytochemical techniques and morphometric analyses were employed to measure the changes in muscle weight, fiber size, satellite cell (SC) composition, and number of myonuclei. Mesterolone increased both body and muscle weights and induced hypertrophy in glycolytic PM fibers but not in oxidative ALD fibers. Mesterolone induced SC proliferation in both muscles; however, the myonuclear accretion was noticeable only in the PM muscle. In both muscles, the collective changes maintained a constant myonuclear domain size and the changes were dose independent. In conclusion, mesterolone induced distinct dose-independent effects in avian oxidative and glycolytic skeletal muscle fibers; these findings might be clinically valuable in the treatment of age-related sarcopenia.


Assuntos
Mesterolona/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Células Satélites de Músculo Esquelético/metabolismo , Músculos Superficiais do Dorso/crescimento & desenvolvimento , Anabolizantes/farmacologia , Androgênios/farmacologia , Animais , Galinhas , Glicólise/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Esteroides/farmacologia , Músculos Superficiais do Dorso/efeitos dos fármacos
7.
Phytochemistry ; 189: 112816, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34087503

RESUMO

Five undescribed sterol derivatives, (22E,24R)-7α-methoxy-5α,6α-epoxyergosta-8(14),22-diene-3ß,15ß-diol, (22E,24R)-5α,6α-epoxyergosta-8(14),22-diene-3ß,7ß,15α-triol, (22E,24R)-3ß,5α-dihydroxy-14ß,15ß-epoxyergosta-7,22-diene-6-one, (22E,24R)-6α-methoxy-7α,15ß-dihydroxyergosta-4,8(14),22-triene-3-one, and (25S)-ergosta-7,24(28)-diene-3ß,4α,6α,26-tetraol were isolated from the extract of Talaromyces stipitatus, along with eight known congeners. This is the first example of a class of ergosterols isolated from T. stipitatus. Their structures with absolute configurations were elucidated based on NMR spectroscopic data, ECD calculations, and X-ray crystallographic analyses. All these compounds were tested for their effects on three hepatoma cell lines including Hep3B, HepG2, and Huh-7. Moreover, (22E,24R)-5α,6α-epoxyergosta-8(14),22-diene-3ß,7ß,15α-triol and (22E,24R)-9α,15α-dihydroxyergosta-4,6,8(14),22-tetraen-3-one were further evaluated for their impacts on cell cycle progression and apoptosis due to their pronounced cytotoxicity, to uncover their underlying mechanisms. Our results suggested that their antiproliferative activities were mainly mediated by inducing cell apoptosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Talaromyces , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Estrutura Molecular , Esteroides/farmacologia
8.
Fitoterapia ; 152: 104938, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34022295

RESUMO

Two new steroidal glycosides oxystauntoside A (1) and oxystauntoside B (2), together with sixteen known compounds (3-18) were isolated from the 95% ethanol extract of Merrillanthus hainanensis. Their structures were characterized by extensive spectroscopic analysis including NMR and mass spectra and single crystal X-ray crystallography. The absolute configuration of 1 and 2 were further determined by ECD calculations. All of these compounds were isolated from M. hainanensis for the first time. All the fractions and compounds were tested for the anti-inflammatory activity against the TNF-α factor. The ethyl acetate fraction showed the most potent inhibition (71.3%) at 10 µg/mL and compounds 5 (78.9%) and 9 (73.4%) in this fraction with both carboxyl and phenolic hydroxyl groups showed significant inhibition at 10 µM. Our study provided the first scientific report for the medicinal value of M. hainanensis.


Assuntos
Anti-Inflamatórios/farmacologia , Apocynaceae/química , Glicosídeos/farmacologia , Esteroides/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/isolamento & purificação , China , Glicosídeos/isolamento & purificação , Estrutura Molecular , Esteroides/isolamento & purificação
9.
Free Radic Biol Med ; 171: 112-123, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33992678

RESUMO

Defective autophagy occurred in osteoblasts under stress induced by high glucose and played an essential role in the development of diabetic osteoporosis. Timosaponin BII, a steroidal saponin isolated from the rhizomes of Anemarrhena asphodeloides Bunge, possessed anti-osteoporosis properties. In this study, we investigated the efficacy and mechanism of timosaponin BII on diabetic osteoporosis. Timosaponin BII attenuated the deterioration in the microarchitecture of the tibias in diabetic rats. Furthermore, treatment with timosaponin BII dose-dependently reduced hyperglycemia-induced cell apoptosis in primary osteoblasts from rat calvaria. High glucose-exposed osteoblasts exhibited increased mitochondrial superoxide level, decreased mitochondrial membrane potential and impaired autophagic flux, which was attenuated by timosaponin BII, as evidenced by the upregulation of autophagosome numbers, LC3B puncta formation and Beclin1 expression. The antiapoptotic and antioxidative effect of timosaponin BII were repressed by the autophagy inhibitor 3-methyladenine and enhanced by the autophagy inducer rapamycin. Further studies showed that timosaponin BII suppressed the phosphorylation of mTOR and S6K, as well as the downstream factors NFκB and IκB, consequently activating autophagy and decreasing apoptosis. Of note, coincubation of timosaponin BII with MHY1485, a pharmacological activator of mTOR, diminished the protein expression of Bcl2 induced by timosaponin BII, which was in parallel with decreased autophagy and increased phosphorylation of NFκB and IκB. Overexpression of NFκB reduced timosaponin BII-evoked autophagy and promoted apoptosis. The in vivo results showed that oral administration of timosaponin BII downregulated the phosphorylation of mTOR and NFκB and upregulated Beclin1 expression in the proximal tibias of diabetic rats. These results suggested that timosaponin BII attenuated high glucose-induced oxidative stress and apoptosis through activating autophagy by inhibiting mTOR/NFκB signalling in osteoblasts.


Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Osteoporose , Saponinas , Animais , Apoptose , Autofagia , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Osteoblastos , Osteoporose/tratamento farmacológico , Ratos , Saponinas/farmacologia , Transdução de Sinais , Esteroides/farmacologia , Serina-Treonina Quinases TOR/genética
10.
Phytochemistry ; 188: 112798, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34020274

RESUMO

As part of our ongoing study of the specialised metabolites present in brown algae belonging to the Cystophora genus, eight new steroids including three pairs of diastereoisomers were isolated from Cystophora xiphocarpa (Harvey) (Sargassacea, Fucales). The metabolites identified by standard spectrometric methods are (16S,22S)-16,22-dihydroxyergosta-4,24(28)-dien-3-one and (16S,22R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one, (16S,22S,24R)-16,22,24-trihydroxyporifera-4,28-dien-3-one and (16S,22S,24S)-16,22,24-trihydroxystigma-4,28-dien-3-one along with (16S,22S,24E)-16,22-dihydroxystigma-4,24(28)-dien-3-one and (16S,20S)-16,20-dihydroxyergosta-4,24(28)-dien-3-one. (16S,22S,24E)-16,22-Dihydroxystigma-4,24(28)-dien-3-one possessed the most potent cytotoxicity of the steroids in this series with cell growth inhibitions of GI50 8.7 ± 0.7 µM against colon cancer HT29, GI50 5.6 ± 0.8 µM against the breast cancer line MCF-7 and GI50 4.5 ± 0.2 µM against the ovarian cancer cell line A2780. (16S,22R)-16,22-dihydroxyergosta-4,24(28)-dien-3-one was found to be active against the ovarian cancer cell line A2780 with a GI50 of 6.2 ± 0.1 µM.


Assuntos
Neoplasias Ovarianas , Feófitas , Austrália , Linhagem Celular Tumoral , Feminino , Humanos , Esteroides/farmacologia
11.
Bioorg Chem ; 111: 104893, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33882364

RESUMO

To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure-activity relationship analysis.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Esteroides/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/síntese química , Alcaloides/química , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Estrutura Molecular , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade
12.
Molecules ; 26(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807346

RESUMO

Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been demonstrated to have bioactive polyphenols, flavonoids, phytosterols, and essential nutrients for health benefits, including anticancer effects in humans. However, little is known about the effect of adlay seeds on endometrial cancer. Our study aimed to investigate the potential growth inhibitory effects of several adlay seed fractions, including ethyl acetate (ATE-EA) and its bioactive constituents, separately on endometrial cancer cells-HEC-1A (phosphatase and tensin homolog-positive) and RL95-2 (phosphatase and tensin homolog-negative)-and identify related active ingredients. In addition, the potential active fractions and the phytochemical compounds were elucidated. The results demonstrate superior activity of ATE-EA with significant in vitro cell proliferation inhibitory capacity, particularly its C.D.E.F-subfraction. Moreover, HPLC- and GC/FID-based quantification of ATE-EA subfractions showed that phenolic compounds (caffeic acid, protocatechuic acid, and p-hydroxybenzaldehyde), flavonoids, steroids, and fatty acid compounds exert anti-proliferative effects in the cell model. Finally, it was shown that cell growth and cell cycle arrest most significantly occurred in the in G1 or G2/M phase under ATE-EA treatment. Collectively, our results demonstrate an antiproliferative effect of ATE-EA on endometrial cancer cells that suggest a positive health outcome for women from consumption of these compounds.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Coix/metabolismo , Neoplasias do Endométrio/tratamento farmacológico , Extratos Vegetais , Linhagem Celular Tumoral , Feminino , Flavonoides/farmacologia , Humanos , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Esteroides/farmacologia
13.
Mar Drugs ; 19(5)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923288

RESUMO

The review focuses on sulfated steroids that have been isolated from seaweeds, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. Sulfur-containing steroids and triterpenoids are sourced from sedentary marine coelenterates, plants, marine sediments, crude oil, and other geological deposits. The review presents the pharmacological profile of sulfated steroids, sulfur-containing steroids, and triterpenoids, which is based on data obtained using the PASS program. In addition, several semi-synthetic and synthetic epithio steroids, which represent a rare group of bioactive lipids that have not yet been found in nature, but possess a high level of antitumor activity, were included in this review for the comparative pharmacological characterization of this class of compounds. About 140 steroids and triterpenoids are presented in this review, which demonstrate a wide range of biological activities. Therefore, out of 71 sulfated steroids, thirteen show strong antitumor activity with a confidence level of more than 90%, out of 50 sulfur-containing steroids, only four show strong antitumor activity with a confidence level of more than 93%, and out of eighteen epithio steroids, thirteen steroids show strong antitumor activity with a confidence level of 91% to 97.4%.


Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/metabolismo , Esteroides/farmacologia , Compostos de Enxofre/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Humanos , Estrutura Molecular , Esteroides/isolamento & purificação , Relação Estrutura-Atividade , Compostos de Enxofre/isolamento & purificação
14.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918373

RESUMO

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17ß-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds.


Assuntos
Compostos de Benzilideno/farmacologia , Esteroides/farmacologia , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Modelos Moleculares , Esteroides/síntese química , Esteroides/química
15.
J Egypt Natl Canc Inst ; 33(1): 7, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661420

RESUMO

BACKGROUND: In 2018, leukaemia accounted for 2.6% of all new cancers, it being the 13th most common cause of cancer and the 10th most common cause of cancer death. Glucocorticoids are commonly used in lymphoid leukaemia treatment, where they are cytotoxic. The aim of this review is to highlight ongoing research of steroid use in myeloid leukaemias. MAIN TEXT: Glucocorticoids increase infection risks in acute myeloid leukaemia, but with adequate antifungal cover, they can help in hyperleucocytic disease. They also show some benefits in sensitising multidrug-resistant AML cell lines to cytotoxic agents, induce differentiation marker expression and can also induce CD38 expression, making AML cells possible targets of daratumumab. Cardiotonic steroids, like digitalis, are being recognised as sensitising AML cells to the chemotherapeutic effects of many cytotoxic agents, primarily by inhibiting efflux pumps, thus minimising AML resistance. Ecdysteroids enhance sensitivity in multidrug-resistant AML, but also in non-resistant AML cell lines, through pathways including the activation of mitochondrial apoptosis. Their anti-apoptotic effects on non-malignant cell lines help their target specificity. Sensitisation is chemotherapy-specific, enhancing the effects of doxorubicin and tubulin inhibitors but increasing resistance to cisplatinum. SHORT CONCLUSION: Cardiotonic steroids and ecdysteroids both show chemosensitisation to the cytotoxic effects of chemotherapy on AML cell lines. It is likely time to consider clinical trials to assess whether these, as well as traditional glucocorticoids, can contribute to the AML armamentarium, particularly in chemo-resistant disease.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/uso terapêutico , Apoptose , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Esteroides/farmacologia , Esteroides/uso terapêutico
16.
EBioMedicine ; 64: 103235, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33581643

RESUMO

BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Pirimidinas/farmacologia , Pirróis/farmacologia , Esteroides/farmacologia , Esteroides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Mediators Inflamm ; 2021: 8896055, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574732

RESUMO

The aim of the study was to evaluate the distribution of blood dendritic cells (DCs) in patients with Graves' orbitopathy (GO) and to assess the influence of methylprednisolone therapy on subsets of peripheral blood mononuclear cells (PBMCs). Peripheral blood DC subsets were analyzed by flow cytometry in patients with active GO (n = 17), inactive GO (n = 8), and Graves' disease (GD) without GO (n = 8) and controls (n = 15); additionally, in patients with active GO (n = 17), analyses were done at three time points, i.e., before methylprednisolone treatment and after 6 weeks and after 12 weeks of the treatment. Percentage of myeloid DCs (mDCs) in PBMC fraction was significantly lower in patients with both active and inactive GO, compared to patients with GD without GO and controls (p < 0.05). In addition, mDCs were also documented to be an independent factor negatively associated with GO, however without essential differences between active and inactive phases. On the other hand, we did not observe any changes in the percentage of DCs after methylprednisolone therapy (p > 0.05). In the present study, we have succeeded to firstly demonstrate-according to our knowledge-that blood mDCs are negatively related to GO incidence.


Assuntos
Células Dendríticas/citologia , Oftalmopatia de Graves/sangue , Células Mieloides/citologia , Órbita/fisiopatologia , Adulto , Idoso , Autoimunidade , Feminino , Citometria de Fluxo , Oftalmopatia de Graves/epidemiologia , Humanos , Incidência , Leucócitos Mononucleares/metabolismo , Masculino , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Análise de Regressão , Esteroides/farmacologia
18.
Food Funct ; 12(5): 1856-1881, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33576366

RESUMO

Phellinus Quél is one of the largest genera of Hymenochaetaceae, which is comprised of about 220 species. Most Phellinus macro-fungi are perennial lignicolous mushrooms, which are widely distributed on Earth. Some Phellinus fungi are historically recorded as traditional medicines used to treat various diseases in eastern Asian countries, especially China, Japan and Korean. Previous phytochemical studies have revealed that Phellinus fungi produce diverse secondary metabolites, which mainly contain polysaccharides, flavones, coumarins, terpenes, steroids, and styrylpyranones. Pharmacological documents have demonstrated that Phellinus mushrooms and their compounds have a variety of bioactivities, such as anti-tumor, immunomodulation, anti-oxidative and anti-inflammation, anti-diabetes, neuro-protection, and anti-viral effects. This review surveys the literature reporting the isolation, characterization, and bioactivities of secondary metabolites from the fungi of the genus Phellinus, focusing on studies published in the literature up to April 2020. Herein, a total of more than 300 compounds from 13 Phellinus species and their isolation, characterization, chemistry, pharmacological activities, and relevant molecular mechanisms are comprehensively summarized.


Assuntos
Flavonas , Phellinus/química , Polifenóis , Polissacarídeos , Esteroides , Terpenos , Anti-Inflamatórios , Antineoplásicos , Antioxidantes , Antivirais , Flavonas/química , Flavonas/isolamento & purificação , Flavonas/farmacologia , Carpóforos/química , Hipoglicemiantes , Medicina Tradicional , Estrutura Molecular , Phellinus/metabolismo , Polifenóis/química , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Esteroides/química , Esteroides/isolamento & purificação , Esteroides/farmacologia , Terpenos/química , Terpenos/isolamento & purificação , Terpenos/farmacologia
19.
Molecules ; 26(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445584

RESUMO

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding ß-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit µM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.


Assuntos
Glucosefosfato Desidrogenase/metabolismo , Estágios do Ciclo de Vida , Esteroides/farmacologia , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/crescimento & desenvolvimento , Androsterona/química , Androsterona/farmacologia , Sítios de Ligação , Citosol/enzimologia , Desidroepiandrosterona/química , Desidroepiandrosterona/farmacologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Glucosefosfato Desidrogenase/química , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Modelos Moleculares , Oxirredução , Reprodutibilidade dos Testes , Trypanosoma brucei brucei/efeitos dos fármacos
20.
Fitoterapia ; 150: 104838, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33515649

RESUMO

Vernoramyosides A-F (1-6), six new Δ7,9(11) stigmastane-type steroid saponins, along with four known analogues (7-10) were isolated from the leaves of Vernonia amygdalina Delile (Compositae). Their structures were determined by the combination of NMR, ECD and HR-ESI-MS data. These compounds all possessed highly oxidized side chain and a γ-lactam or α,ß-unsaturated five-membered lactone ring. All isolates were screened for their activities in reversing resistance in MCF/DOX cells.


Assuntos
Saponinas/farmacologia , Esteroides/farmacologia , Vernonia/química , China , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Saponinas/isolamento & purificação , Esteroides/isolamento & purificação
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