Amino Acid Derivatives Research Articles

2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

Antibiotic resistance has emerged as a pressing global health issue. Polymyxin E, commonly regarded as a clinically important antibiotic, faces limitations due to its dose-dependent toxicity. A crucial strategy to combat this is the development of an antibiotic adjuvant to enhance efficacy while reducing dosage. Screening from our extensive in-house compound library, KJ1071 emerged as a promising adjuvant candidate for polymyxin E. Subsequent structure–activity relationship studies led to the discovery of compound A35, which demonstrated superior synergistic activity. However, its limited aqueous solubility posed challenges for biological experiments. To address this, we carried out a structural derivatization aimed at enhancing its solubility. The amino acid derivative A59 notably improved aqueous solubility to 3.237 mg/mL, a substantial 3237-fold increase compared to compound A35. Moreover, A59 amplified the efficacy of polymyxin E in eradicating a variety of Gram-negative bacteria, including certain clinical strains that are resistant to polymyxin E. The mechanism studies indicated that A59 might target the bacterial membrane. These findings suggest that the discovery of this innovative scaffold could provide critical insights for new adjuvant therapies.

C-OH Bond Activation for Stereoselective Radical C-Glycosylation of Native Saccharides.

Radical C-glycosylation presents a flexible and efficient method for synthesizing C-glycosides. Existing methods always require multistep processes for generating anomeric radicals. In this study, we introduce a streamlined approach to produce anomeric radicals through direct C-OH bond homolysis of unmodified saccharides, eliminating the need for protection, deprotection, or activation steps. These anomeric radicals selectively couple with activated alkenes, yielding C-glycosylation products with high stereoselectivity (>20:1). This method is applicable to a variety of native monosaccharides, such as l-arabinose, d-arabinose, d-xylose, l-xylose, d-galactose, β-d-glucose, α-d-glucose, and l-ribose, as well as oligosaccharides including α-lactose, d-(+)-melibiose, and acarbose. We also extend this approach to C-glycosylation of amino acid and peptide derivatives, and demonstrate a streamlined synthesis of an anti-inflammatory agent.

Metabolomic characterization of unintentional weight loss among community-dwelling older Black and White men and women.

This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long-chain poly-unsaturated triglycerides, and higher levels of amino acid derivatives, poly-unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid-thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%-48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite.

Water-Soluble Bimodal Magnetic-Fluorescent Radical Dendrimers as Potential MRI-FI Imaging Probes.

Dual or multimodal imaging probes have become potent tools for enhancing detection sensitivity and accuracy in disease diagnosis. In this context, we present a bimodal imaging dendrimer-based structure that integrates magnetic and fluorescent imaging probes for potential applications in magnetic resonance imaging and fluorescence imaging. It stands out as one of the rare examples where bimodal imaging probes use organic radicals as the magnetic source, despite their tendency to entirely quench fluorophore fluorescence. Opting for organic radicals over metal-based contrast agents like gadolinium (Gd3+)-chelates is crucial to mitigate associated toxicity concerns. We utilized an amino-terminated polyamide dendrimer containing a 1,8-naphthalimide (Naft) fluorescent group, amino acid derivatives as linkers to enhance water solubility, and TEMPO organic radicals as terminal groups. The same dendrimer structure, featuring an equivalent number of branches but lacking the fluorophore group, was also functionalized with amino acid and terminal radicals to serve as a reference. Remarkably, we achieved a fully water-soluble dendrimer-based structure exhibiting both magnetic and fluorescent properties simultaneously. The fluorescence of the Naft group in the final structure is somewhat quenched by the organic radicals, likely due to photoinduced electron transfer with the nitroxyl radical acting as an electron acceptor, which has been supported by density functional theory calculations. Molecular dynamics simulations are employed to investigate how the dendrimers' structure influences the electron paramagnetic resonance characteristics, relaxivity, and fluorescence. In summary, despite the influence of the radicals-fluorophore interactions on fluorescence, this bimodal dendrimer demonstrates significant fluorescent properties and effective r1 relaxivity of 1.3 mM-1 s-1. These properties have proven effective in staining the live mesenchymal stem cells without affecting the cell nucleus.

Effect of Aminophenol and Amino Acids Derivatives on the Level of Nitrosyl Radical and Its Active Forms &lt;i&gt;In Vitro&lt;/i&gt;

The effect of aminophenol, amino acids and their derivatives on the level of •NO and its intermediates (•NO2, N2O3) in an aqueous aerobic media (pH = 7.4) was studied using nitroprusside as a •NO donor. It was found that the highest NOx scavenging activity is exhibited by 3-aminophenol (IC50 = 0.11 mM), 2-aminophenol (IC50 = 0.195 mM) and 4,6-di-tert-butyl-2-aminophenol (IC50 = 0.12 mM), standards: trolox (IC50 = 0.19 mM) and ascorbate (IC50 = 4.88 mM). Methylation of the OH group reduced the effectiveness of aminophenol. In the studied concentration range (0–70 mM), Tyr-Ala (IC50 = 5.0 mM) and β-Ala-His (IC50 = 35.0 mM) were more active than Phe-Ala (IC50 50 mM) and Gly-Gly (IC50 50 mM). Complexes Cu(Gly)2 and Cu(Gly-Gly)2 at low concentrations (0.05–0.5 mM) are 1.4–1.8 times more effective than Gly and Gly-Gly.

Computational investigation of the effect of BODIPY labelling on peptide-membrane interaction.

Optical monitoring of peptide binding to live cells is hampered by the abundance of naturally occurring fluorophores such as tryptophan. Unnatural amino acids incorporating synthetic fluorophores such as BODIPY overcome these optical limitations. A drawback to using fluorophores in lipid binding peptide design is their propensity to override other interactions, potentially causing the peptides to lose their binding selectivity. Here, the binding strength of a selection of peptides incorporating a variety of BODIPY derivatized amino acids has been studied via molecular dynamics simulations to quantify the impact of BODIPY incorporation on peptide-membrane binding behaviour.

RBIO-05. IPAX-2: PHASE 1 SAFETY AND DOSE FINDING STUDY OF [131I]IPA PLUS STANDARD OF CARE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) overexpresses the L-type amino transporter (LAT) 1 &amp; 2, which supports internalization of the therapeutic small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine ([131I]IPA) and its companion diagnostic, 18F-FET. Previous studies of [123I]IPA SPECT have shown uptake by &amp;gt;85% of gliomas. Results from a phase 1 trial (IPAX-1) that explored [131I]IPA + radiotherapy in patients with recurrent GBM demonstrated a favorable safety and tolerability profile and promising efficacy. The objective of IPAX-2 (NCT05450744) is to evaluate the safety and tolerability of [131I]IPA in patients newly diagnosed with GBM. METHODS IPAX-2 is a phase 1, multicenter, open-label, single-arm, parallel-group, dose-finding study to evaluate the safety of ascending radioactive dose levels of [131I]IPA + best standard of care in newly diagnosed patients with GBM. Eligible participants (N=12) will be 18-65 years of age with histologically-confirmed intracranial GBM following surgical resection; no prior systemic therapy or radiation for GBM; a Karnofsky Performance Status ≥70; a plan to begin chemoradiation 3-6 weeks after surgical resection with Stupp regimen; adequate organ function; and adequate tissue samples previously archived. Four cohorts will encompass a 3 + 3 dose escalation, with [131I]IPA administered in 2 fractions corresponding to ½ of full dose activity via intravenous infusion (2x3.0 GBq, 2x4 GBq, 2x5 GBq, 2x6 GBq). Dose 1 will be administered prior to external beam radiation therapy (EBRT), and Dose 2 will be administered following completion of EBRT. 18F-FET PET will be used to identify suitable candidates with LAT1/2 overexpression, establish a baseline, and provide quantitative follow-up information. Primary outcome measures are 1) incidence rate treatment-emergent adverse events and 2) safety and tolerability by determining the dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. DISCLOSURES: Telix Pharmaceuticals is the sponsor of this study.

LC-MS/MS Profiling of the Poisonous Wild Mushroom, Entoloma mastoideum, (Entolomataceae, Basidiomycota) in Sabah (Northern Borneo), Malaysia

In Malaysia, mushroom poisoning poses a significant public health concern, particularly as local communities frequently consume wild mushrooms without fully recognizing the potential dangers they present. Ingestion of wild mushrooms, which resemble edible species but contain deadly chemicals, is the main cause of poisoning risk. The genus Entoloma (Fr.) P. Kumm is dispersed worldwide, with over 1,500 species recorded. Entoloma mastoideum, a poisonous mushroom, was recorded for the first time at Kota Marudu district, Sabah, Malaysia, where ten cases of mushroom poisoning outbreaks were recorded during the rainy season of October 2019. The morphological characters of the specimens were documented and their microscopic features were analyzed using compound microscope and scanning electron microscope. A phylogenetic tree was constructed using Maximum likelihood and Bayesian analysis. Chemical profiling of the poisonous mushroom specimen was done via liquid chromatograph mass spectrometry (LC-MS/MS) to identify toxic metabolites. The phylogenetic analysis showed that the Bornean E. mastoideum is closely related to the Chinese isolates (100% BS/1.0 PP). LC-MS/MS profiling detected a total of 162 metabolites that were classified into ten general groups, where several toxic compounds were detected amongst the aromatics, essential amino acids, and fatty acid derivatives. The toxic compounds identified in the mushroom extract, including amino acid derivatives such as 3,4,5,6-tetrahydroxyynorleucine, valpromide, and betaine, have been reported to cause neurotoxicity, cardiotoxicity, liver damage, and gastrointestinal harm. The presence of these toxic compounds underscores the need for caution when consuming wild mushrooms. Further research on poisonous Entoloma species is vital for developing accurate identification methods and understanding their toxic potential. This knowledge is essential for enhancing public awareness, preventing mushroom poisoning incidents and safeguarding public health.

Photo-Induced Three-Component Reaction for the Construction Of α-Tertiary Amino Acid Derivatives.

The synthesis of α-tertiary amino acids (ATAAs), which are pivotal components in natural metabolism and pharmaceutical innovation, continues to attract significant research interest. Despite substantial advancements, the pursuit of a facile, versatile, and resource-efficient methodology remains an area of active development. In this work, we introduce a visible light-triggered three-component reaction involving readily available nitrosoarenes, N-acyl pyrazoles, and allyl or (bromomethyl)benzenes under mild conditions. This approach enables the straightforward assembly of a wide array of ATAA derivatives (42 examples) in commendably high yields (up to 89 %). Mechanistic investigations elucidate that the reaction proceeds through a dehydration condensation between nitrosoarenes and N-acyl pyrazoles to generate ketimine intermediates. This is followed by a light-driven halogen atom transfer (XAT) process and a radical addition, culminating in the formation of the desired products. The approach showcases excellent functional group compatibility and late-stage derivatization potential, offering new insights and avenues for the synthesis of ATAA analogs.

Construction of Aryl Azide‐ and Triazole‐Based Unnatural Amino Acid Motifs via the Pd(II)‐Catalyzed C(sp3)−H Arylation

AbstractThis paper reports a method for the synthesis of examples of aryl azide‐ and triazole moiety‐based unnatural amino acid motifs using the Pd(II)‐catalyzed arylation of the prochiral C(sp3)−H bonds of carboxamides of amino acids as one of the key transformations. Synthesis of racemic and enantioenriched aryl azide‐based unnatural amino acid motifs including, norvaline, leucine, norleucine, phenylalanine, 2‐aminobutyric acid, 2‐aminooctanoic acid, and non‐α‐amino acid derivatives were shown. Additionally, we attempted the synthesis of triazole moiety‐installed norvaline, leucine, norleucine, phenylalanine, 2‐aminobutyric acid, 2‐aminooctanoic acid, and non‐α‐amino acid derivatives via the Cu‐catalyzed Click reaction. We also demonstrated the removal of the protecting groups and the synthesis of free amino group‐containing aryl azide‐ or triazole‐based unnatural amino acid motifs and peptides. Generally, azide moiety‐containing unnatural amino acid motifs are important molecular tools in chemical biology. Furthermore, aryl azide‐ and triazole moiety‐containing unnatural amino acid scaffolds are notable substrates in medicinal chemistry and drug discovery research. Accordingly, this work contributes to enriching the library of aryl azide‐ and triazole‐based unnatural amino acid derivatives.

HRMAS-NMR-Based Metabolomics Approach to Discover Key Differences in Cow and Goat Milk Yoghurt Metabolomes.

This study highlights the differences in the metabolomes of cow milk yoghurt (CY) and goat milk yoghurt (GY) using a nuclear magnetic resonance (NMR)-based metabolomic approach. The 1H HRMAS-NMR spectrum displayed 21 metabolites comprising organic acids, sugars, amino acids, amino acid derivatives and phospholipids. The orthogonal partial least squares discriminant analysis model clearly separated CY and GY groups, implying differences in metabolite composition. The corresponding Variable Importance in Projection (VIP) plot revealed that choline, sn-glycero-3-phosphocholine, O-phosphocholine, fucose, citrate, sucrose, glucose and lactose mainly contributed to the group separation (VIP > 1). Hierarchical cluster analysis further confirmed the metabolome similarities and differences between CY and GY. Additionally, 12 significantly differential metabolites (with a fold change > 1.5 and p-value < 0.05) were identified, with 1 downregulated and 11 upregulated. Pathway impact analysis revealed the correlation of significant metabolites with starch and sucrose metabolism, galactose metabolism, and the citrate cycle. Furthermore, receiver operating characteristic curve analysis identified eight metabolites (choline, sn-glycero-3-phosphocholine, fucose, O-phosphocholine, glucose, citrate, 2-oxoglutarate, lactose and sucrose) as candidate biomarkers. This study represents the first utilization of HRMAS-NMR to analyze the metabolomic profiles of yoghurt made from cow and goat milk. In conclusion, these findings provide preliminary information on how NMR-based metabolomics can discriminate the metabolomes of yoghurt prepared from the milk of two different animals, which may be valuable for authenticity and adulteration assessments.

Enantioselective Preparation of Cyclopentene-Based Amino Acids with a Quaternary Carbon Center.

Azlactone is an important starting material for synthesizing amino acids containing a quaternary α-carbon. In this study, we have developed a sequential "one-pot" procedure involving an enantioselective spirocyclization reaction followed by acidic azlactone opening, which led to amino acid derivatives. The key step of this procedure is a spirocyclization between propargylated azlactones and enals by using a cooperative catalytic approach that combines chiral secondary amine and achiral Pd(0) complexes. The final acid opening of the azlactone motif allows isolation of the corresponding amino acid derivatives as major diastereoisomers in yields ranging from 37% to 70% with enantioselectivities of 85-97% ee. These synthesized amino acid derivatives hold great potential in the pharmaceutical and bioactive compound industries. Moreover, the final amino acid products with a cyclopentene moiety can be further derivatized, opening up even more possibilities for their application.

Inhibition Effects of Some Non-Proteinogenic Amino Acid Derivatives on Carbonic Anhydrase Isoenzymes and Acetylcholinesterase: An In Vitro Inhibition and Molecular Modeling Studies.

Amino acid derivatives are molecules of interest for medicinal chemistry and drug design studies due to their important chemical properties. In this study, the inhibition effects of some non-proteinogenic amino acid derivatives (hippuric acid (A), N-(9-Fluorenylmethoxycarbonyl)-D-valine (B), N-Z-(1-Benzotriazolylcarbonyl) methylamine (C), (S)-N-Z-1-Benzotriazolylcarbonyl-2-phenylethylamine (D)) on carbonic anhydrase I (hCA-I), II (hCA-II) isoenzymes and acetylcholinesterase (AChE) activity, whose inhibitors are of vital pharmacological importance, were examined. While carbonic anhydrase (CA) inhibitors are effective molecule candidates for the treatment of many diseases from glaucoma to cancer, acetylcholinesterase inhibitors are target molecules for the treatment of Alzheimer's disease. According to the results of this study, compound D had a strong inhibitory effect on hCA-I (IC50: 0.836 μM) and hCA-II (IC50: 0.661 μM), while compound B (IC50: 100 μM) showed a strong inhibitory effect on AChE activity. In addition, inhibition results were supported by molecular modeling studies. We hope that the obtained results will contribute to the synthesis of new and effective amino acid derivative inhibitors for CA and AChE.

Aggression shapes the gut microbiome; a study in rats.

The gut-brain axis is regarded as a bidirectional communication system that integrates signals from the gut microbiome into behavioral aspects and vice versa. The aim of the present study was to investigate the gut microbiome-behavior interaction in relation to aggression. For that, male rats from a group-housed colony were individually housed with a female to become territorial. Next, a coping strategy was assigned to them, by evaluating their aggression levels against an intruder, during the Resident-Intruder test (RI). To investigate if their microbiome would change as a consequence of the developed coping strategy, fecal samples were collected before and after the RI test. We found that the relative abundances of Ruminococcaceae UCG-5 and Gram-negative bacterium cTPY-13 in rats sampled before the RI test were negatively correlated with the aggression that was demonstrated during the RI test. After the RI test, several bacterial taxa could be assigned to each coping strategy, with Clostridium sensu stricto 1 being strongly associated with less aggressive rats and higher abundances of Bifidobacterium. Furthermore, the family of Lachnospiraceae was not only associated with more aggressive rats, but functional prediction analysis found it to be the main contributor of betaine reductase; an enzyme catalyzing betaine production that was indicative of aggressive rats. This amino acid derivative, which has been connected with higher energy and testosterone levels, could potentially explain the connection of Lachnospiraceae with demonstrated aggression. Overall, our data revealed that the gut bacterial communities are responsive to the imposed social challenge of building and defending territoriality in co-habitation with a female. At the same time, predisposing microbiome characteristics may have predictive value for the development of a coping strategy.

Novel pilot study on plasma metabolites and biomarkers in a rat model of silica-induced lung inflammation and fibrosis

Silica-induced lung damage may be associated with changes in distinct metabolites potentially serving as biomarkers. Due to the lack of metabolomic data from animal models, this pilot study aimed to evaluate changes in markers of inflammation and fibrosis, as well as plasma metabolites in rats at 14 and 28 days after silica instillation.Adult male Wistar rats were administered a single oropharyngeal intratracheal dose of silica suspension or sterile saline in controls. Selected markers of inflammation, oxidative stress, fibrosis, and cell counts in blood and bronchoalveolar lavage fluid have been evaluated. Finally, plasma metabolites were detected using a targeted metabolomics approach with an MxP® Quant 500 kit.Silica instillation induced noticeable inflammatory, oxidative, and fibrotic changes in lung tissue within the first 14 days. During the next two weeks, the shifts in some markers were further accentuated. After exposure to silica, the metabolomic analysis identified significant changes in metabolites associated with lipid metabolism, biogenic amines, amino acid derivatives, carboxylic acids, bile acids, putrescine, glycosylceramides, and acylcarnitines.This pilot study provides initial evidence that significant alterations in plasma metabolite profiles accompany silica-induced lung injury in rats. These findings suggest a possible systemic impact, particularly on lipid metabolism, and indicate the urgent need for a deeper understanding of the metabolic reprogramming associated with silica-induced lung injury to pave the way for the discovery of novel biomarkers.

Comprehensive evaluation of ibuprofenate amino acid isopropyl esters: insights into antioxidant activity, cytocompatibility, and cyclooxygenase inhibitory potential.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain relief and inflammation management, but there are challenges related to poor solubility and bioavailability. We explored modifications of ibuprofen (IBU) by forming ionic pairs using amino acid alkyl esters to enhance solubility without compromising the ability to inhibit cyclooxygenase (COX)-1 and COX-2). We comprehensively evaluated the pharmacological properties of the IBU derivatives, focusing on antioxidant activity (based on the ability to scavenge DPPH and ABTS), biocompatibility (using human dermal fibroblasts), and COX inhibitory potential. The antioxidant activity assays significantly enhanced DPPH scavenging activity for several IBU derivatives, particularly [L-SerOiPr][IBU], suggesting potential therapeutic benefits. There was enhanced cell viability with select derivatives, indicating possible stimulatory effects on cellular proliferation. Finally, predominant COX-1 inhibition across derivatives was consistent with IBU's profile. This study provides insights into the pharmacological properties of IBU amino acid derivatives, highlighting their potential as therapeutic agents. Further exploration into structure-activity relationships and in vivo efficacy warranted to advance these derivatives toward clinical applications, offering prospects for novel NSAIDs with enhanced efficacy and reduced side effects.

Biomolecular Condensates Based on Amino Acid for Enhancing Oral Bioavailability and Therapeutic Efficacy of Hydrophobic Drugs.

The oral administration of chemo- or immunotherapeutic drugs presents a compelling alternative for patients with malignant colorectal cancer, offering a convenient and patient-compliant "hospital-free" strategy. Unfortunately, the hydrophobic nature of many drug candidates, alongside the harsh conditions of the gastrointestinal tract, frequently results in suboptimal bioavailability and heightened systemic toxicity. To address these challenges, we harnessed the unique properties of biomolecular condensates, which form through a liquid-liquid phase separation mechanism, to develop a versatile platform for drug encapsulation and delivery. In this study, we introduce a reliable and effective amorphous oral drug delivery system based on biomolecular condensates derived from the amino acid derivative N-(benzyloxycarbonyl)-l-proline (ZP). These ZP condensates exhibit dynamic intermolecular interactions and possess unique physicochemical attributes such as fluidity and viscoelasticity. They significantly improve the solubility of hydrophobic drugs, ensuring enhanced stability and optimized pharmacokinetics under physiological and gastrointestinal conditions. By maintaining drugs in an amorphous state, we substantially increased drug bioavailability and markedly improved pharmacokinetics. Furthermore, the ZP condensates demonstrate potential as an integrated therapeutic platform capable of potentiating the synergies between chemotherapy and immunotherapy while concurrently reducing systemic toxicity. This has resulted in a significant enhancement of chemo-immunotherapy efficacy in the treatment of colorectal cancer, representing a notable advancement in drug delivery and oncology.

Fast and Selective Cysteine Conjugation Using para-Quinone Methides.

An efficient and selective method for cysteine conjugation utilizing para-quinone methides (p-QMs) was developed. p-QM labeling exhibits high specificity toward the cysteine residue, as evidenced by its reactivity with various amino acid derivatives, peptides, and proteins. Notably, the p-QM-cysteine reactions display robust kinetics with rate constants up to 1.67 × 104 M-1·s-1. Furthermore, p-QM conjugation enables us to attach a fluorescent probe to a HER2 nanobody, resulting in selective labeling of HER2-positive SK-BR-3 cells.

Engineering Plant Metabolism for Synthesizing Amino Acid Derivatives of Animal Origin Using a Synthetic Modular Approach.

The biosynthesis of amino acid derivatives of animal origin in plants represents a promising frontier in synthetic biology, offering a sustainable and eco-friendly approach to enhancing the nutritional value of plant-based diets. This study leverages the versatile capabilities of Nicotiana benthamiana as a transient expression system to test a synthetic modular framework for the production of creatine, carnosine, and taurine-compounds typically absent in plants but essential for human health. By designing and stacking specialized synthetic modules, we successfully redirected the plant metabolic flux toward the synthesis of these amino acid derivatives of animal origin. Our results revealed the expression of a standalone creatine module resulted in the production of 2.3 μg/g fresh weight of creatine in N. benthamiana leaves. Integrating two modules significantly carnosine yield increased by 3.8-fold and minimized the impact on plant amino acid metabolism compared to individual module application. Unexpectedly, introducing the taurine module caused a feedback-like inhibition of plant cysteine biosynthesis, revealing complex metabolic adjustments that can occur when introducing foreign pathways. Our findings underline the potential for employing plants as biofactories for the sustainable production of essential nutrients of animal origin.

The ginkgo biloba extract EGb761® mitigates ischemic stroke via metabolic pathway modulation

ObjectiveTo confirm the therapeutic efficacy of the ginkgo biloba extract EGb761® on ischemic stroke and elucidate its underlying mechanism. MethodsMale Sprague-Dawley rats were divided into three groups: sham, model, and EGb761 (ginkgo biloba extract). Ischemic stroke was then simulated in these rats via embolic middle cerebral artery occlusion surgery, with the extract administered half an hour before surgery. Neurological deficit scores, infarct volume, cerebral edema rate, and inflammatory factors served as the primary metrics for drug efficacy. Serum metabolites were analyzed using 1H-nuclear magnetic resonance to elucidate the operative mechanism. ResultsTreatment with the ginkgo biloba extract EGb761® significantly ameliorated the neurological deficit scores (P = 0.0343), diminished the cerebral infarct volume (P = 0.0001) and cerebral edema rate (P = 0.0030), and alleviated neuroinflammation (all P < .05) in middle cerebral artery occlusion rats. In addition, it significantly altered the concentrations of various metabolites, such as 2-hydroxybutyrate, isoleucine, isopropanol, isobutyric acid, N6-acetyllysine, glutamate, glutamine, methionine, and N,N-dimethylglycine (all P < .05). Enrichment analysis of the differential metabolites indicated that EGb761® may be involved in the regulation of amino acid metabolism, betaine metabolism, glucose-alanine cycle, Warburg effect, and urea cycle. ConclusionThe ginkgo biloba extract EGb761® demonstrates anti-ischemic stroke properties by regulating amino acids and amino acid derivatives, such as isoleucine, N6-acetyllysine, glutamate, methionine, and N,N-dimethylglycine.