Amino Acids最新文献

Interleukin-2-inducible T-cell kinase (ITK) is an essential enzyme that plays a key role in both the activation and differentiation of T-cells. As a member of the Tec family of non-receptor tyrosine kinases, ITK is predominantly expressed in T cells, exerting a critical influence on T-cell receptor signaling and downstream pathways. Moreover, ITK regulates cytokine production, notably interleukin-2 (IL-2), and the differentiation of Th2 cells. In the context of immunology, ITK has garnered significant attention, particularly for its potential to address immune-related conditions such as cancer and autoimmune diseases, including lymphoproliferative diseases. In this study, we performed a structure-based virtual screening utilizing a library of plant-based small molecules to identify inhibitors of ITK. The initial selection of phytochemicals was guided by adherence to the Lipinski rule of five. After molecular docking, top-ranked hits in terms of binding affinity underwent screening for physicochemical and pharmacokinetic properties and PASS analyses. The three selected phytochemicals, Withanolide A, Amorphispironon E, and 27-Deoxy-14-hydroxywithaferin A (27-DHA) demonstrated remarkable binding affinity to ITK with a docking score of − 9.2, − 9.1, and − 9.1 kcal/mol, respectively. All the phytochemicals showed specific binding to the ATP-binding site of ITK as revealed by protein structure network analysis. These selected phytoconstituents underwent all-atom molecular dynamics (MD) simulations, spanning 100 ns each. The simulation results showed that ITK with elucidated compounds exhibited stability with minimal dynamics. In addition, we performed an MM-PBSA analysis, which indicated a strong binding affinity. This study highlights the potential of Withanolide A, Amorphispironon E, and 27-DHA as preliminary leads for further experimental validation and preclinical investigation toward therapeutic development.

l-threonine is used in dietary supplements and nutritional products ingested by healthy consumers. The objective of this study was to determine in a randomized double blind controlled clinical trial the safety and tolerability of l-threonine used as graded doses in supplements for 4 weeks. Healthy male adults (age 42.9) ingested randomly placebo or different doses of L-threonine (0, 3, 6, 9, 12 g/day) for 4 weeks using a crossover design. At the end of supplementation period, the subjects visited the clinic for medical examination, anthropometric parameter measurements, blood sampling for biochemical tests including amino acid concentrations in plasma, measurement of blood pressure and heart rate, and dietary intake evaluation. Adverse events were recorded all along the trial. None of the anthropometric parameters measured, dietary intake and the biochemical parameters were affected by l-threonine supplementation except a non-specific minor increase in plasma aspartate amino transferase and creatine kinase which was measured in the group supplemented with 9 g l-threonine per day but not with the 12 g per day dose. Also, the concentration of L-threonine as well as the concentration of its metabolite L-2-amino butylate were found to be increased in plasma after supplementation with 6, 9, 12 g/day L-threonine. The moderate and mild adverse events were found to occur at random. All symptoms disappeared during the supplementation period despite continuous L-threonine supplementation. These results of this study indicate a no-observed-adverse-effect-level (NOAEL) value for L-threonine to be 12 g/day in healthy adult males. This study was registered at jRCT as jRCT1050230137.

Pseudo-peptides are an important category of biologically active artificial small molecules. To access these important molecules, a novel series of bisazlactones was synthesized via the Erlenmeyer-Plöchl reaction, using glycine- and terephthaloyl-based diacid with aldehydes. These bisazlactones were then utilized as efficient intermediates in reactions with primary and secondary amines, providing novel pseudo-peptides containing enamide groups in high to excellent yields. The selected pseudo-peptide enamides exhibited selective cytotoxicity against hepatocarcinoma cells, while exhibiting negligible impact on normal mammalian cells. Notably, compound 6y displayed superior anti-cancer activity compared to the others.

Background

Creatine is a semi-essential nutrient that plays a critical role in energy metabolism, with dietary intake and endogenous synthesis contributing to overall creatine availability. While dietary creatine intake has been studied extensively, limited data exist on the dietary exposure to its precursor amino acids—glycine, arginine, and methionine—and their contribution to endogenous creatine synthesis. This study aimed to assess the dietary intake of these precursors in U.S. children and adults using data from the Third National Health and Nutrition Examination Survey (NHANES III) and to compare endogenous creatine synthesis with direct dietary creatine intake.

Methods

We analyzed NHANES III dietary recall data from 29,945 individuals aged 2 years and older. Intakes of glycine, arginine, methionine, and creatine were calculated per kilogram of body weight. The contribution of precursor amino acids to endogenous creatine synthesis was estimated using established metabolic conversion factors.

Results

The mean daily intakes of glycine, arginine, methionine, and creatine were 59.6 ± 0.4 mg/kg, 77.2 ± 0.5 mg/kg, 31.9 ± 0.2 mg/kg, and 15.5 ± 0.1 mg/kg, respectively. Estimated endogenous creatine synthesis from precursor amino acids was significantly greater than dietary creatine intake across all age groups (P < 0.01), with precursor-derived creatine production averaging 41.9 ± 0.3 mg/kg body weight per day, approximately 2.7 times higher than dietary creatine intake. Creatine precursor availability declined with age, with the lowest values observed in individuals aged ≥ 65 years.

Conclusion

This study provides the first comprehensive evaluation of total creatine availability in a representative U.S. population, highlighting the predominance of endogenous synthesis over direct dietary intake. These findings suggest that creatine metabolism is largely dependent on precursor amino acid intake and that certain populations, particularly older adults, may be at higher risk for reduced creatine availability. Future research should explore the physiological implications of these findings and potential dietary interventions to optimize creatine status across the lifespan.

To evaluate the potential of antimicrobial peptide CC34 for use as therapeutic agents for gastric cancer SGC-7901 and hepatocellular carcinoma HepG-2. In this study, the antibacterial activity and antibacterial mechanism were tested by the minimum inhibitory concentration (MIC) analysis, minimal bactericidal concentration (MBC) analysis, bacterial biofilm and NaCl permeability assays. Then, we assessed the hemolytic activity and cytotoxicity of CC34 for red blood cells and cancer cells, respectively. Apoptosis assay, cell cycle analysis, determination of intracellular ROS, western blot analysis caspase activity assay and ATP assay were further performed to investigate the mechanism of CC34 affected cancer cells. The novel peptide could inhibit Gram-negative and Gram-positive bacteria, with low hemolytic activity against mouse and chicken erythrocytes. Moreover, CC34 exhibited higher inhibitory activity against biofilm formation. In addition, our data showed that CC34 significantly suppressed cell proliferation, in a dose dependent manner. CC34 induced apoptosis, induced reactive oxygen species (ROS) generation, inhibited B-cell lymphoma-2 (Bcl-2) expression, increase B-cell lymphoma protein 2 associated X protein (Bax) expression, release of cytochrome c (Cyt C), promoted caspase-3 and − 9 activities and reduced cellular ATP levels in cancer cells. Our results indicate that CC34 with antimicrobial activity have a highly potent ability to induced apoptosis via mitochondrial-mediated apoptotic pathway in cancer cells.

The competitive uptake of essential amino acids (EAAs) by breast cancer cells is associated with poor patient prognosis and the development of an immunosuppressive tumor microenvironment. L-type amino acid transporters, LAT1 (SLC7 A5) and LAT2 (SLC7 A8) are major mediators of EAAs transmembrane uptake and are overexpressed in some tumor tissues. However, the distribution and functional roles of these transporters across breast cancer subtypes have not been fully elucidated. This study aims to investigate the therapeutic potential of targeting EAA transporters, particularly LAT1, in triple-negative breast cancer (TNBC) and its role in remodeling the tumor immune microenvironment. The distribution of EAA transporters across breast cancer subtypes was analyzed using multi-omics data. The effects of LAT1 targeting on TNBC cell proliferation and EAA uptake were evaluated using SLC7 A5 knockout and LAT1 inhibitors in vitro experiments. A 4T1-BALB/c tumor-bearing mouse model with normal immune function was constructed to investigate the effects of LAT1 targeting on tumor growth and immune microenvironment remodeling in vivo. TNBC demonstrated a strong dependence on LAT1-mediated EAAs uptake. Targeting LAT1 limited the exogenous supply of EAAs, leading to amino acid starvation, cell cycle arrest, and increased apoptosis in TNBC cells. The in vivo experiments, using a 4T1-BALB/c tumor-bearing mouse model, showed that LAT1 targeting inhibited tumor growth and remodeled the immunosuppressive tumor microenvironment. Targeting LAT1 improved PD-L1-associated immune suppression and improved the efficacy of PD-1 antibody treatment, producing synergistic anti-tumor effects. This study highlights the therapeutic potential of targeting LAT1 in TNBC, particularly in remodeling the tumor immune microenvironment. The findings provide a promising strategy for immune combination therapy in TNBC.

Graphical abstract

Histidine and carnosine can form complexes with divalent metal ions such as Fe²⁺, potentially providing stability to intracellular labile iron. Anaemia is a common comorbidity in the late stages of kidney disease, and patients are treated with erythropoiesis-stimulating agents (ESAs) and iron supplementation. However, iron supplementation is also associated with worse long-term outcomes. The purpose of this study is to investigate how histidine and carnosine supplementation can reduce symptoms of anaemia of chronic kidney disease (CKD) and the effects associated with iron-overloaded conditions. Adenine-induced chronic kidney disease mice were treated with histidine and carnosine by oral gavage for 10 days. Additionally, a model involving iron overload in mice was established, and these mice received concurrent treatment with histidine and carnosine. Haemoglobin, non-haem iron, malondialdehyde (MDA) and iron parameters were measured. Carnosine increased erythropoietin (EPO) levels (35.62 µg/ml ± 11.43) and resulted in haemoglobin repletion (16.7 g/dL ± 3.4). When iron was supplemented alongside with histidine or carnosine, there were better effects on haemoglobin repletion (14.22 ± 1.7 and 13.82 ± 2.15 g/ dL respectively), ferritin (59.5 ± 16.4, 52 ± 29.5 µg/ml) and non-haem iron (0.8 ± 0.21, 0.7 ± 0.38 nmol/mg), than the group receiving iron alone (p < 0.05). Furthermore, histidine and carnosine reduced non-haem iron and MDA, in iron-loaded conditions (p < 0.05). These positive effects observed in histidine and carnosine could be associated with reactive oxygen species (ROS) scavenging. EPO restoring levels in CKD model and the increment in haemoglobin and ferritin in carnosine treatments suggested the potential formation of a ternary complex with iron-glutathione. In conclusion, our results indicate the beneficial effect of histidine and carnosine in the context of iron supplementation for the correction of haemoglobin and protection against iron-loaded conditions.

Therapeutic peptides, as a unique form of medication composed of orderly arranged sequences of amino acids, are valued for their high affinity, specificity, low immunogenicity, and economical production costs. Currently, more than 100 peptides have already secured market approval. Over 150 are actively undergoing clinical trials, while an additional 400–600 are in the preclinical research stage. Despite this, their clinical application is limited by factors such as salt sensitivity, brief residence in the bloodstream, inadequate cellular uptake, and high structural flexibility. By employing suitable chemical methods to modify peptides, it is possible to regulate important physicochemical factors such as charge, hydrophobicity, conformation, amphiphilicity, and sequence that affect the physicochemical properties and biological activity of peptides. This can overcome the inherent deficiencies of peptides, enhance their pharmacokinetic properties and biological activity, and promote continuous progress in the field of research. A diverse array of modified peptides is currently being developed and investigated across numerous therapeutic fields. Drawing on the latest research, this review encapsulates the essential physicochemical factors and significant chemical modification strategies that influence the properties and biological activity of peptides as pharmaceuticals. It also assesses how physicochemical factors affect the application of peptide drugs in disease treatment and the effectiveness of chemical strategies in disease therapy. Concurrently, this review discusses the prospective advancements in therapeutic peptide development, with the goal of offering guidance for designing and optimizing therapeutic peptides and to delve deeper into the therapeutic potential of peptides for disease intervention.

This study explored the relationship between the concentrations of homoarginine and arginine and between homoarginine concentration and laboratory parameters in coronavirus disease 2019 (COVID-19) patients with different severity to demonstrate the role of homoarginine in the progress of COVID-19. The laboratory-confirmed COVID-19 patients were included from Peking University Third Hospital during December 2022 to January 2023. Serum, urine, and stool samples were collected from the patients and detected by liquid chromatography-mass spectrometry. Totally 46 patients were recruited, including 18 in the mild group, 19 in the severe group, and 9 fatal. The concentration of homoarginine was positively correlated with the concentration of arginine in serum (r = 0.50), urine (r = 0.55), and stool samples (r = 0.39), respectively (all P < 0.001). The serum concentration and urine concentration of homoarginine were lower in severe patients than in mild patients (both P < 0.05). 13 indicators reflecting immunity and coagulation, including but not limited to T cell, white blood cell, natural killer cell, interleukin 6 (IL-6), and IL-8, had statistically significant correlations with both disease severity and the homoarginine concentration. Patients with hypertension were significantly associated with the decreased serum homoarginine (odds ratio 10.905, 95% confidence interval 1.454 − 137.144). Our results suggest that the homoarginine plays a role in the progress of COVID-19, which may be achieved by influencing arginine metabolism.

L-Ornithine (L-Orn) is a nonessential amino acid but has many physiological roles. Accordingly, L-Orn has been used as a functional food or dietary supplement to ameliorate various maladies, but there is only limited information available about its safety. The safety of a chemical compound is generally assessed via non-clinical and clinical studies, but safety information derived from human studies is particularly important. Recently, systematic reviews have been used to assess the safety as well as the effectiveness and usefulness of such studies. Therefore, we conducted an assessment of the safety of L-Orn by systematically reviewing clinical studies. Specifically, we performed a comprehensive search of databases for clinical trials in which L-Orn was added to ordinary diets (i.e., orally administered) in healthy individuals. Focusing on PubMed, Cochrane Library, Ichushi-Web, and EBSCOhost, we comprehensively searched for reports on human studies on the oral ingestion of L-Orn. We identified 22 articles as subjects for this SR. Among these articles, the maximum L-Orn dose was 14,025 mg/person/day in the form of L-Orn hydrochloride and the maximum duration of administration was 156 days. The main observed adverse events were gastrointestinal disorders. Indexing these adverse events, the no observed adverse effect level was estimated to be 12,000 mg/person/day for L-Orn in the form of L-Orn hydrochloride. When we conducted an integration analysis on the risk of adverse events, the difference between those with and without L-Orn supplementation in the risk of gastrointestinal disorders was 0.00 (95% confidence interval: ±0.02, P = 1.00), so no significant effects were observed. (UMIN000033371)