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1.
Braz J Med Biol Res ; 52(11): e8441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721904

RESUMO

The heptapeptide Bj-PRO-7a, isolated and identified from Bothrops jararaca (Bj) venom, produces antihypertensive and other cardiovascular effects that are independent on angiotensin converting enzyme inhibition, possibly relying on cholinergic muscarinic receptors subtype 1 (M1R). However, whether Bj-PRO-7a acts upon the central nervous system and modifies behavior is yet to be determined. Therefore, the aims of this study were: i) to assess the effects of acute administration of Bj-PRO-7a upon behavior; ii) to reveal mechanisms involved in the effects of Bj-PRO-7a upon locomotion/exploration, anxiety, and depression-like behaviors. For this purpose, adult male Wistar (WT, wild type) and spontaneous hypertensive rats (SHR) received intraperitoneal injections of vehicle (0.9% NaCl), diazepam (2 mg/kg), imipramine (15 mg/kg), Bj-PRO-7a (71, 213 or 426 nmol/kg), pirenzepine (852 nmol/kg), α-methyl-DL-tyrosine (200 mg/kg), or chlorpromazine (2 mg/kg), and underwent elevated plus maze, open field, and forced swimming tests. The heptapeptide promoted anxiolytic and antidepressant-like effects and increased locomotion/exploration. These effects of Bj-PRO-7a seem to be dependent on M1R activation and dopaminergic receptors and rely on catecholaminergic pathways.


Assuntos
Ansiedade , Comportamento Animal/efeitos dos fármacos , Venenos de Crotalídeos/química , Depressão , Comportamento Exploratório/efeitos dos fármacos , Oligopeptídeos/farmacologia , Prolina/farmacologia , Animais , Comportamento Animal/fisiologia , Masculino , Oligopeptídeos/isolamento & purificação , Prolina/isolamento & purificação , Ratos , Ratos Wistar
2.
Chem Pharm Bull (Tokyo) ; 67(10): 1139-1143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582633

RESUMO

We have discovered that ß-amino acid homooligomers with cis- or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike α-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are autogenous conformations that are stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. A structural overlap comparison of helical cis/trans bicyclic ß-proline homooligomers with typical α-helix structure of α-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridgehead substituents of the present homooligomers point outwards from the helical surface. We were interested to know whether such non-naturally occurring divergent helical molecules could mimic α-helix structures. In this study, we show that bicyclic ß-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.


Assuntos
Proteínas Nucleares/química , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas/química , Proteína Supressora de Tumor p53/química , Proteínas de Ciclo Celular , Humanos , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Prolina/análogos & derivados , Prolina/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
3.
J Appl Microbiol ; 127(6): 1768-1775, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487414

RESUMO

AIMS: Persister cells are stressed cells that have transient tolerance to antibiotics; these cells undergo no genetic change, but instead, their tolerance is due to reduced metabolism. Unfortunately, little is known about how persisters resuscitate, so we explored the waking of cells in the presence of the interkingdom signal indole. METHODS AND RESULTS: To generate a large population of persister cells, we induced the persister phenotype in the opportunistic pathogen Pseudomonas aeruginosa by pretreating cells with carbonyl cyanide m-chlorophenylhydrazone to reduce translation by depleting ATP levels, and found, via single cell observations, that proline is sufficient to wake the persister cells. P. aeruginosa is often present in the gastrointestinal tract, and indole from commensal bacteria such as Escherichia coli has been shown to inhibit P. aeruginosa quorum sensing and pathogenicity without influencing growth. Furthermore, indole is not toxic to P. aeruginosa persister cells. However, we find here that physiological concentrations of indole inhibit P. aeruginosa persister cell resuscitation with an efficiency of higher than 95%. Critically, when contacted with E. coli stationary-phase cultures, the indole produced by E. coli completely inhibits persister cell resuscitation of P. aeruginosa. CONCLUSIONS: Therefore, E. coli has devised a method to outcompete its competitors by preventing their resuscitation with indole. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides insight into why indole is produced by commensal bacteria.


Assuntos
Escherichia coli/metabolismo , Indóis/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Técnicas de Cocultura , Indóis/metabolismo , Prolina/farmacologia , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos
4.
J Agric Food Chem ; 67(35): 9805-9811, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407895

RESUMO

Stachydrine (STA) is a constituent of citrus fruits and Leonurus heterophyllus Sweet. In the present study, we established that STA caused acute endothelium-dependent relaxation. The vascular action of STA was mediated by nitric oxide (NO) via cyclic guanosine monophosphate. Mechanistically, STA activated AMP-activated protein kinase (AMPK), protein kinase B/Akt, and endothelial NO synthase (eNOS) in vascular endothelial cells (ECs). AMPK inhibition by compound C blocked STA-induced Akt/eNOS phosphorylation, suggesting that AMPK is the upstream of Akt and eNOS. Inhibition of Akt by MK2206 blocked STA-stimulated eNOS phosphorylation without altering AMPK phosphorylation. Furthermore, we showed that STA activated AMPK via the induction of liver kinase B1 phosphorylation. These results indicated that STA can induce eNOS phosphorylation and vasorelaxation by regulating the interplay between AMPK and Akt pathways in ECs. These findings further highlighted the potential of STA as a nutritional factor in the beneficial effects of fruit intake in preventing the endothelial dysfunction-related metabolic cardiovascular diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aorta Torácica/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Prolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vasodilatadores/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Bovinos , Citrus/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Técnicas In Vitro , Leonurus/química , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação/efeitos dos fármacos , Prolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
5.
J Therm Biol ; 84: 154-163, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31466748

RESUMO

L-proline (L-PROL) is an essential amino acid, a constituent of many proteins and the osmoprotective molecule produced and accumulated in higher plants and some freshwater microalgae in response to various environmental stressors. Knowledge on thermoprotective effects of this amino acid on freshwater invertebrates is very scarce. Therefore the aim of our study was to determine the effect of L-PROL at concentrations: 10 mg/L, 20 mg/L and 50 mg/L on swimming behavior (immobilization, swimming track density, swimming speed, turning ability) of Daphnia magna subjected to temperatures: 22 °C, 35 °C and 38 °C. We found that L-PROL elevated all the measured swimming parameters at 22 °C when compared to the untreated crustaceans. Furthermore, L-PROL alleviated heat-induced inhibition of these parameters in the experimental animals subjected to 35 °C. The results suggest that L-PROL stimulates swimming performance and alleviates alterations of swimming parameters induced by heat stress in D. magna. Moreover, these findings may support the hypothesis that in natural conditions, L-PROL may protect crustaceans against thermal stress.


Assuntos
Daphnia/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Prolina/farmacologia , Natação , Animais , Comportamento Animal/efeitos dos fármacos , Daphnia/fisiologia , Feminino , Resposta ao Choque Térmico/fisiologia
6.
Plant Physiol Biochem ; 142: 1-7, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247444

RESUMO

Proline is one of the amino acids that compose proteins and has various roles under non-stress and stress conditions. In this study, we investigated the effect of proline on the growth and browning of two plants, tobacco and rice, by exogenous application and endogenous increase of proline. Exogenous proline had a different effect on the growth and browning between tobacco and rice: proline affected negatively the growth of tobacco seedlings and favorably that of rice seedlings. In addition, proline prevented browning only in rice cultured cells, consistent with the increase of proline contents, but not in tobacco BY-2 cells. These results might be due to the difference of exogenous proline uptake activity in these cells. From the Lineweaver-Burk plots, proline inhibited polyphenol oxidase activity in vitro, which is a major factor of enzymatic browning in plants, by affecting the enzyme-substrate complex. Proline could suppress the browning of the plant callus by inhibition of PPO activity.


Assuntos
Oryza/efeitos dos fármacos , Oryza/crescimento & desenvolvimento , Prolina/farmacologia , Tabaco/efeitos dos fármacos , Tabaco/crescimento & desenvolvimento , Catecol Oxidase/antagonistas & inibidores , Catecol Oxidase/metabolismo , Células Cultivadas , Malondialdeído/metabolismo , Oryza/citologia , Oryza/genética , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Polifenóis/metabolismo , Prolina/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento
7.
Plant Physiol Biochem ; 140: 136-150, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103796

RESUMO

Escalating temperatures are adversely impacting the production potential of various cool- and warm-season crops, such as Mungbean, therefore effective strategies are required to improve heat tolerance of various crops. Mungbean, a summer season food legume, is seriously affected at temperatures more than 35/25 °C, especially at its reproductive stage, resulting in pollen infertility to induce loss of flowers and potential pods. Proline (Pro), a well-researched stress-related molecule, has been implicated in determining pollen fertility, but its involvement in affecting reproductive function under heat stress is not reported so far. In the present study, it was hypothesised that depletion of endogenous Pro in reproductive components of the flowers of heat-stressed Mungbean plants might impair the reproductive function. To test this hypothesis, Mungbean genotypes (heat tolerant and heat-sensitive), growing in outdoor environment (32.5/17.5 ±â€¯1 °C mean day/night temperature), until on the onset of flowering (30 days after sowing) were subjected to mild heat stress (MS; 40/28 °C) and high heat stress (HS; 45/33 °C), in the absence or presence of 5 mM proline treatment, applied as soil drenching and foliar spray, 2 days before imposition of heat stress. In MS plants, the endogenous Pro showed a significant increase in leaves, anthers, pollen and ovules, while in SS plants, a marked reduction was noticed. In later case, the activity of proline synthesising enzymes (pyrolline-5-carboxylate synthase and pyrroline-5-carboxylate reductase) declined severely, along with a proline catabolism enzyme (proline dehydrogenase) suggesting disruption in proline metabolism in vegetative and reproductive components. This was associated with considerable decrease in pollen germination, stigma receptivity and ovule viability in heat-stressed plants. Simultaneously, leaf tissue showed high damage to cell membranes, leaf water status, stomatal conductance and cellular respiration. Photosynthetic ability (Chlorophyll, Photo system II function), carbon fixation (RuBisCo activity) and assimilation processes (sucrose synthesis and its hydrolysis) were significantly inhibited, in heat-stressed (HS) plants, which impacted the pod number, pod and seed weight per plant. Pro treatment, especially to HS plants resulted in appreciable increase in its endogenous concentration in vegetative and reproductive parts, which significantly improved the pollen fertility as well as stigma and ovule function. At the same time, stress damage to leaves was reduced significantly, leaf water status and chlorophyll were significantly higher, as a result the carbon fixation and assimilation capacity improved notably to increase the pod set, filled pod number, pod weight and seed weight per plants, suggesting a vital role of proline in enhancing the thermo-tolerance. The effects of Pro treatment were more pronounced in heat-sensitive genotype.


Assuntos
Temperatura Alta , Prolina/farmacologia , Vigna/metabolismo , Genótipo , Reprodução/efeitos dos fármacos , Sacarose/metabolismo , Vigna/efeitos dos fármacos , Vigna/fisiologia
8.
J Biol Chem ; 294(26): 10278-10289, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31110046

RESUMO

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells between the choroid and the retina. RPE dysfunction underlies many retinal degenerative diseases, including age-related macular degeneration, the leading cause of age-related blindness. To perform its various functions in nutrient transport, phagocytosis of the outer segment, and cytokine secretion, the RPE relies on an active energy metabolism. We previously reported that human RPE cells prefer proline as a nutrient and transport proline-derived metabolites to the apical, or retinal, side. In this study, we investigated how RPE utilizes proline in vivo and why proline is a preferred substrate. By using [13C]proline labeling both ex vivo and in vivo, we found that the retina rarely uses proline directly, whereas the RPE utilizes it at a high rate, exporting proline-derived mitochondrial intermediates for use by the retina. We observed that in primary human RPE cell culture, proline is the only amino acid whose uptake increases with cellular maturity. In human RPE, proline was sufficient to stimulate de novo serine synthesis, increase reductive carboxylation, and protect against oxidative damage. Blocking proline catabolism in RPE impaired glucose metabolism and GSH production. Notably, in an acute model of RPE-induced retinal degeneration, dietary proline improved visual function. In conclusion, proline is an important nutrient that supports RPE metabolism and the metabolic demand of the retina.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Prolina/administração & dosagem , Retina/metabolismo , Degeneração Retiniana/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Animais , Radioisótopos de Carbono/análise , Diferenciação Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oxirredução , Prolina/farmacologia , Retina/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/etiologia , Epitélio Pigmentado da Retina/efeitos dos fármacos
9.
Molecules ; 24(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096694

RESUMO

In this study, we evaluated antioxidant, antihyperuricemic, and herbicidal activities of essential oils (EOs) from Piper cubeba Bojer and Piper nigrum L.; two pepper species widely distributed in tropics, and examined their chemical compositions. Dried berries of P. cubeba and P. nigrum were hydro-distilled to yield essential oil (EO) of 1.23 and 1.11% dry weight, respectively. In the antioxidant assay, the radical scavenging capacities of P. cubeba EO against DPPH and ABTS free radicals were 28.69 and 24.13% greater than P. nigrum, respectively. In the antihyperuricemic activity, P. cubeba EO also exhibited stronger inhibitory effects on xanthine oxidase (IC50 = 54.87 µg/mL) than P. nigrum EO (IC50 = 77.11 µg/mL). In the herbicidal activity, P. cubeba EO showed greater inhibition on germination and growth of Bidens pilosa and Echinochloa crus-galli than P. nigrum EO. Besides, P. cubeba EO decreased 15.98-73.00% of photosynthesis pigments of B. pilosa and E. crus-galli, while electrolyte leakages, lipid peroxidations, prolines, phenolics, and flavonoids contents were increased 10.82-80.82% at 1.93 mg/mL dose. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) analyses revealed that P. nigrum and P. cubeba EOs principally possessed complex mixtures of monoterpenes and sesquiterpenes. Terpinen-4-ol (42.41%), α-copaene (20.04%), and γ-elemene (17.68%) were the major components of P. cubeba EO, whereas ß-caryophyllene (51.12%) and ß-thujene (20.58%) were the dominant components of P. nigrum EO. Findings of this study suggest both P. cubeba and P. nigrum EOs were potential to treat antioxidative stress and antihyperuricemic related diseases. In addition, the EOs of the two plants may be useful to control B. pilosa and E. crus-galli, the two invasive and problematic weeds in agriculture practice.


Assuntos
Óleos Voláteis/química , Óleos Voláteis/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Piper nigrum/química , Piper/química , Antioxidantes/química , Antioxidantes/farmacologia , Relação Dose-Resposta a Droga , Flavonoides/química , Flavonoides/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fenol/química , Fenol/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Prolina/química , Prolina/farmacologia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/química
10.
Indian J Med Res ; 149(1): 41-46, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31115373

RESUMO

Background & objectives: : Amino acids are general nutrients having anti-diabetic property. The present study was undertaken to investigate the mechanism of anti-diabetic effects of amino acids in human visceral adipocyte cells in high glucose environment. Methods: : Experiments were carried out in human visceral adipocytes. Adiponectin (APN) siRNAs were designed using Ambion tools. APN mRNA expression was quantified using real-time polymerase chain reaction, and protein level was studied using ELISA. AMP-activated kinase (AMPK) activity was measured and glucose uptake by 2-deoxyglucose uptake method. Results: : Amino acids (proline and phenylalanine) exposure to adipocytes significantly (P <0.01) increased APN mRNA by 1.5-folds when compared to control whereas proline increased APN secretion by 10.6-folds (P <0.01), phenylalanine by 12.7-folds (P <0.001) and alanine by 6.3-folds (P <0.01). Free amino acid-induced AMPK activity and glucose uptake were decreased with the transient knockdown of APN. Interpretation & conclusions: : Antidiabetic effect of the tested amino acids was exhibited by increased glucose uptake through the AMPK pathway by an APN-dependent mechanism in human visceral adipocytes. This should be tested and confirmed in in vivo system. Newer treatment modalities with amino acids which can enhance glucose uptake and APN secretion can be developed as drug for treating both diabetes and obesity.


Assuntos
Adiponectina/genética , Diabetes Mellitus/dietoterapia , Glucose/metabolismo , Obesidade/dietoterapia , Proteínas Quinases/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Aminoácidos/farmacologia , Células Cultivadas , Diabetes Mellitus/metabolismo , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Fenilalanina/farmacologia , Prolina/farmacologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
11.
Plant Physiol Biochem ; 139: 558-568, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31029029

RESUMO

The interplaying defensive roles of silicon (Si) and proline (Pro) in improving growth and yield attributes, physio-biochemical attributes, and antioxidant defense systems in common bean plant grown under saline (NaCl) and/or cadmium (Cd2+) stress were assessed. Seed were sown in plastic pots filled with sand-free ions as a growing medium that watered with a ½-strength Hoagland's nutrient solution. Twenty five days after planting, pots were split into 4 plots; control (no stress), 150 mM NaCl (salt stress), 1.5 mM Cd2+ in CdCl2 (Cd2+ stress), and 100 mM NaCl + 1.0 mM Cd2+ (salt + Cd2+ stress). Four treatments; foliar spray with distilled water, 6 mM Si (in K2SiO3.nH2O) solution, 6 mM Pro solution, and a combination of Si and Pro were allotted under each of the 4 plots. The experimental layout was a completely randomized design with 15 replicates. Compared to control, NaCl or Cd2+ stress significantly (P ≤ 0.05) reduced plant growth and yield attributes, leaf contents of chlorophylls, carotenoids, N, P, and K+, K+/Na+ ratio, RWC, MSI, Pn and Tr, while elevated significantly leaf EL, leaf contents of proline, soluble sugar, glutathione, MDA, Na+, and root, leaf and pod contents of Cd2+. The activities of antioxidant enzymes were also raised. The combined stress (NaCl + Cd2+) was more influential. Addition of Si and/or Pro for common bean plants under NaCl and/or Cd2+ stress significantly enhanced all investigated attributes of physiology, morphology, and biochemistry, and further increased the activities of antioxidant enzymes. Supplementation of Si + Pro was the best treatment having more positive influential, especially reducing the Cd2+ content in Phaseolus vulgaris pods to the limits (0.27 mg kg-1) for legumes. Therefore, this combined treatment is recommended to use for alleviating environmental stress effects, especially salinity and Cd2+ for common bean production.


Assuntos
Cádmio/farmacologia , Phaseolus/efeitos dos fármacos , Phaseolus/metabolismo , Prolina/farmacologia , Silício/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cloreto de Sódio/farmacologia
12.
Toxins (Basel) ; 11(4)2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995739

RESUMO

The toxicity and related mechanisms of aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) in the mouse kidney were studied, and the role of l-proline in alleviating kidney damage was investigated. In a 28-day toxicity mouse model, thirty mice were divided into six groups: control (without treatment), l-proline group (10 g/kg body weight (b.w.)), AFB1 group (0.5 mg/kg b.w.), AFM1 (3.5 mg/kg b.w.), AFB1 + l-proline group and AFM1 + l-proline group. Kidney index and biochemical indicators were detected, and pathological staining was observed. Using a human embryonic kidney 293 (HEK 293) cell model, cell apoptosis rate and apoptotic proteins expressions were detected. The results showed that AFB1 and AFM1 activated pathways related with oxidative stress and caused kidney injury; l-proline significantly alleviated abnormal expressions of biochemical parameters and pathological kidney damage, as well as excessive cell apoptosis in the AF-treated models. Moreover, proline dehydrogenase (PRODH) was verified to regulate the levels of l-proline and downstream apoptotic factors (Bax, Bcl-2, and cleaved Caspase-3) compared with the control (p < 0.05). In conclusion, l-proline could protect mouse kidneys from AFB1 and AFM1 through alleviating oxidative damage and decreasing downstream apoptosis, which deserves further research and development.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Aflatoxina B1/toxicidade , Aflatoxina M1/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Prolina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Prolina/farmacologia , Prolina Oxidase/metabolismo , Substâncias Protetoras/farmacologia , Testes de Toxicidade Subaguda
13.
Zygote ; 27(1): 49-53, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30714556

RESUMO

SummaryIn eutherian mammals, the placenta plays a critical role in embryo development by supplying nutrients and hormones and mediating interaction with the mother. To establish the fine connection between mother and embryo, the placenta needs to be formed normally, but the mechanism of placental differentiation is not fully understood. We previously revealed that mouse prolyl oligopeptidase (POP) plays a role in trophoblast stem cell (TSC) differentiation into two placental cell types, spongiotrophoblasts (SpT) and trophoblast giant cells. Here, we focused on SpT differentiation and attempted to elucidate a molecular mechanism. For Ascl2, Arnt, and Egfr genes that are indispensable for SpT formation, we found that a POP-specific inhibitor, SUAM-14746, significantly decreased Ascl2 expression, which was consistent with a significant decrease in expression of Flt1, a gene downstream of Ascl2. Although this downregulation was unlikely to be mediated by the PI3K-Akt pathway, our results indicated that POP controls TSC differentiation into SpT by regulating the Ascl2 gene.


Assuntos
Placenta/citologia , Serina Endopeptidases/genética , Trofoblastos/citologia , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Receptores ErbB/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Gravidez , Prolina/análogos & derivados , Prolina/farmacologia , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Tiazolidinas/farmacologia , Trofoblastos/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
14.
Cell Biol Int ; 43(3): 279-289, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632646

RESUMO

Long-standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL-1ß. However, how IL-1ß, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL-1ß could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK-2 cells by real-time PCR and Western-blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL-1ß also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF-κB pathway partly dampened the inhibitory effect of IL-1ß on ABCG2, indicating that IL-1ß reduced the ABCG2 expression partially through the NF-ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL-1ß, which is dependent on the NF-κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL-1ß, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Transporte/metabolismo , Interleucina-1beta/farmacologia , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Sequência de Bases , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Humanos , Proteínas de Membrana , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Polimorfismo de Nucleotídeo Único/genética , Prolina/análogos & derivados , Prolina/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sulfonas/farmacologia , Tiocarbamatos/farmacologia , Fatores de Tempo , Ácido Úrico/metabolismo
15.
Plant Cell Rep ; 38(3): 403-416, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30684024

RESUMO

KEY MESSAGE: Mitigation of deleterious effects of salinity promoted by exogenous proline can be partially explained by changes in proline enzymatic metabolism and expression of specific proline-related genes. Proline accumulation is a usual response to salinity. We studied the ability of exogenous proline to mitigate the salt harmful effects in sorghum (Sorghum bicolor) leaves. Ten-day-old plants were cultivated in Hoagland's nutrient solution in either the absence or presence of salinity (NaCl at 75 mM) and sprayed with distilled water or 30 mM proline solution. Salinity deleterious effects were alleviated by exogenous proline 14 days after treatment, with a return in growth and recovery of leaf area and photosynthetic parameters. Part of the salinity response reflected an improvement in ionic homeostasis, provided by reduction in Na+ and Cl- ions and increases in K+ and Ca2+ ions as well as increases of compatible solutes. In addition, the application of proline decreased membrane damage and did not increase relative water content. Proline-treated salt-stressed plants displayed increase in proline content, a response counterbalanced by punctual modulation in proline synthesis (down-regulation of Δ1-pyrroline-5-carboxylate synthetase activity) and degradation (up-regulation of proline dehydrogenase activity) enzymes. These responses were correlated with expression of specific proline-related genes (p5cs1 and prodh). Our findings clearly show that proline treatment results in favorable changes, reducing salt-induced damage and improving salt acclimation in sorghum plants.


Assuntos
Prolina/farmacologia , Sorghum/efeitos dos fármacos , Sorghum/metabolismo , Cálcio/metabolismo , Potássio/metabolismo , Sódio/metabolismo
16.
ChemMedChem ; 14(3): 343-348, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30615305

RESUMO

The spread of antibiotic-resistant pathogens has boosted the search for new antimicrobial drugs. Proline-rich antimicrobial peptides are promising lead compounds for the development of next-generation antibiotics, given their very low cytotoxicity and their good antimicrobial activity targeting the bacterial ribosome. Bac5(1-25) is an N-terminal fragment of the bovine proline-rich antimicrobial peptide Bac5, whose mode of action has been recently described. In this work we tested a number of Bac5(1-25) fragments, and we characterized their antimicrobial activity against Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, Salmonella enterica, and Pseudomonas aeruginosa. We evaluated their cytotoxicity toward human cells and their efficacy in inhibiting bacterial protein synthesis. This allowed us to identify some shorter fragments of Bac5(1-25) with a good balance between antibacterial efficacy, protein synthesis inhibition, and ease/cost-effectiveness of synthesis, suitable as lead compounds to develop new antibacterials.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Prolina/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Proteínas de Bactérias/biossíntese , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/metabolismo , Testes de Sensibilidade Microbiana , Prolina/síntese química , Prolina/química , Inibidores da Síntese de Proteínas/síntese química , Inibidores da Síntese de Proteínas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
17.
ACS Chem Biol ; 14(2): 296-303, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30620575

RESUMO

The interplay between the activities of lytic transglycosylases (LTs) and penicillin-binding proteins (PBPs) is critical for the health of the bacterial cell wall. Bulgecin A (a natural-product inhibitor of LTs) potentiates the activity of ß-lactam antibiotics (inhibitors of PBPs), underscoring this intimate mechanistic interdependence. Bulgecin A in the presence of an appropriate ß-lactam causes bulge deformation due to the formation of aberrant peptidoglycan at the division site of the bacterium. As Pseudomonas aeruginosa, a nefarious human pathogen, has 11 LT paralogs, the answer as to which LT activity correlates with ß-lactam potentiation is important and is currently unknown. Growth of P. aeruginosa PAO1 strains harboring individual transposon-insertion mutants at each of the 11 genes for LTs, in the presence of the ß-lactam antibiotic ceftazidime or meropenem, implicated the gene products of slt, mltD, and mltG (of the 11), in bulge formation and potentiation. Hence, the respective enzymes would be the targets of inhibition by bulgecin A, which was indeed documented. We further demonstrated by imaging in real time and by SEM that cell lysis occurs by the structural failure of this bulge. Upon removal of the ß-lactam antibiotic prior to lysis, P. aeruginosa experiences delayed recovery from the elongation and bulge phenotype in the presence of bulgecin A. These observations argue for a collaborative role for the target LTs in the repair of the aberrant cell wall, the absence of activities of which in the presence of bulgecin A results in potentiation of the ß-lactam antibiotic.


Assuntos
Acetilglucosamina/análogos & derivados , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Prolina/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamas/farmacologia , Acetilglucosamina/farmacologia , Testes de Sensibilidade Microbiana , Prolina/farmacologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/fisiologia
18.
Plant Physiol Biochem ; 135: 385-394, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30616113

RESUMO

Soil salinity is one of the major abiotic stress factors that hampers plant growth and productivity by limiting photosynthesis and other related metabolic processes. In this study we investigated whether treatment with proline and/or 24-epibrassinolide (EBL) to two contrasting cultivars of Brassica juncea (L.) Czern and Coss viz. Varuna and RH-30 could counteract with the adverse effects of salinity on photosynthesis and seed yield. Plants were treated with proline and/or 24-epibrassinolide (EBL) at 28 and 29d-stages of growth. Salt stress reduced plant growth, photosynthetic attributes, efficiency of PSII (Fv/Fm), leaf water potential and finally seed yield, at harvest but improved the activity of antioxidant enzymes in both the cultivars in a concentration dependent manner. Exogenous application of EBL with proline completely neutralised the adverse effects of salt at 78 mM or 117 mM stress levels whereas the treatment partially neutralised the impact of highest salt concentration of 156 mM, through the upregulation of the antioxidant system.


Assuntos
Antioxidantes/fisiologia , Brassinosteroides/farmacologia , Mostardeira/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Prolina/farmacologia , Esteroides Heterocíclicos/farmacologia , Antioxidantes/metabolismo , Anidrases Carbônicas/metabolismo , Catalase/metabolismo , Clorofila/metabolismo , Relação Dose-Resposta a Droga , Mostardeira/crescimento & desenvolvimento , Mostardeira/metabolismo , Mostardeira/fisiologia , Peroxidase/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , Transpiração Vegetal/efeitos dos fármacos , Transpiração Vegetal/fisiologia , Estresse Salino , Superóxido Dismutase/metabolismo
19.
Int J Mol Sci ; 20(3)2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678338

RESUMO

Gliomas are the most aggressive adult primary brain tumors. Expression of inducible Nitric Oxide Synthase has been reported as a hallmark of chemoresistance in gliomas and several studies have reported that inhibition of inducible Nitric Oxide Synthase could be related to a decreased proliferation of glioma cells. The present work was to analyze the molecular effects of the acetamidine derivative compound 39 (formally CM544, N-(3-{[(1-iminioethyl)amino]methyl}benzyl) prolinamide dihydrochloride), a newly synthetized iNOS inhibitor, in a C6 rat glioma cell model. There is evidence of CM544 selective binding to the iNOS, an event that triggers the accumulation of ROS/RNS, the expression of Nrf-2 and the phosphorylation of MAPKs after 3 h of treatment. In the long run, CM544 leads to the dephosphorylation of p38 and to a massive cleavage of PARP-1, confirming the block of C6 rat glioma cell proliferation in the G1/S checkpoint and the occurrence of necrotic cell death.


Assuntos
Amidinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glioma/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Prolina/análogos & derivados , Animais , Linhagem Celular Tumoral , Poli(ADP-Ribose) Polimerase-1/metabolismo , Prolina/farmacologia , Proteólise , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Basic Clin Pharmacol Toxicol ; 124(1): 40-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29998529

RESUMO

Prolyl oligopeptidase (PREP) is an abundant peptidase in the brain and periphery, but its physiological functions are still largely unknown. Recent findings point to a role for PREP in inflammatory processes. This study assessed the cellular and extracellular PREP activities in cultures of mouse primary cortical neurons, microglial cells and astrocytes, and immortalized microglial BV-2 cells under neuroinflammatory conditions induced by lipopolysaccharide (LPS) and interferon gamma (IFNγ). Furthermore, we evaluated the neuroprotective effect of a specific PREP inhibitor, KYP-2047, in a neuroinflammation model based on a coculture of primary cortical neurons and activated BV-2 cells. The inflammatory insult reduced intracellular and increased extracellular PREP activity specifically in microglial cells, suggesting that activated microglia excretes active PREP. A targeted proteomics approach revealed up-regulation in PREP protein levels in BV-2 cell growth medium but down-regulation in crude membrane-bound PREP after LPS+IFNγ. In the coculture of BV-2 cells and primary neurons, an increase in extracellular PREP activity was also detected after inflammation. KYP-2047 (10 µmol/L) significantly protected neurons against microglial toxicity and reduced the levels of the pro-inflammatory cytokine tumour necrosis factor alpha. In conclusion, these data point to an extracellular role for microglial PREP in the inflammatory process. Inhibition of PREP during neuroinflammation is a potential target for neuroprotection. Thus, PREP inhibitors may offer a novel therapeutic approach for the treatment of neurodegenerative disorders with an inflammatory component including Parkinson's and Alzheimer's diseases.


Assuntos
Microglia/metabolismo , Inflamação Neurogênica/tratamento farmacológico , Prolina/análogos & derivados , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Animais , Animais Recém-Nascidos , Membrana Celular/metabolismo , Córtex Cerebral/citologia , Técnicas de Cocultura , Meios de Cultura/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Embrião de Mamíferos , Feminino , Humanos , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/imunologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Inflamação Neurogênica/imunologia , Neurônios , Neuroproteção/efeitos dos fármacos , Cultura Primária de Células , Prolina/farmacologia , Prolina/uso terapêutico , Serina Endopeptidases/imunologia , Inibidores de Serino Proteinase/uso terapêutico , Regulação para Cima
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