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1.
Toxicon ; 203: 121-128, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34662629

RESUMO

Leucaena leucocephala is a worldwide plant used as forage; however, its use in animal production has been limited because of the presence of a toxic nonprotein amino acid, L-mimosine. L-mimosine exhibits negative effects not only in ruminants but also in monogastric animals; however, there is little information available on the effect of this amino acid in monogastric species. Thus, this study aimed to evaluate the general toxicity of L-mimosine in rats, as well as its effects on the endocrine and reproductive systems. L-mimosine was extracted from seeds of L. leucocephala that were administered orally by gavage to adult Wistar rats at different doses of 25, 40 and 60 mg/kg body weight/day for 28 days. The following parameters were evaluated: weight gain, feed intake, serum enzymes, histopathology (liver, kidney, thyroid, thymus, and spleen), serum hormones (testosterone, corticosterone, T3 and T4) and sexual behavior. No clinical signs of toxicity were observed in animals, but histopathology revealed consistent lesions in the thyroids. Additionally, rats exposed to L-mimosine presented low serum levels of testosterone, decreased mount numbers and increased mount intervals. Therefore, our study reinforces the assumption that L-mimosine has goitrogenic potential and causes impairment in male reproductive performance.


Assuntos
Fabaceae , Mimosina , Animais , Genitália , Mimosina/toxicidade , Ratos , Ratos Wistar , Glândula Tireoide
2.
Toxicon ; 202: 82-89, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34582830

RESUMO

L-mimosine is a compound found in Leucaena leucocephala, that is used as animal feed due to its high protein content, but it can also cause intoxication. Due to its low solubility in organic and aqueous solvents, its administration in laboratory animals is difficult, especially in delicate periods such as pregnancy. Thus, to circumvent such problems, this study proposes a stress-free form of oral administration with gelatin tablets with flavoring (meat broth) for 14 consecutive days of the gestational period (GD06 to GD20). For that, 17 pregnant Wistar rats divided into 3 groups were used: control (CO; n = 5) not treated; gelatin (GEL; n = 6), which received a gelatin tablet with flavoring; and gelatin with flavoring added 140 mg/kg of L-mimosine (GM; n = 6). All animals received feed and water ad libitum. The parameters analyzed were body weight gain, water and feed consumption, serum biochemistry, blood count and reproductive indices. Among these, only the real and total weight gains of dams showed statistically significant differences, with a decrease in the group GM. Thus, we could observe that flavored gelatin was an efficient and effective administration method to insoluble compounds and long-term administration to pregnant rats, with quick adaptation and without refusal by the animals. In addition, we could observe a direct effect of L-mimosine on the animals' weight gain; however, the dose administered was not sufficient to confer maternal and fetal toxicity.


Assuntos
Mimosina , Reprodução , Administração Oral , Ração Animal , Animais , Feminino , Gravidez , Ratos , Ratos Wistar
3.
Elife ; 92020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32720645

RESUMO

Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.


Assuntos
Cisplatino , Substâncias Protetoras/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/toxicidade , Dopamina/farmacologia , Combinação de Medicamentos , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Sistema da Linha Lateral/efeitos dos fármacos , Sistema da Linha Lateral/patologia , Mimosina/farmacologia , Modelos Animais , Peixe-Zebra
4.
Redox Rep ; 25(1): 59-63, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32615878

RESUMO

Objectives: Prooxidant properties of iron-binding hydroxypyridone compounds including deferiprone and mimosine were analyzed. Methods: Hydroxypyridone/iron-dependent production of reactive oxygen species was evidenced by the inactivation of aconitase, the most sensitive enzyme to oxidative stress in permeabilized yeast cells. Results and Discussion: Deferiprone and mimosine produced reactive oxygen species in the presence of ferrous sulfate. The inactivation required sodium azide the inhibitor of catalase, and addition of TEMPOL, a scavenger of superoxide radical, protected aconitase from the inactivation, suggesting that the superoxide radical produced from the hydroxypyridone/iron complex is responsible for the inactivation of aconitase. A principal role of superoxide radical was further supported by the finding that the hydroxypyridone/iron complex can inactivate aconitase in the presence of cyanide the inhibitor of superoxide dismutase. Deferiprone and mimosine stimulated the Fe2+ oxidation, resulting in the one-electron reduction of oxygen to form superoxide anion, which can inactivate aconitase by oxidizing the prosthetic iron-sulfur cluster. Mimosine further stimulated the ascorbate/iron-dependent formation of 8-hydroxy-2'-deoxyguanosine in DNA. Conclusion: Biological toxicity of mimosine and deferiprone reported previously can be accounted for by the prooxidant properties of hydroxypyridone compounds: coordination complex with iron generates reactive oxygen species resulting in the disturbance of mitochondrial energy metabolism and DNA damage.


Assuntos
Aconitato Hidratase/metabolismo , Deferiprona/farmacologia , Compostos Ferrosos/farmacologia , Mimosina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Dano ao DNA , Quelantes de Ferro/farmacologia , Oxirredução , Estresse Oxidativo
5.
Dalton Trans ; 49(9): 2862-2879, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32067003

RESUMO

Mimosine is a non-protein amino acid with various properties, such as antibacterial, anti-inflammatory, anti-cancer and anti-virus among others. Due to its structural similarity with deferiprone (DFP), mimosine is a potential excellent metal chelator. In the present work, we combine experimental and theoretical (DFT) approaches in order to investigate the properties of mimosine peptides. Six different peptides were synthesized and their complex stoichiometry and stability were characterized by means of UV-Vis spectrophotometry. Then, the binding mode and self-assembly features of the peptides were evaluated using a DFT approach, taking into account different number of mimosine amino acids and varying the length of the spacer between the mimosine residues, and there was good agreement between experimental data and computational calculations. Further elucidations of the structural properties of these peptides allowed us to propose improvements in the structure of the mimosine moiety which can lead to enhanced affinity for high-valent metals. Moreover, we demonstrate that these peptides show an anti-microbial activity against Gram positive bacteria that is enhanced by the formation of a complex with iron(iii) ions. The mimosine peptides could be an alternative to antimicrobial peptides (AMPs), which are expensive and susceptible to proteolytic degradation. In summary, in the present work, we propose a new generation of multipurpose mimosine-based peptides as new metal self-assembly chelators which could be a turning point in biomedical and nanotechnological applications.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Quelantes/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Mimosina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Biofilmes/efeitos dos fármacos , Quelantes/síntese química , Quelantes/química , Cobre/química , Cobre/farmacologia , Teoria da Densidade Funcional , Compostos Férricos/química , Compostos Férricos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Mimosina/química , Estrutura Molecular
6.
Plant Mol Biol ; 102(4-5): 431-445, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31907707

RESUMO

KEY MESSAGE: Iron deficiency conditions as well as iron supplied as a Fe(III)-mimosine complex induced a number of strategy I and strategy II genes for iron uptake in leucaena. Leucaena leucocephala (leucaena) is a tree-legume that can grow in alkaline soils, where metal-cofactors like Fe(III) are sparingly available. Mimosine, a known chelator of Fe(III), may facilitate Fe(III) uptake in leucaena by serving as a phytosiderophore. To test if mimosine can serve as a phytosiderophore, three sets of experiments were carried out. First, the binding properties and solubility of metal-mimosine complexes were assessed through spectrophotometry. Second, to study mimosine uptake in plants, pole bean, common bean, and tomato plants were supplied with mimosine alone and metal-mimosine complexes. Third, the expression of strategy I (S1) and strategy II (S2) genes for iron uptake from the soil was studied in leucaena plants exposed to different Fe(III) complexes. The results of this study show that (i) mimosine has high binding affinity for metallic cations at alkaline pH, Fe(III)-mimosine complexes are water soluble at alkaline pH, and that mimosine can bind soil iron under alkaline pH; (ii) pole bean, common bean, and tomato plants can uptake mimosine and transport it throughout the plant; and (iii) a number of S1 and S2 genes were upregulated in leucaena under iron-deficiency condition or when Fe(III) was supplied as a Fe(III)-mimosine complex. These findings suggest that leucaena may utilize both S1 and S2 strategies for iron uptake; and mimosine may play an important role in both strategies.


Assuntos
Fabaceae/efeitos dos fármacos , Fabaceae/metabolismo , Mimosina/farmacocinética , Transporte Biológico , Tampões (Química) , Cátions , Compostos Férricos/metabolismo , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ferro/metabolismo , Metais/metabolismo , Nitrogênio , Phaseolus/efeitos dos fármacos , Phaseolus/metabolismo , Folhas de Planta/metabolismo , Caules de Planta/metabolismo , Ligação Proteica , Sideróforos/metabolismo , Solo , Solanum/efeitos dos fármacos , Solanum/metabolismo , Solubilidade
7.
J Plant Res ; 133(1): 95-108, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31828681

RESUMO

Cysteine biosynthesis is directed by the successive commitments of serine acetyltransferase, and O-acetylserine (thiol) lyase (OASTL) compounds, which subsequently frame the decameric cysteine synthase complex. The isoforms of OASTL are found in three compartments of the cell: the cytosol, plastid, and mitochondria. In this investigation, we first isolated putative chloroplastic OASTL (Ch-OASTL) from Leucaena leucocephala, and the Ch-OASTL was then expressed in BL21-competent Escherichia coli. The putative Ch-OASTL cDNA clone had 1,543 base pairs with 391 amino acids in its open reading frame and a molecular weight of 41.54 kDa. The purified protein product exhibited cysteine synthesis ability, but not mimosine synthesis activity. However, they both make the common α-aminoacrylate intermediate in their first half reaction scheme with the conventional substrate O-acetyl serine (OAS). Hence, we considered putative Ch-OASTL a cysteine-specific enzyme. Kinetic studies demonstrated that the optimum pH for cysteine synthesis was 7.0, and the optimum temperature was 40 °C. In the cysteine synthesis assay, the Km and kcat values were 838 ± 26 µM and 72.83 s-1 for OAS, respectively, and 60 ± 2 µM and 2.43 s-1 for Na2S, respectively. We can infer that putative Ch-OASTL regulatory role is considered a sensor for sulfur constraint conditions, and it acts as a forerunner of various metabolic compound molecules.


Assuntos
Cloroplastos , Clonagem Molecular , Cisteína Sintase , Cinética , Mimosina
8.
Invest New Drugs ; 38(3): 621-633, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31240512

RESUMO

The anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues of L-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that the L-enantiomer of a methylated analogue of L-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of reactive oxygen species (ROS), ii) activate both intrinsic and extrinsic apoptosis and iii) induce perturbations in cell cycle growth arrest. Our data highlights the potential of compound 22 to act as a promising therapeutic agent against an in vitro model of human malignant melanoma.


Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Mimosina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Int. j. morphol ; 37(4): 1463-1468, Dec. 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1040154

RESUMO

Acute effect of purified mimosine (MiMo) extracted from Leucaena leucocephala on testicular histopathology has been documented with seminal vesicle (SV) atrophy. Since protein phosphorylation and seminal secretions play important roles in sperm physiology, this study aimed to study the alteration of substances including tyrosine phosphorylated (TyrPho) proteins in seminal vesicle treated with MiMo. Male mice were divided into a control and experimental groups treated with purified MiMo at 3 doses of 15, 30, and 60 mg/KgBW, respectively for 35 consecutive days. The morphology and weights of SV were compared among groups. The levels of magnesium and fructosamine in SV fluid were assayed. The profiles of equally SV total proteins were compared using SDS-PAGE. The expression of seminal TyrPho proteins was detected by western blotting. Recent results showed the decreased weights of SV in MiMo treated mice compared to control. However MiMo in all doses did not affect the levels of magnesium and fructosamine in SV fluid. The SV protein expression of 130 and 55 kDas was obviously decreased in a high dose MiMo. In dose-dependent response, the expressions of 72 and 55 kDas TyrPho proteins of SV were increased. In conclusion, MiMo could affect SV morphological size and protein secretions especially TyrPho proteins.


El efecto agudo de la mimosina purificada (MiMo) extraída de Leucaena leucocephala en la histopatología testicular se ha documentado con atrofia de vesícula seminal (VS). Debido a que la fosforilación de proteínas y las secreciones seminales tienen un papel importante en la fisiología de los espermatozoides, este estudio tuvo como objetivo estudiar la alteración de sustancias como la proteína tirosina fosforilada (TyrPho) en vesículas seminales tratadas con MiMo. Los ratones se dividieron en un grupo control y un grupo experimental y se trataron con MiMo purificado en 3 dosis de 15, 30 y 60 mg / KgBW, respectivamente, durante 35 días seguidos. La morfología y los pesos de VS se compararon entre los grupos. Fueron analizados los niveles de magnesio y fructosamina en el fluido VS. Los perfiles de las proteínas totales de VS se compararon utilizando SDS-PAGE. La expresión de la proteína TyrPho en las vesículas seminales se detectó mediante transferencia de Western blot. Los resultados recientes muestran la disminución del peso de las VS en ratones tratados con MiMo, en comparación con el grupo control. Sin embargo, en ninguna de las dosis se vieron afectados por mimosina purificada los niveles de magnesio y fructosamina en el líquido de las VS. La expresión de la proteína en VS de 130 y 55 kDas disminuyó notablemente en una dosis alta de MiMo. En la respuesta dependiente de la dosis, aumentaron las expresiones de 72 y 55 kDas de las proteínas TyrPho en las VS. En conclusión, la mimosina purificada podría afectar el tamaño morfológico de las VS y la expresión de proteínas, especialmente las proteínas TyrPho.


Assuntos
Animais , Masculino , Camundongos , Fosfoproteínas/efeitos dos fármacos , Glândulas Seminais/efeitos dos fármacos , Mimosina/administração & dosagem , Tamanho do Órgão , Fosfoproteínas/metabolismo , Fosforilação , Glândulas Seminais/patologia , Tirosina/análogos & derivados , Western Blotting , Fosfotirosina , Eletroforese em Gel de Poliacrilamida , Camundongos Endogâmicos ICR , Mimosina/farmacologia
10.
Sci Rep ; 9(1): 7117, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068630

RESUMO

Functional imaging has become an important tool in oncology because it not only provides information about the size and localization of the tumour, but also about the pathophysiological features of the tumoural cells. One of the characteristic features of some tumour types is that their fast growth leads to deficient intratumoral vascularization, which results in low oxygen availability. To overcome this lack of oxygen, tumoural cells activate the neoangiogenic program by upregulating the transcription factor HIF-1α. Herein we report a non-invasive in vitro detection method of hypoxia using designed fluorescent peptide probes based on the oxygen-dependent degradation domain of HIF-1α. The fluorescent probe retains the oxygen-sensing capability of HIF-1α, so that it is stabilized under hypoxia and readily degraded by the proteasome under normoxia, thus providing direct information of the cellular oxygen availability.


Assuntos
Técnicas Biossensoriais/métodos , Neoplasias da Mama/metabolismo , Hipóxia Celular/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Domínios Proteicos/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cobalto/farmacologia , Feminino , Corantes Fluorescentes , Humanos , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mimosina/farmacologia , Peptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Espectrometria de Fluorescência/métodos
11.
J Periodontal Res ; 54(5): 489-498, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30891777

RESUMO

BACKGROUND AND OBJECTIVE: A key factor in the modulation of angiogenesis as well as in bone resorption is angiopoietin-like 4. However, the role of angiopoietin-like 4 in periodontal tissue is unknown. Here, we hypothesized that hypoxia and the hypoxia mimetic agent L-mimosine can induce the production of angiopoietin-like 4 in periodontal fibroblasts. METHODS: Human periodontal ligament fibroblasts (PDLF) were cultured in monolayer and spheroid cultures. The cultures were incubated in the presence of hypoxia or L-mimosine. Angiopoietin-like 4 mRNA and protein levels were measured by qPCR and ELISA, respectively. Also, the impact of Lipopolysaccharides of E. coli and P. gingivalis, interleukin (IL)-1ß and tumor necrosis factor (TNF)α was evaluated. Furthermore, we tested dependency on hypoxia-inducible factor (HIF)-1 activity by Western blotting for HIF-1 and inhibitor studies with echinomycin. Potential autocrine effects were assessed by exposure of PDLF to recombinant angiopoietin-like 4 in full length, C-terminal and N-terminal fragments. The impact on viability, DNA synthesis, alkaline phosphatase, and matrix mineralization was evaluated. RESULTS: Both hypoxia and L-mimosine elevated angiopoietin-like 4 mRNA and protein levels in monolayer cultures of PDLF. HIF-1 was elevated after both hypoxia and L-mimosine treatment. LPS, IL-1ß, and TNFα did not modulate angiopoietin-like 4 levels significantly. Addition of echinomycin in the cultures inhibited the production of angiopoietin-like 4. In spheroid cultures of PDLF, the increase did not reach the level of significance at mRNA and protein levels. Angiopoietin-like 4 in full length, C-terminal, and N-terminal fragments did not modulate viability, DNA synthesis, alkaline phosphatase, and matrix mineralization. CONCLUSION: Overall, we found that hypoxia and the hypoxia mimetic agent L-mimosine can stimulate angiopoietin-like 4 production in monolayer cultures of PDLF. This increase depends on HIF-1 activity. Future studies will reveal how the modulation of angiopoietin-like 4 in the periodontium contributes to periodontal disease and regeneration.


Assuntos
Escherichia coli , Hipóxia , Mimosina , /metabolismo , Angiopoietinas , Células Cultivadas , Fibroblastos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mimosina/farmacologia , Ligamento Periodontal/metabolismo
12.
J Biomater Appl ; 33(9): 1277-1284, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760093

RESUMO

Thixotropic clays have favorable properties for tissue regeneration. Hypoxia mimetic agents showed promising results in pre-clinical models for hard and soft tissue regeneration. It is unclear if clays can be used as carrier for hypoxia mimetic agent in a periodontal regenerative setting. Here, we tested the response of human fibroblasts of the periodontal soft tissue to synthetic clay hydrogels and assessed hypoxia mimetic agent release. Cells were cultured on synthetic clay hydrogels (5.00%-0.15%). We assessed viability and differentiation capacity with resazurin-based toxicity assays, MTT staining, Live-Dead staining, and alkaline phosphatase staining. To reveal the response of fibroblasts to hypoxia mimetic agent-loaded clay hydrogels, cells were exposed to clay supplemented with dimethyloxalylglycine, deferoxamine, l-mimosine, and CoCl2. Supernatants from hypoxia mimetic agent-loaded clay hydrogels were harvested and replaced with medium at hour 1, 3, 6, 24, 48, and 72. To reveal the hypoxia mimetic capacity of supernatants, vascular endothelial growth factor production in the fibroblasts was assessed in the culture medium. Our data show that clay did not induce relevant toxic effects in the fibroblasts which remained capable to differentiate into alkaline phosphatase-positive cells at the relevant concentrations. Fibroblasts cultured on clay hydrogel loaded with dimethyloxalylglycine, deferoxamine, l-mimosine, and CoCl2 remained vital, however, no significant increase in vascular endothelial growth factor levels was found in the culture medium. Only dimethyloxalylglycine-loaded clay supernatants taken in the first hours stimulated vascular endothelial growth factor production in fibroblasts. In conclusion no pronounced toxic effects of synthetic clay were observed. Supplementation with dimethyloxalylglycine leads to hypoxia mimetic activity. This pilot study provides first insights into the impact of synthetic clay on periodontal tissue.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Argila/química , Fibroblastos/efeitos dos fármacos , Hidrogéis/química , Periodonto/citologia , Aminoácidos Dicarboxílicos/administração & dosagem , Aminoácidos Dicarboxílicos/farmacologia , Materiais Biocompatíveis/química , Células Cultivadas , Cobalto/administração & dosagem , Cobalto/farmacologia , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Sistemas de Liberação de Medicamentos , Fibroblastos/citologia , Humanos , Mimosina/administração & dosagem , Mimosina/farmacologia , Periodonto/efeitos dos fármacos , Tecidos Suporte/química
13.
J Plant Res ; 132(2): 263-271, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30637553

RESUMO

Seed priming is a treatment that controls seed water content to partially activate germination processes such as metabolism but prevents full germination of the seeds. The treatment is well known to enhance seed performance, including germination, but sometimes reduces seed storability or longevity as a side effect. Toward developing a novel priming technique that can maintain seed longevity for a longer time period, chemicals that suppress the seed deterioration under a controlled condition were screened from 80 known biologically active compounds contained in the RIKEN NPDepo authentic library using Arabidopsis thaliana seeds. Seeds primed with mimosine, a cell cycle inhibitor, retained higher survival rate after a controlled deterioration treatment compared to seeds primed without the chemical. In addition, other cell cycle inhibitors such as aphidicolin, hydroxyurea and oryzalin had similar effects on the seed storability after priming. Our results suggest that progression of the cell cycle during priming is an important checkpoint that determines the storability of seeds after the treatment.


Assuntos
Ciclo Celular/efeitos dos fármacos , Mimosina/farmacologia , Sementes/efeitos dos fármacos , Arabidopsis
14.
Chem Biol Drug Des ; 93(3): 222-231, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30251480

RESUMO

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant-based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERα-SRC1 coactivator activity and expression of specific ERα-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17ß-oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 µM with significant cell proliferation (120.5%) compared to 17ß-oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 µM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 µM) and PGR (13.9-fold at 0.01 µM) genes. ERα-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα-LBD. The results suggested that mimosine has oestrogenic activity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Mimosina/farmacologia , Sítios de Ligação , Estradiol/farmacologia , Receptor alfa de Estrogênio/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Mimosina/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios Proteicos , Tamoxifeno/farmacologia , Fator Trefoil-1/genética , Fator Trefoil-1/metabolismo
15.
Plant Physiol Biochem ; 135: 432-440, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30482504

RESUMO

Mimosine is a non-protein amino acid of Fabaceae, such as Leucaena spp. and Mimosa spp. Several relevant biological activities have been described for this molecule, including cell cycle blocker, anticancer, antifungal, antimicrobial, herbivore deterrent and allelopathic activities, raising increased economic interest in its production. In addition, information on mimosine dynamics in planta remains limited. In order to address this topic and propose strategies to increase mimosine production aiming at economic uses, the effects of several stress-related elicitors of secondary metabolism and UV acute exposure were examined on mimosine accumulation in growth room-cultivated seedlings of Leucaena leucocephala spp. glabrata. Mimosine concentration was not significantly affected by 10 ppm salicylic acid (SA) treatment, but increased in roots and shoots of seedlings treated with 84 ppm jasmonic acid (JA) and 10 ppm Ethephon (an ethylene-releasing compound), and in shoots treated with UV-C radiation. Quantification of mimosine amidohydrolase (mimosinase) gene expression showed that ethephon yielded variable effect over time, whereas JA and UV-C did not show significant impact. Considering the strong induction of mimosine accumulation by acute UV-C exposure, additional in situ ROS localization, as well as in vitro antioxidant assays were performed, suggesting that, akin to several secondary metabolites, mimosine may be involved in general oxidative stress modulation, acting as a hydrogen peroxide and superoxide anion quencher.


Assuntos
Fabaceae/metabolismo , Mimosina/metabolismo , Antioxidantes/metabolismo , Ciclopentanos/farmacologia , Fabaceae/efeitos dos fármacos , Fabaceae/efeitos da radiação , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Peróxido de Hidrogênio/metabolismo , Compostos Organofosforados/farmacologia , Estresse Oxidativo , Oxilipinas/farmacologia , Raízes de Plantas/metabolismo , Brotos de Planta/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ácido Salicílico/farmacologia , Plântula/metabolismo , Estresse Fisiológico , Superóxidos/metabolismo , Raios Ultravioleta
16.
J Periodontol ; 90(6): 674-681, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30549272

RESUMO

BACKGROUND: A major mediator of angiogenesis is angiogenin, which is expressed in the early phase of healing in oral tissue engineering strategies. It is unclear how angiogenin is regulated in the periodontal tissue. The objective of this study was to reveal the regulation of angiogenin in response to hypoxia and the hypoxia mimetic agent l-mimosine in periodontal fibroblasts. METHODS: Human fibroblasts of the periodontal ligament (PDLF) and the gingiva (GF) in monolayer and spheroid cultures were exposed to hypoxia or l-mimosine. The production of angiogenin was evaluated at mRNA and protein levels with reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Echinomycin, an inhibitor of hypoxia-inducible factor (HIF)-1 activity, was used to test the involvement of HIF-1. RESULTS: Our data show that hypoxia and l-mimosine can increase angiogenin mRNA and protein levels in PDLF monolayer cultures. In GF monolayer cultures, we found an increase of angiogenin at the mRNA level in response to hypoxia. The increase of angiogenin can be blocked by inhibition of HIF-1 signaling via echinomycin. In PDLF and GF spheroid cultures, the impact of hypoxia and l-mimosine did not reach the level of significance. CONCLUSION: Hypoxia and the hypoxia mimetic agent l-mimosine can increase the production of angiogenin via HIF-1 signaling in PDLF monolayer cultures but not in spheroid cultures. GF were less sensitive to the impact of hypoxia and l-mimosine. Overall, these results suggest a link between hypoxia, HIF-1 signaling and angiogenin in the periodontium.


Assuntos
Hipóxia , Mimosina , Células Cultivadas , Fibroblastos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Ligamento Periodontal , Ribonuclease Pancreático
17.
Biomed Res Int ; 2018: 5872865, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581861

RESUMO

Hypoxia mimetic agents (HMAs) have been shown to have a positive influence on cellular functions in a multitude of tissue regenerative strategies. Novel experimental approaches use biomaterials as carriers for controlled delivery of these HMAs. Here, the cytotoxic aspects of biocompatibility are of key relevance. The MTT assay is widely used to evaluate cytotoxicity and proliferation. Based on the implications from the proceeding research we hypothesized that specific HMAs such as deferoxamine at high concentrations can interfere with the MTT assay. Thus, the aim of this study was to test the repercussions of the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2 on the validity of the MTT assay. Murine MC3T3-E1 cells were cultured in serum-free alphaMEM and in alphaMEM supplemented with 10 % fetal bovine serum with the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2, respectively, at 3 mM-0.3 mM for 24 h (experimental groups). Cells without HMAs served as control (control groups). The same experiments were performed with medium and phosphate buffered saline (PBS) without cells. In all settings MTT solution was added to PBS-washed or unwashed culture plates for the last two hours of the incubation period. Then MTT solution was removed and dimethyl sulfoxide was added to dissolve the formazan crystals and absorption was measured. Our data show that the presence of deferoxamine can interfere with the MTT assay if not removed before the addition of MTT. This is particularly important when evaluating cell viability in setups where deferoxamine-loaded biomaterials are used.


Assuntos
Aminoácidos Dicarboxílicos/química , Cobalto/química , Desferroxamina/química , Mimosina/química , Sais de Tetrazólio/química , Tiazóis/química , Células 3T3 , Animais , Materiais Biocompatíveis/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dimetil Sulfóxido/química , Camundongos
18.
Int. j. morphol ; 36(3): 1062-1069, Sept. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-954231

RESUMO

This study aimed to determine the mimosine level and examine the male reproductive toxicity effects of Leucaena leucocephala (LL) shoot tips plus young leaf extract. Mimosine level in LL extract was determined by thin layer chromatography before administration in animals. Male rats were divided into control and LL (1,500 mg/KgBW) groups (n = 6). After 60 days of experiment, serum sex hormones, sperm quality, and testicular histopathology were assayed and observed. Malondialdehyde (MDA) level and expressions of steroidogenic acute regulatory (StAR) and phosphorylated proteins in testicular lysate were examined by western blotting. Results showed that mimosine levels in LL extract was 17.35 ± 1.12 % of dry weight. LL significantly decreased FSH & LH levels, sperm qualities, and seminiferous tubule diameter compared to the control (p<0.05). Seminiferous tubular atrophies, germ cell sloughing, and degenerations were observed in LL group. In addition, testicular MDA level and StAR protein expression were significantly decreased in LL group. LL extract could increase the expression of a 50 kDa phohorylated protein in testicular lysate. In conclusion, LL extract has mimosine and reproductive toxicity effects on males.


Este trabajo tuvo como objetivo determinar el nivel de mimosina y examinar los efectos de la toxicidad reproductiva de los brotes de Leucaena leucocephala (LL), más el extracto de hojas jóvenes, en ratas macho. El nivel de mimosina en el extracto de LL se determinó mediante cromatografía en capa fina antes de la administración en animales. Las ratas se dividieron en grupos de control y LL (1,500 mg / kgBW) (n = 6). Después de 60 días, se analizaron y observaron las hormonas sexuales séricas, la calidad de los espermatozoides y la histopatología testicular. A través de Western Blot se examinaron el nivel de malondialdehído (MDA), las expresiones de reguladores agudos esteroidogénicos (StAR) y las proteínas fosforiladas en el lisado testicular. Los resultados mostraron que los niveles de mimosina en el extracto de LL fueron 17.35 ± 1.12 % del peso seco. LL disminuyó significativamente los niveles de FSH y LH, la calidad de los espermatozoides y el diámetro de los túbulos seminíferos en comparación con el control (p <0,05). Se observaron atrofias en los túbulos seminíferos, desprendimiento de células germinales y degeneraciones en el grupo LL. Además, el nivel de MDA testicular y la expresión de la proteína StAR se redujeron significativamente en el grupo LL. El extracto de LL podría aumentar la expresión de la proteína fosforilada de 50 kDa en el lisado testicular. En conclusión, el extracto de LL tiene mimosina y efectos de toxicidad reproductiva en los hombres.


Assuntos
Animais , Masculino , Ratos , Extratos Vegetais/toxicidade , Extratos Vegetais/química , Genitália Masculina/efeitos dos fármacos , Fabaceae , Mimosina/análise , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Western Blotting
19.
Eur J Oral Sci ; 126(4): 263-271, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30006964

RESUMO

Core circadian clock genes set the pace for a wide range of physiological functions, including regeneration. The role of these genes and their regulation in the dental pulp, in particular under hypoxic conditions, is unknown. Here we investigated if core clock genes are expressed in human dental pulp-derived cells (DPC) and if their expression is modulated by the hypoxia mimetic agent, L-mimosine (L-MIM), hypoxia or echinomycin. Dental pulp-derived cells in monolayers and spheroids were treated with L-MIM, hypoxia or echinomycin. mRNA levels of the core circadian clock genes were analysed using quantitative PCR (qPCR) and their protein levels were analysed by western blot. All core clock genes and proteins were produced in DPC monolayer and spheroid cultures. The expression of cryptochrome circadian regulators and period circadian regulators was reduced by L-MIM, hypoxia and echinomycin at mRNA, but not at protein levels. Time course experiments indicated that modulations were based on alterations in overall mRNA levels of core circadian clock genes. Our results suggest a potential role of the core circadian clock in the response of dental pulp to hypoxia. Future studies need to consider that regulation of the core circadian clock at mRNA levels might not be paralleled by modulation of protein levels.


Assuntos
Relógios Circadianos/genética , Polpa Dentária/citologia , Equinomicina/farmacologia , Regulação da Expressão Gênica , Hipóxia , Mimosina/farmacologia , Western Blotting , Técnicas de Cultura de Células , Eletroforese em Gel de Poliacrilamida , Humanos , Técnicas In Vitro , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo
20.
Int. j. morphol ; 36(2): 507-512, jun. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-954145

RESUMO

This study attempted to examine the acute effect of purified minosine extracted from Leucaena leucocephala on male reproductive system. Adults male mice were divided into 4 groups (n =8); control and 3 experimental groups treated with purified mimosine at different doses of 15, 30, and 60 mg/KgBW, respectively for 7 consecutive days. The morphological features and weights of body and reproductive organs including testis, epididymis plus vas deferens, and seminal vesicle were compared among groups. In addition, epididymal sperm concentration and the changes of histopathology of testicular tissues in all groups were observed. The results showed that mimosine in all doses did not affect mice body weights. However, all doses of mimosine could significantly reduce the absolute and relative weights of testis and seminal vesicle but not of epididymis plus vas deferens. Significantly, mimosine at doses of 30, and 60 mg/KgBW could decrease sperm concentration. Moreover, the seminiferous atrophy and degeneration were obviously found in mimosine treated mice as compared to the control. In conclusion, consumption of Leucaena leucocephala edible parts containing mimosine could damage male reproductive organs which may cause acute male subfertility or infertility.


Este estudio intentó examinar el efecto agudo de la mimosina purificada extraída de Leucaena leucocephala en el sistema reproductivo masculino. Se dividieron ratones machos adultos en 4 grupos (n = 8): un grupo control y tres grupos experimentales tratados con mimosina purificada a diferentes dosis de 15, 30 y 60 mg / Kg por peso, respectivamente, durante 7 días consecutivos. Se compararon entre los grupos, las características morfológicas y el peso corporal, los órganos reproductivos, incluyendo los testículos, el epidídimo más conducto deferente y vesícula seminal. Además, se observó la concentración de espermatozoides epididimarios y los cambios de la histopatología de los tejidos testiculares en todos los grupos. Los resultados mostraron que la mimosina no afectó los pesos corporales de los ratones. Sin embargo, todas las dosis de mimosina podrían reducir significativamente los pesos absolutos y relativos de los testículos y las glándulas seminales, pero no así del epidídimo y los conductos deferentes. La mimosina en dosis de 30 y 60 mg / Kg por peso podría disminuir significativamente la concentración de esperma. Además, se observó la atrofia y degeneración seminífera en ratones tratados con mimosina en comparación con el grupo control. En conclusión, el consumo de partes comestibles de Leucaena leucocephala que contienen mimosina podría dañar los órganos reproductivos masculinos, lo que puede causar subfertilidad masculina aguda o infertilidad.


Assuntos
Animais , Masculino , Camundongos , Testículo/efeitos dos fármacos , Fabaceae , Mimosina/farmacologia , Tamanho do Órgão , Glândulas Seminais/efeitos dos fármacos , Camundongos Endogâmicos ICR
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