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1.
Proc Natl Acad Sci U S A ; 119(35): e2209729119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35994647

RESUMO

Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.


Assuntos
Aminoaciltransferases , Culicidae , Malária , Processamento de Proteína Pós-Traducional , Esporozoítos , Aminoaciltransferases/imunologia , Animais , Culicidae/imunologia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Malária/genética , Malária/imunologia , Malária/parasitologia , Plasmodium berghei/genética , Plasmodium berghei/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia
2.
J Transl Med ; 22(1): 220, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429732

RESUMO

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.


Assuntos
Antígeno CD47 , Neoplasias , Animais , Humanos , Neoplasias/patologia , Fagocitose , Macrófagos/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Modelos Animais de Doenças , Antígenos de Diferenciação/metabolismo , Antígenos de Diferenciação/farmacologia , Antígenos de Diferenciação/uso terapêutico
3.
Environ Sci Technol ; 58(15): 6693-6703, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38577981

RESUMO

A major component of human skin oil is squalene, a highly unsaturated hydrocarbon that protects the skin from atmospheric oxidants. Skin oil, and thus squalene, is continuously replenished on the skin surface. Squalene is also quickly consumed through reactions with ozone and other oxidants. This study examined the extent of squalene depletion in the skin oils of the forearm of human volunteers after exposure to ozone in a climate chamber. Temperature, relative humidity (RH), skin coverage by clothing, and participants' age were varied in a controlled manner. Concentrations of squalene were determined in skin wipe samples collected before and after ozone exposure. Exposures to ozone resulted in statistically significant decreases in post-exposure squalene concentrations compared to pre-exposure squalene concentrations in the skin wipes when squalene concentrations were normalized by concentrations of co-occurring cholesterol but not by co-occurring pyroglutamic acid (PGA). The rate of squalene loss due to ozonolysis was lower than its replenishment on the skin surface. Within the ranges examined, temperature and RH did not significantly affect the difference between normalized squalene levels in post-samples versus pre-samples. Although not statistically significant, skin coverage and age of the volunteers (three young adults, three seniors, and three teenagers) did appear to impact squalene depletion on the skin surfaces.


Assuntos
Poluição do Ar em Ambientes Fechados , Ozônio , Humanos , Adolescente , Esqualeno/análise , Ozônio/análise , Poluição do Ar em Ambientes Fechados/análise , Pele/química , Oxidantes
4.
Molecules ; 28(21)2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37959820

RESUMO

Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.


Assuntos
Ácido Pirrolidonocarboxílico , Trombose , Humanos , Idoso , Ácido Pirrolidonocarboxílico/química , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Amidas/farmacologia , Trombose/tratamento farmacológico , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Inibidores da Agregação Plaquetária/química
5.
Am J Kidney Dis ; 78(4): 590-600, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400023

RESUMO

The anion gap (AG) is a mathematical construct that compares the blood sodium concentration with the sum of the chloride and bicarbonate concentrations. It is a helpful calculation that divides the metabolic acidoses into 2 categories: high AG metabolic acidosis (HAGMA) and hyperchloremic metabolic acidosis-and thereby delimits the potential etiologies of the disorder. When the [AG] is compared with changes in the bicarbonate concentration, other occult acid-base disorders can be identified. Furthermore, finding that the AG is very small or negative can suggest several occult clinical disorders or raise the possibility of electrolyte measurement artifacts. In this installment of AJKD's Core Curriculum in Nephrology, we discuss cases that represent several very common and several rare causes of HAGMA. These case scenarios highlight how the AG can provide vital clues that direct the clinician toward the correct diagnosis. We also show how to calculate and, if necessary, correct the AG for hypoalbuminemia and severe hyperglycemia. Plasma osmolality and osmolal gap calculations are described and when used together with the AG guide appropriate clinical decision making.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Desequilíbrio Ácido-Base/metabolismo , Desequilíbrio Ácido-Base/terapia , Acidose/metabolismo , Acidose/terapia , Currículo , Desequilíbrio Ácido-Base/diagnóstico , Acidose/diagnóstico , Adulto , Idoso , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/metabolismo , Cetoacidose Diabética/terapia , Feminino , Hidratação/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Adulto Jovem
6.
Rheumatology (Oxford) ; 60(2): 598-606, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259244

RESUMO

OBJECTIVE: The spectrum of clinical manifestations and serological phenomena of SLE is heterogeneous among patients and even changes over time unpredictably in individual patients. For this reason, clinical diagnosis especially in complicated or atypical cases is often difficult or delayed leading to poor prognosis. Despite the medical progress nowadays in the understanding of SLE pathogenesis, disease-specific biomarkers for SLE remain an outstanding challenge. Therefore, we undertook this study to investigate potential biomarkers for SLE diagnosis. METHODS: Serum samples from 32 patients with SLE and 25 gender-matched healthy controls (HCs) were analysed by metabolic profiling based on liquid chromatography-tandem mass spectrometry metabolomics platform. The further validation for the potential biomarker was performed in an independent set consisting of 36 SLE patients and 30 HCs. RESULTS: The metabolite profiles of serum samples allowed differentiation of SLE patients from HCs. The levels of arachidonic acid, sphingomyelin (SM) 24:1, monoacylglycerol (MG) 17:0, lysophosphatidyl ethanolamine (lysoPE) 18:0, lysoPE 16:0, lysophosphatidyl choline (lysoPC) 20:0, lysoPC 18:0 and adenosine were significantly decreased in SLE patients, and the MG 20:2 and L-pyroglutamic acid were significantly increased in SLE group. In addition, L-pyroglutamic acid achieved an area under the receiver-operating characteristic curve of 0.955 with high sensitivity (97.22%) and specificity (83.33%) at the cut-off of 61.54 µM in the further targeted metabolism, indicating diagnostic potential. CONCLUSION: Serum metabolic profiling is differential between SLE patients and HCs and depicts increased L-pyroglutamic acid as a promising bitformatomarker for SLE.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Metabolômica/métodos , Ácido Pirrolidonocarboxílico/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Curva ROC
7.
J Biol Chem ; 294(17): 6719-6732, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30814252

RESUMO

Amyloid-ß (Aß) pathology in Alzheimer's disease (AD) is characterized by the formation of polymorphic deposits comprising diffuse and cored plaques. Because diffuse plaques are predominantly observed in cognitively unaffected, amyloid-positive (CU-AP) individuals, pathogenic conversion into cored plaques appears to be critical to AD pathogenesis. Herein, we identified the distinct Aß species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated Aß polymorphism with amyloid conformation-sensitive dyes and a novel in situ MS paradigm for chemical characterization of hyperspectrally delineated plaque morphotypes. We found that maturation of diffuse into cored plaques correlated with increased Aß1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that Aß1-40 aggregates at the core structure of mature plaques, whereas Aß1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Aßx-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating Aß1-40 deposition. Experiments in tgAPPSwe mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of Aß1-42 and that Aß plaque maturation over time is associated with increases in Aß1-40. Finally, we found that Aß1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Aßx-42 pyroglutamation and Aß1-40 deposition are critical events in priming and maturation of pathogenic Aß from diffuse into cored plaques, underlying neurotoxic plaque development in AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Conformação Proteica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
8.
Crit Care ; 23(1): 162, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064391

RESUMO

AIM: The aim of this study was to evaluate oxidative stress from glutathione depletion in critically ill patients with a septic shock through the abnormal presence of pyroglutamic acid (PyroGlu) in the urine (indirectly) and through its serum level (directly). METHODS: This was a prospective analytical study of 28 critically ill patients with a septic shock who were monitored from admission (initial) to 3 days of stay (final) in the intensive care unit (ICU). Data collected included PyroGlu and glutamic acid (Glu) using liquid chromatography/mass spectrometry, and glutathione peroxidase (GPX) activity with a colorimetric assay. The differences in Glu, PyroGlu, and GPX activity between the septic shock group and healthy control group serving as reference values were evaluated using the Mann-Whitney test. The correlations between Glu, PyroGlu, and GPX activity and clinical outcomes were determined using Spearman's correlation coefficient. RESULTS: In patients with septic shock, serum and urine PyroGlu levels were higher, erythrocyte GPX activity/gr Hb was lower, and urine Glu levels were lower compared to healthy control reference values, for both initial and final values. Initial serum Glu levels were also lower. Serum PyroGlu levels had a correlation with both initial and final serum Glu levels; levels also correlated in the urine. Initial serum Glu correlated with the days of mechanical ventilation (P = 0.016) and the days of ICU stay (P = 0.05). Urine Glu/mg creatinine correlated with APACHE II (P = 0.030). This positive correlation observed for serum Glu was not observed for PyroGlu. CONCLUSIONS: The current study found that septic patients have higher levels of PyroGlu, lower levels of Glu, and lower erythrocyte GPX activity, suggesting that these biomarkers could be used as an indicator of glutathione depletion. In addition, Glu is related to severity parameters. This study can guide future studies on the importance of monitoring the levels of pyroglutamic acidosis in critical patients with septic shock in order to preserve the oxidative status and its evolution during the stay in the ICU.


Assuntos
Circulação Cerebrovascular/fisiologia , Glutationa/fisiologia , Estresse Oxidativo/fisiologia , Choque Séptico/complicações , APACHE , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Estado Terminal/terapia , Feminino , Glutationa/análise , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Pirrolidonocarboxílico/análise , Ácido Pirrolidonocarboxílico/sangue , Ácido Pirrolidonocarboxílico/urina , Choque Séptico/fisiopatologia , Espanha
9.
J Sci Food Agric ; 99(4): 1780-1786, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30226928

RESUMO

BACKGROUND: To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of γ-aminobutyric acid, has never been studied in the context of plant protection. RESULTS: The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance. CONCLUSION: Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture. © 2018 Society of Chemical Industry.


Assuntos
Ascomicetos/fisiologia , Doenças das Plantas/imunologia , Ácido Pirrolidonocarboxílico/imunologia , Ácido Salicílico/imunologia , Triticum/imunologia , Resistência à Doença , Doenças das Plantas/microbiologia , Ácido Pirrolidonocarboxílico/química , Ácido Salicílico/química , Triticum/microbiologia
10.
J Proteome Res ; 17(8): 2695-2703, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-29947227

RESUMO

The post-translational modification of N-terminal glutamine (Q) to a pyroglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Four complete QC sequences from the species C. araneosus, C. frigidus, C. litteratus, and C. monile and two partial sequences from C. amadis and C. miles have been obtained by analysis of transcriptomic data. Comparisons with mammalian enzyme sequences establish a high level of identity and complete conservation of functional active site residues, including a cluster of hydrogen-bonded acidic side chains. Mass spectrometric analysis of crude venom samples coupled to conotoxin precursor protein sequences obtained from transcriptomic data establishes the presence of pyroglutamyl conotoxins in the venom of C. frigidus and C. amadis. The C. frigidus peptide belongs to the M superfamily, with cysteine framework III, whereas the C. amadis peptide belongs to the divergent superfamily with cysteine framework VI/VII. Additionally, gamma carboxylation of glutamic acid and hydroxylation of proline are observed in the C. frigidus peptide. Mass spectral data are available via ProteomeXchange with identifier PXD009006.


Assuntos
Aminoaciltransferases/química , Conotoxinas/química , Caramujo Conus/química , Ácido Pirrolidonocarboxílico/metabolismo , Sequência de Aminoácidos , Aminoaciltransferases/metabolismo , Animais , Caramujo Conus/enzimologia , Perfilação da Expressão Gênica , Espectrometria de Massas , Processamento de Proteína Pós-Traducional
11.
Bioorg Med Chem ; 26(16): 4644-4649, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119995

RESUMO

A series of l-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of l-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC50 values of 1.44 and 1.21 µg mL-1, which were about seven times that of commercial azoxystrobin (7.85 µg mL-1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.


Assuntos
Antifúngicos/síntese química , Produtos Biológicos/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Linhagem Celular , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Células PC12 , Phytophthora infestans/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/síntese química , Ácido Pirrolidonocarboxílico/farmacologia , Ratos , Relação Estrutura-Atividade
12.
Bioprocess Biosyst Eng ; 40(7): 981-988, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28382460

RESUMO

During the production of bio-based bulk chemicals, such as lactic acid (LA), organic impurities have to be removed to produce a ready-to-market product. A capillary electrophoresis method for the simultaneous detection of LA and organic impurities in less than 10 min was developed. LA and organic impurities were detected using a direct UV detection method with micellar background electrolyte, which consisted of borate and sodium dodecyl sulfate. We investigated the effects of electrolyte composition and temperature on the speed, sensitivity, and robustness of the separation. A few validation parameters, such as linearity, limit of detection, and internal and external standards, were evaluated under optimized conditions. The method was applied for the detection of LA and organic impurities, including tyrosine, phenylalanine, and pyroglutamic acid, in samples from a continuous LA fermentation process from post-extraction tapioca starch and yeast extract.


Assuntos
Ácido Láctico/análise , Aminoácidos , Eletroforese Capilar
13.
Molecules ; 22(11)2017 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-29165329

RESUMO

Four new compounds, aneglycoside A-C (1-3) and timosaponin U (4), were isolated from the rhizomes of Anemarrhena asphodeloides. Their structures were determined through extensive spectroscopic analysis, chemical characteristics, and high-resolution mass spectrometry (HRMS). All the isolations were evaluated for cytotoxicity against HepG2, Hela, and SGC7901 human cancer lines. Compounds 1, 2, and 4 showed weak antiproliferative activities on HepG2, Hela, and SGC7901 cells.


Assuntos
Anemarrhena/química , Glicosídeos/química , Rizoma/química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hidrólise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia
14.
Bioorg Chem ; 60: 98-101, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25981125

RESUMO

Phosphate ions and glutaminyl cyclase (QC) both catalyze the formation of pyroglutamate (pE, pGlu) from N-terminal glutamine residues of peptides and proteins. Here, we studied the mechanism of glutamine cyclization using kinetic secondary deuterium and solvent isotope effects. The data suggest that proton transfer(s) are rate determining for the spontaneous reaction, and that phosphate and QC are accelerating the reaction by promoting synchronized proton transfers in a concerted mechanism. Thus, non-enzymatic and enzymatic catalysis of pyroglutamate formation exploit a similar mode of transition-state stabilization.


Assuntos
Aminoaciltransferases/metabolismo , Drosophila melanogaster/enzimologia , Fosfatos/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Animais , Ciclização , Drosophila melanogaster/metabolismo , Glutamina/metabolismo , Prótons
15.
Biosci Biotechnol Biochem ; 79(5): 795-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25495055

RESUMO

We purified pyroglutamic acid from human placental extract and identified it as a potent stimulator of rat primary hepatocyte DNA synthesis. Pyroglutamic acid dose-dependently stimulated DNA synthesis, and this effect was inhibited by PD98059, a dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) inhibitor. Therefore, pyroglutamic acid stimulated DNA synthesis in rat primary hepatocytes via MAPK signaling.


Assuntos
DNA/biossíntese , Hepatócitos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/farmacologia , Animais , Células Cultivadas , Cromatografia Líquida/métodos , DNA/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Hepatócitos/fisiologia , Humanos , Imidazóis/farmacologia , Masculino , Espectrometria de Massas/métodos , Placenta/química , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ácido Pirrolidonocarboxílico/isolamento & purificação , Ratos Sprague-Dawley
16.
Food Chem ; 463(Pt 4): 141450, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39362095

RESUMO

This study aimed to elucidate the changes of browning-related metabolite in fresh-cut potato and to identify anti-browning agents. Metabolomics and weighted correlation network analysis (WGCNA) were used to identify metabolites and correlate them with potato browning traits. A total of 79 browning trait-positive-related metabolites and 19 browning trait-negative-related metabolites were obtained from four key modules via WGCNA. The accumulation of metabolites with rich reducing groups and acidic groups were found to enhance anti-browning activity in potatoes. Among these metabolites, only L-pyroglutamic acid (L-PA) and ascorbic acid had variable importance for the projection (VIP) values greater than 1.5. In addition, it was found that L-PA inhibited polyphenol oxidase (PPO) activity by lowering pH and interacting with amino acid residues of PPO. L-PA also inhibited the growth of microorganisms in fresh-cut potato. Our results show that L-AP is an effective novel anti-browning agent with antibacterial activity.

17.
ACS Appl Mater Interfaces ; 16(13): 16340-16350, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38511525

RESUMO

As an additive for perovskites, in addition to functional groups, the steric configuration of molecules is worthy of consideration because it influences perovskite crystallization, thus determining whether defect passivation is effective without any side effects. In this work, the chiral molecules l- and d-pyroglutamic acid (l-PA and d-PA) were chosen as additives for perovskite passivators to reveal the reasons for the differences in passivation between amino acids with different steric configurations. Functional groups, such as the C═O groups and N-H groups of l-PA and d-PA, can passivate the perovskite defects. However, l-PA exhibited a more distorted steric configuration, while d-PA was more planar, leading to differences in the distances between the two C═O groups. Taking the Pb-Pb bond length as a reference, the shorter distance between the two C═O groups of l-PA distorts the perovskite lattice structure, which results in poor device stability. Conversely, the similar distance between the two C═O groups of d-PA promoted the preferred orientational growth of the perovskite. Finally, the d-PA-doped device accomplished an excellent efficiency of 24.11% with an improved open-circuit voltage of 1.17 V. Furthermore, the efficiency of the unencapsulated d-PA-doped device was maintained at 93% in N2 for more than 3000 h and 74% after 500 h of operation at maximum power point tracking under continuous illumination.

18.
Int Immunopharmacol ; 138: 112452, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38943972

RESUMO

Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research.


Assuntos
Eritropoetina , Fármacos Neuroprotetores , Traumatismos dos Nervos Periféricos , Eritropoetina/uso terapêutico , Humanos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Animais , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Peptídeos/uso terapêutico , Peptídeos/farmacologia , Oligopeptídeos
19.
Beilstein J Org Chem ; 9: 1432-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23946839

RESUMO

The cis- and trans-stereoselective radical additions to α-methylene-γ-alkyl- γ-lactams were investigated and the scope and limitation of the reaction were also revealed. This stereoselective radical reaction was used for synthesis of chiral pyroglutamic acid derivatives starting from a commercially available chiral amino acid.

20.
Pharmaceutics ; 15(8)2023 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-37631381

RESUMO

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

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