RESUMO
The storage and processing of Litopenaeus vannamei are often challenged by the freeze-thaw (F-T) cycle phenomenon. This study delved into the influence of pretreatment with l-arginine (Arg) and l-lysine (Lys) on the myofibrillar proteins oxidation and quality of shrimp subjected to F-T cycles. Arg and Lys pretreatment notably improved water-holding capacity (WHC), textural integrity as well as the myofibrillar structure of the shrimps. A lesser reduction in the amounts of immobile and bound water was found in the amino acid-treated groups, and the oxidation of lipids and proteins were both decelerated. Molecular simulation results indicated that Arg and Lys could form hydrogen and salt-bridge bonds with myosin, enhancing the stability of Litopenaeus vannamei. The study concludes that Arg and Lys are effective in alleviating the adverse effects of F-T cycles on the quality of Litopenaeus vannamei, and provides a new solution for the quality maintenance during storage and processing.
Assuntos
Arginina , Lisina , Proteínas Musculares , Oxirredução , Penaeidae , Animais , Penaeidae/química , Arginina/química , Lisina/química , Proteínas Musculares/química , Congelamento , Conservação de Alimentos/métodos , Frutos do Mar/análise , Miofibrilas/químicaRESUMO
One of the more common diseases affecting zoo-managed cheetahs (Acinonyx jubatus) is chronic renal disease, which can impact their welfare and ultimately shortens their lifespan. Early diagnosis, for which estimating Glomerular Filtration Rate (GFR) is one such tool, is imperative to help mitigate the negative impacts of this insidious disease. GFR was determined by measuring the serum clearance of iohexol in nine clinically normal, cheetahs managed under human care that presented for voluntary blood collection. A 2-sample iohexol clearance method was performed, along with serum symmetric dimethylarginine (SDMA) determination. SDMA has shown promise in humans, dogs, and cats, as an early biomarker of renal disease. Additionally, the relationship between GFR and SDMA, along with serum creatinine and BUN were analyzed. The mean values for the uncorrected GFR and corrected GFR were 2.08 ± 0.215 mL/min/kg body weight and 1.87 ± 0.173 mL/min/kg body weight, respectively. No significant correlations were observed between GFR, SDMA, serum creatinine, or BUN. Both the uncorrected and corrected iohexol-based GFR values were similar to an inulin-based GFR reference interval determined in zoo managed cheetahs and a reported domestic cat iohexol-based GFR reference interval. Serum SDMA values support previous research suggesting cheetahs have a separate reference interval from domestic cats (0-14 µg/dL). Measuring GFR by the serum clearance of iohexol shows promise as a readily available, cheap, and easily administered clearance marker that can be used in cheetahs trained for voluntary blood collection, thereby avoiding the need for anesthesia.
Assuntos
Acinonyx , Arginina , Taxa de Filtração Glomerular , Iohexol , Acinonyx/sangue , Acinonyx/fisiologia , Animais , Iohexol/farmacocinética , Feminino , Masculino , Arginina/análogos & derivados , Arginina/sangue , Creatinina/sangue , Biomarcadores/sangue , Meios de Contraste/farmacocinéticaRESUMO
Primary Hyperparathyroidism (PHPT) is characterized by excessive parathormone (PTH) secretion and disrupted calcium homeostasis. Untargeted metabolomics offers a valuable approach to understanding the complex metabolic alterations associated with different diseases, including PHPT. Plasma untargeted metabolomics was applied to investigate the metabolic profiles of PHPT patients compared to a control group. Two complementary liquid-phase separation techniques were employed to comprehensively explore the metabolic landscape in this retrospective, single-center study. The study comprised 28 female patients diagnosed following the current guidelines of PHPT diagnosis and a group of 30 healthy females as a control group. To evaluate their association with PHPT, we identified changes in plasma metabolic profiles in patients with PHPT compared to the control group. The primary outcome measure included detecting plasma metabolites and discriminating PHPT patients from controls. The study unveiled specific metabolic imbalances that may link L-amino acids with peptic ulcer disease, gamma-glutamyls with oxidative stress, and asymmetric dimethylarginine (ADMA) with cardiovascular complications. Several metabolites, such as gamma-glutamyls, caffeine, sex hormones, carnitine, sphingosine-1-phosphate (S-1-P), and steroids, were connected with reduced bone mineral density (BMD). Metabolic profiling identified distinct metabolic patterns between patients with PHPT and healthy controls. These findings provided valuable insights into the pathophysiology of PHPT.
Assuntos
Hiperparatireoidismo Primário , Metabolômica , Humanos , Feminino , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/metabolismo , Metabolômica/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Metaboloma , Arginina/sangue , Arginina/metabolismo , Arginina/análogos & derivados , Densidade Óssea , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/metabolismo , Estudos de Casos e Controles , Adulto , Aminoácidos/sangue , Aminoácidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/sangue , Esfingosina/metabolismo , Lisofosfolipídeos/sangue , Lisofosfolipídeos/metabolismo , Biomarcadores/sangueRESUMO
INTRODUCTION: Asymmetric dimethylarginine (ADMA), a cardiovascular risk factor, increases in renal failure. The aim of this study was to investigate ADMA levels in normal weight and obese patients on hemodialysis. METHODS: In this cross-sectional study, 43 normal weight and 43 obese patients on regular hemodialysis were examined. Malnutrition-inflammation score (MIS), anthropometry, circulating ADMA, lipid profiles including triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipid ratios, glucose homeostasis parameters, blood pressure, and high-sensitivity C-reactive protein (hs-CRP) were assessed. RESULTS: Serum levels of ADMA were significantly lower in the obese compared to the normal weight patients (10268.2 ± 10092.4 vs. 13765.2 ± 9951.3 ng/l, P = 0.03). At the same time MIS score (6.1 ± 2.4 vs. 10.7 ± 3.2, P < 0.001), systolic blood pressure (119 ± 26.8 vs. 134.2 ± 24.7 mmHg, P = 0.018) and mean arterial pressure (91.3 ± 18.6 vs. 100.9 ± 15.9 mmHg, P = 0.028) were significantly lower in the obese than the normal weight group. Fasting blood glucose (P = 0.045), TG/HDL (P = 0.03), TC/HDL (P = 0.019), and LDL/HDL (P = 0.005) ratios, and hs-CRP (P = 0.015) levels were significantly higher in the obese than in the normal weight group. CONCLUSION: Circulating ADMA was significantly lower in obese than in normal weight patients on hemodialysis, which was concomitant with lower MIS, indicating a better nutritional inflammatory status, and lower blood pressure.
Assuntos
Arginina , Obesidade , Diálise Renal , Humanos , Arginina/análogos & derivados , Arginina/sangue , Masculino , Feminino , Obesidade/sangue , Obesidade/complicações , Pessoa de Meia-Idade , Estudos Transversais , Adulto , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Biomarcadores/sangue , IdosoRESUMO
The l -arginine ( l -Arg)/nitric oxide/cyclic GMP/potassium channel (K ATP ) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l -Arg/nitric oxide/cyclic GMP/K ATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l -Arg/nitric oxide/cyclic GMP/K ATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l -Arg (a precursor of nitric oxide), S-nitroso- N -acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro- l -arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a K ATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20â min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/K ATP channel pathway.
Assuntos
Analgésicos , Arginina , GMP Cíclico , Canais KATP , NG-Nitroarginina Metil Éster , Óxido Nítrico , Receptores Opioides , Rutina , Transdução de Sinais , Animais , Masculino , Camundongos , Arginina/farmacologia , Óxido Nítrico/metabolismo , Rutina/farmacologia , Analgésicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides/efeitos dos fármacos , Canais KATP/metabolismo , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Glibureto/farmacologia , Citrato de Sildenafila/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Naloxona/farmacologia , Sulfonas/farmacologia , Piperazinas/farmacologia , Purinas/farmacologia , S-Nitroso-N-Acetilpenicilamina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Antagonistas de Entorpecentes/farmacologia , Relação Dose-Resposta a Droga , Doadores de Óxido Nítrico/farmacologiaRESUMO
The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels. It inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. The prokaryotic SthK channel from Spirochaeta thermophila shares features with CNG and HCN channels and is an established model for this channel family. Here, we show SthK activity is inhibited by PIP2. A cryo-EM structure of SthK in nanodiscs reveals a PIP2-fitting density coordinated by arginine and lysine residues from the S4 helix and the C-linker, located between voltage-sensing and pore domains of adjacent subunits. Mutation of two arginine residues weakens PIP2 inhibition with the double mutant displaying insensitivity to PIP2. We propose that PIP2 inhibits SthK by gluing S4 and S6 together, stabilizing a resting channel conformation. The PIP2 binding site is partially conserved in CNG channels suggesting the possibility of a similar inhibition mechanism in the eukaryotic homologs.
Assuntos
Microscopia Crioeletrônica , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Fosfatidilinositol 4,5-Difosfato , Spirochaeta , Fosfatidilinositol 4,5-Difosfato/metabolismo , Spirochaeta/metabolismo , Spirochaeta/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/química , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Sítios de Ligação , Ativação do Canal Iônico , Mutação , Modelos Moleculares , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Arginina/metabolismo , Arginina/químicaRESUMO
Agricultural yields are often limited by damage caused by pathogenic microorganisms, including plant-pathogenic bacteria. The chemical control options to cope with bacterial diseases in agriculture are limited, predominantly relying on copper-based products. These compounds, however, possess limited efficacy. Therefore, there is an urgent need to develop novel technologies to manage bacterial plant diseases and reduce food loss. In this study, a new antimicrobial agent was developed using a doping method that entraps small bioactive organic molecules inside copper as the metal matrix. The food preservative agent lauroyl arginate ethyl ester (ethyl lauroyl arginate; LAE) was chosen as the doped organic compound. The new composites were termed LAE@[Cu]. Bactericidal assays against Acidovorax citrulli, a severe plant pathogen, revealed that LAE and copper in the composites possess a synergistic interaction as compared with each component individually. LAE@[Cu] composites were further characterised in terms of chemical properties and in planta assays demonstrated their potential for further development as crop protection agents.
Assuntos
Cobre , Proteção de Cultivos , Doenças das Plantas , Cobre/química , Cobre/farmacologia , Proteção de Cultivos/métodos , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Comamonadaceae/efeitos dos fármacos , Comamonadaceae/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Arginina/química , Arginina/farmacologia , Arginina/análogos & derivados , Antibacterianos/farmacologia , Antibacterianos/química , Viabilidade Microbiana/efeitos dos fármacosRESUMO
Although arginine methylation (R-methylation) is one of the most important post-translational modifications (PTMs) conserved in eukaryotes, it has not been studied to the same extent as phosphorylation and ubiquitylation. Technical constraints, which are in the process of being resolved, may partly explain this lack of success. Our knowledge of R-methylation has recently evolved considerably, particularly in metazoans, where misregulation of the enzymes that deposit this PTM is implicated in several diseases and cancers. Indeed, the roles of R-methylation have been highlighted through the analyses of the main actors of this pathway: the PRMT writer enzymes, the TUDOR reader proteins, and potential "eraser" enzymes. In contrast, R-methylation has been much less studied in plants. Even so, it has been shown that R-methylation in plants, as in animals, regulates housekeeping processes such as transcription, RNA silencing, splicing, ribosome biogenesis, and DNA damage. R-methylation has recently been highlighted in the regulation of membrane-free organelles in animals, but this role has not yet been demonstrated in plants. The identified R-met targets modulate key biological processes such as flowering, shoot and root development, and responses to abiotic and biotic stresses. Finally, arginine demethylases activity has mostly been identified in vitro, so further studies are needed to unravel the mechanism of arginine demethylation.
Assuntos
Arginina , Desenvolvimento Vegetal , Plantas , Processamento de Proteína Pós-Traducional , Metilação , Desenvolvimento Vegetal/genética , Plantas/metabolismo , Plantas/genética , Arginina/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Animais , Estresse Fisiológico , Regulação da Expressão Gênica de PlantasRESUMO
Persistent neurochemical and biological disturbances resulting from repeated cycles of drug reward, withdrawal, and relapse contribute to drug dependence. Methamphetamine (MA) is a psychostimulant with substantial abuse potential and neurotoxic effects, primarily affecting monoamine neurotransmitter systems in the brain. In this study, we aimed to explore the progression of drug dependence in rat models of MA self-administration, extinction, and reinstatement through targeted and non-targeted metabolomics analyses. Metabolic profiles were examined in rat plasma during the following phases: after 16 days of MA self-administration (Group M); after 16 days of self-administration followed by 14 days of extinction (Group MS); and after self-administration and extinction followed by a reinstatement injection of MA (Group MSM). Each group of MA self-administration, extinction, and reinstatement induces distinct changes in the metabolic pathways, particularly those related to the TCA cycle, arginine and proline metabolism, and arginine biosynthesis. Additionally, the downregulation of glycerophospholipids and sphingomyelins in Group MSM suggests their potential role in MA reinstatement. These alterations may signify the progressive deterioration of these metabolic pathways, possibly contributing to drug dependence following repeated cycles of drug reward, withdrawal, and relapse. These results provide valuable insights into the metabolic changes associated with MA use at various stages, potentially facilitating the discovery of early diagnostic biomarkers and therapeutic targets for MA use disorders.
Assuntos
Modelos Animais de Doenças , Metabolômica , Metanfetamina , Autoadministração , Animais , Metanfetamina/administração & dosagem , Metanfetamina/efeitos adversos , Metabolômica/métodos , Ratos , Masculino , Progressão da Doença , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Ratos Sprague-Dawley , Redes e Vias Metabólicas/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metaboloma/efeitos dos fármacos , Glicerofosfolipídeos/metabolismo , Extinção Psicológica/efeitos dos fármacos , Arginina/administração & dosagem , Arginina/metabolismoRESUMO
Plant growth regulators are cost-effective and efficient methods for enhancing plant defenses under stress conditions. This study investigates the ability of two plant growth-regulating substances, thiourea (TU) and arginine (Arg), to mitigate salinity stress in wheat. The results show that both TU and Arg, particularly when used together, modify plant growth under salinity stress. Their application significantly increases the activities of antioxidant enzymes while decreasing the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and relative electrolyte leakage (REL) in wheat seedlings. Additionally, these treatments significantly reduce the concentrations of Na+ and Ca2+ and the Na+/K+ ratio, while significantly increasing K+ levels, thereby preserving ionic osmotic balance. Importantly, TU and Arg markedly enhance the chlorophyll content, net photosynthetic rate, and gas exchange rate in wheat seedlings under salinity stress. The use of TU and Arg, either individually or in combination, results in a 9.03-47.45% increase in dry matter accumulation, with the maximum increase observed when both are used together. Overall, this study highlights that maintaining redox homeostasis and ionic balance are crucial for enhancing plant tolerance to salinity stress. Furthermore, TU and Arg are recommended as potential plant growth regulators to boost wheat productivity under such conditions, especially when applied together.
Assuntos
Arginina , Homeostase , Oxirredução , Estresse Salino , Plântula , Tioureia , Triticum , Triticum/metabolismo , Triticum/efeitos dos fármacos , Triticum/crescimento & desenvolvimento , Tioureia/farmacologia , Tioureia/análogos & derivados , Arginina/metabolismo , Plântula/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Malondialdeído/metabolismo , Fotossíntese/efeitos dos fármacos , Clorofila/metabolismo , Reguladores de Crescimento de Plantas/metabolismoRESUMO
BACKGROUND: The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. METHODS: We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. RESULTS: A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). CONCLUSIONS: After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. TRIAL REGISTRATION: Registration with PROSPERO for this meta-analysis is number CRD42024520509.
Assuntos
Fístula Anastomótica , Arginina , Neoplasias Colorretais , Infecção da Ferida Cirúrgica , Humanos , Fístula Anastomótica/sangue , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/imunologia , Fístula Anastomótica/prevenção & controle , Arginina/administração & dosagem , Relação CD4-CD8 , Neoplasias Colorretais/sangue , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Imunidade Humoral , Imunoglobulina A/sangue , Tempo de Internação/estatística & dados numéricos , Infecção da Ferida Cirúrgica/sangue , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/imunologia , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
Guanidinoacetic acid, as an energetic substance, has a wide range of applications in the food, pharmaceutical, and feed industries. However, the biosynthesis of guanidinoacetic acid has not been applied in industrial production. In this study, we designed the synthetic route of guanidinoacetic acid in a food-grade strain of Bacillus subtilis. By regulating the expression of key enzymes, lifting feedback inhibition, and increasing membrane permeability, we achieved the efficient synthesis of guanidinoacetic acid by whole-cell catalysis. Firstly, the optimal L-arginine:glycine amidinotransferase was screened based on the phylogenetic tree, and the expression of the key enzyme was enhanced by a strategy combining strong promoter and genome integration. Secondly, the ornithine cycle for L-arginine synthesis in Corynebacterium glutamicum was introduced to alleviate the feedback inhibition of the enzyme by the byproduct L-ornithine, and the L-arginine degradation pathway was knocked down to enhance substrate regeneration. Thirdly, the expression of N-acetylmuramoyl-L-alanine amidase (LytC) was up-regulated to increase the cell membrane permeability. Finally, after optimization of whole-cell production conditions, strain Bs-13 achieved guanidinoacetic acid production at a titer of 13.1 g/L after 24 h, with a proudction rate of 0.54 g/(L·h) and a glycine conversion rate of 92.7%. The above strategy improved the production of guanidinoacetic acid and provided a reference for the biosynthesis of guanidinoacetic acid.
Assuntos
Arginina , Bacillus subtilis , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Arginina/biossíntese , Arginina/metabolismo , Glicina/análogos & derivados , Glicina/metabolismo , Glicina/biossíntese , Amidinotransferases/genética , Amidinotransferases/metabolismo , Corynebacterium glutamicum/metabolismo , Corynebacterium glutamicum/genética , N-Acetil-Muramil-L-Alanina Amidase/genética , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Engenharia Metabólica , Ornitina/biossíntese , Ornitina/metabolismoRESUMO
The African clawed frog (Xenopus laevis) endures prolonged periods of dehydration while estivating underground during the dry season. Epigenetic modifications play crucial roles in regulating gene expression in response to environmental changes. The elucidation of epigenetic changes relevant to survival could serve as a basis for further studies on organ preservation under extreme stress. The current study examined the relative protein levels of key enzymes involved in the arginine methylation of histones in the liver and kidney tissues of control versus dehydrated (35 ± 1%) X. laevis through immunoblotting. Protein arginine methyltransferases (PRMT) 4, 5, and 6 showed significant protein level decreases of 35 ± 3%, 71 ± 7%, and 25 ± 5%, respectively, in the liver tissues of the dehydrated frogs relative to controls. In contrast, PRMT7 exhibited an increase of 36 ± 4%. Similarly, the methylated histone markers H3R2m2a, H3R8m2a, and H3R8m2s were downregulated by 34 ± 11%, 15 ± 4%, and 42 ± 12%, respectively, in the livers of dehydrated frogs compared to controls. By contrast, the kidneys of dehydrated frogs showed an upregulation of histone markers. H3R2m2a, H3R8m2a, H3R8m2s, and H4R3m2a were significantly increased by 126 ± 12%, 112 ± 7%, 47 ± 13%, and 13 ± 3%, respectively. These changes can play vital roles in the metabolic reorganization of X. laevis during dehydration, and are likely to increase the chances of survival. In turn, the tissue-specific regulation of the histone arginine methylation mechanism suggests the importance of epigenetic regulation in the adaptation of X. laevis for whole-body dehydration.
Assuntos
Arginina , Histonas , Fígado , Xenopus laevis , Animais , Xenopus laevis/genética , Histonas/metabolismo , Histonas/genética , Metilação , Arginina/metabolismo , Fígado/metabolismo , Desidratação/genética , Desidratação/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Epigênese Genética , Rim/metabolismo , Regulação da Expressão Gênica , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismoRESUMO
Arginases are key enzymes that hydrolyze L-arginine to urea and L-ornithine in the urea cycle. The two arginase isoforms, arginase 1 (ARG1) and arginase 2 (ARG2), regulate the proliferation of cancer cells, migration, and apoptosis; affect immunosuppression; and promote the synthesis of polyamines, leading to the development of cancer. Arginases also compete with nitric oxide synthase (NOS) for L-arginine, and their participation has also been confirmed in cardiovascular diseases, stroke, and inflammation. Due to the fact that arginases play a crucial role in the development of various types of diseases, finding an appropriate candidate to inhibit the activity of these enzymes would be beneficial for the therapy of many human diseases. In this review, based on numerous experimental, preclinical, and clinical studies, we provide a comprehensive overview of the biological and physiological functions of ARG1 and ARG2, their molecular mechanisms of action, and affected metabolic pathways. We summarize the recent clinical trials' advances in targeting arginases and describe potential future drugs.
Assuntos
Arginase , Neoplasias , Humanos , Arginase/metabolismo , Arginase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/enzimologia , Animais , Arginina/metabolismo , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).
Assuntos
Eptifibatida , Hemorragias Intracranianas , AVC Isquêmico , Peptídeos , Ácidos Pipecólicos , Sulfonamidas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Arginina/administração & dosagem , Arginina/efeitos adversos , Arginina/análogos & derivados , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Eptifibatida/administração & dosagem , Eptifibatida/efeitos adversos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Infusões Intravenosas , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/epidemiologia , AVC Isquêmico/mortalidade , AVC Isquêmico/terapia , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Ácidos Pipecólicos/administração & dosagem , Ácidos Pipecólicos/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Método Simples-Cego , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Terapia Trombolítica/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Trombectomia/efeitos adversos , Trombectomia/métodos , Resultado do Tratamento , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Incidência , AdultoRESUMO
Cationic amino acid binding protein (CLasArgBP), one of the two amino acid binding receptor in Candidatus Liberibacter asiaticus (CLas), is predominately expressed in citrus psyllids as a part of ATP-binding cassette transport system. The present study describes characterization of CLasArgBP by various biophysical techniques and in silico study, to identify potential inhibitor molecules against CLasArgBP through virtual screening and MD simulations. Further, in planta study was carried out to assess the effect of selected inhibitors on Huanglongbing infected Mosambi plants. The results showed that CLasArgBP exhibits pronounced specificity for arginine, histidine and lysine. Surface plasmon resonance (SPR) study reports highest binding affinity for arginine (Kd, 0.14 µM), compared to histidine and lysine (Kd, 15 µΜ and 26 µΜ, respectively). Likewise, Differential Scanning Calorimetry (DSC) study showed higher stability of CLasArgBP for arginine, compared to histidine and lysine. N(omega)-nitro-L-arginine, Gamma-hydroxy-L-arginine and Gigartinine emerged as lead compounds through in silico study displaying higher binding energy and stability compared to arginine. SPR reports elevated binding affinities for N(omega)-nitro-L-arginine and Gamma-hydroxy-L-arginine (Kd, 0.038 µΜ and 0.061 µΜ, respectively) relative to arginine. DSC studies showed enhanced thermal stability for CLasArgBP in complex with selected inhibitors. Circular dichroism and fluorescence studies showed pronounced conformational changes in CLasArgBP with selected inhibitors than with arginine. In planta study demonstrated a substantial decrease in CLas titer in treated plants as compared to control plants. Overall, the study provides the first comprehensive characterization of cationic amino acid binding protein from CLas, as a potential drug target to manage HLB disease.
Assuntos
Proteínas de Bactérias , Proteínas de Bactérias/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Rhizobiaceae/química , Rhizobiaceae/metabolismo , Simulação de Dinâmica Molecular , Doenças das Plantas/microbiologia , Arginina/química , Arginina/metabolismo , Citrus/química , Citrus/microbiologia , Liberibacter/química , Liberibacter/metabolismoRESUMO
PURPOSES: Size exclusion chromatography (SEC) is widely used to characterize molecular size variants of antibody drugs. However, SEC analysis is hindered by secondary interactions (or nonspecific interactions) between proteins and stationary phase packing, which result in poor column efficiency. Previous studies have reported that chaotropic salt can inhibit these interactions, but the corresponding applications of this aspect are relatively rare. Therefore, this study introduces a novel approach using sodium iodide (NaI) as a mobile-phase component in SEC and investigates the influence of the mobile-phase composition on secondary interactions. METHODS: SEC analysis was performed on one antibody-drug conjugate and four monoclonal antibodies (mAbs) using three different mobile-phase systems (i.e., sodium chloride/L-arginine hydrochloride/NaI mobile phases system) to compare the column efficiency. Subsequently, mAb-1 was used as a model to investigate the effects of these factors on secondary interactions by adjusting the ionic strength (salt concentration) and pH of the NaI mobile-phase system. RESULTS: NaI exhibits superior column efficiency performance in the SEC analysis of most products. The ionic strength will affect nonideal electrostatic and hydrophobic interaction. An appropriate ionic strength can inhibit electrostatic interactions, while an excessive ionic strength increases hydrophobic interactions. pH primarily influences electrostatic interactions. Determining the appropriate pH necessitates consideration of the isoelectric point of the protein and the pH tolerance of the column. CONCLUSIONS: In SEC analysis, using NaI as the salt component in the mobile phase reduces secondary interactions and improves column efficiency. This approach is advantageous for samples with intense secondary interactions and is a suitable alternative.
Assuntos
Anticorpos Monoclonais , Cromatografia em Gel , Imunoconjugados , Iodeto de Sódio , Anticorpos Monoclonais/química , Cromatografia em Gel/métodos , Imunoconjugados/química , Iodeto de Sódio/química , Concentração Osmolar , Interações Hidrofóbicas e Hidrofílicas , Concentração de Íons de Hidrogênio , Cloreto de Sódio/química , Eletricidade Estática , Arginina/químicaRESUMO
Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for endothelial and vascular dysfunction. Their concentration levels in blood serum have the potential to be an accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels and their relationship with the clinical status and endothelial and vascular function. Methods: A cross-sectional study, including 36 adult CHD cyanotic patients [(17 males) (42.3 ± 16.3 years)] with an arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males) (38.2 ± 8.5 years)], was performed. All the patients underwent a clinical examination, blood testing, and cardiopulmonary tests. Their endothelial function was assessed using the intima media thickness and flow-mediated dilatation. Vascular function, using applanation tonometry methods, was determined using the aortic systolic pressure, aortic pulse pressure, augmentation pressure, augmentation index, pulse pressure amplification, and pulse wave velocity. Results: The concentrations of e-sel and ADMA were significantly higher in the patients with CHD. The E-sel levels correlated positively with red blood cells, hemoglobin concentration, hematocrit, and augmentation pressure; they correlated negatively with blood oxygen saturation, the forced expiratory one-second volume, forced vital capacity, and oxygen uptake. The ADMA levels were found to correlate only with age. Conclusions: The E-sel level, unlike ADMA concentration, reflects the severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD.
Assuntos
Arginina , Cianose , Selectina E , Cardiopatias Congênitas , Humanos , Masculino , Adulto , Feminino , Arginina/análogos & derivados , Arginina/sangue , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/complicações , Cianose/sangue , Cianose/fisiopatologia , Selectina E/sangue , Estudos Transversais , Pessoa de Meia-Idade , Biomarcadores/sangue , Endotélio Vascular/fisiopatologia , Endotélio Vascular/metabolismo , Estudos de Casos e ControlesRESUMO
As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.