Search Results (347)

A promising direction for the creation of new biologically active derivatives of the alkaloid lupinine is the synthesis of “hybrid molecules” that combine a fragment of the alkaloid and the pharmacophore of 1,2,3-triazole in their structure. From a biological perspective, this work presents the first X-ray diffraction study of a single crystal of (1S,9aR)-1-({4-[4-(Benzyloxy)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}methyl)octahydro-2H-quinolizine, a new, recently synthesized 1,2,3-triazole derivative of lupinine. A comparison of theoretically predicted and experimentally observed structural parameters was carried out. The FTIR spectroscopy study and vibrational properties calculations allowed us to interpret the FTIR absorption spectrum and localize specific vibrational modes in quinolizidine, 1,2,3-triazole, and benzene rings. Such information can be fruitful for further characterization of the synthesis process and products. The molecular docking of the compound was performed. It was shown that the studied molecules are capable of interacting with the Mpro binding site via non-covalent and hydrophobic interactions with subsites S3 (Met165, Glu166, Leu167, Pro168) and S5 (Gln189, Thr190, Gln192), which ensure the stabilization of the Mpro substrate. Blocking of the active site of the enzyme in the region of the oxyanion hole does not occur, but stable stacking interactions with the π-system of one of the catalytic amino acids, His41, are observed. Full article

Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein–protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity. Full article

Fishes are frequently exposed to hypoxic stress, yet their tolerance to hypoxia varies significantly among species. The association between this variation and alterations in the hypoxia-inducible factor (HIF) pathway remains unclear. We discovered that otomorphs generally retain two Hif-1α paralogs (Hif-1αa and Hif-1αb), resulting from the teleost-specific genome duplication (TGD), whereas most euteleosts possess only a single Hif-1αa copy. In otomorphs, key mutations disrupt one conserved Leu-X-X-Leu-Ala-Pro (LXXLAP) motif in the oxygen-dependent degradation (ODD) domain of the Hif-1αa proteins. Molecular dynamics simulations revealed that these mutations impede the recognition of the critical proline residue by prolyl hydroxylase domain protein 2 (PHD2), suggesting enhanced normoxic stability of Hif-1αa. We also investigated the expression profiles of hif-1α and downstream genes in four fish species (two otomorphs and two euteleosts). In otomorphs, the hif-1αa genes were highly expressed specifically in the heart; concomitantly, two critical downstream genes, ldha and mct4, exhibited relatively high expression levels in vital tissues such as the heart, brain, and muscle. This coordinated expression pattern promotes a heightened glycolytic capacity and facilitates lactate shuttling in these tissues, thereby ensuring energy supply during hypoxic stress. Our integrated computational analyses indicate that otomorphs achieve enhanced hypoxia tolerance through the subfunctionalization of Hif-1α paralogs. Full article

Dipeptidyl peptidase-4 (DPP-4) is a protease that degrades incretin and inhibits the secretion of insulin. Consequently, DPP-4 inhibition promotes insulin secretion and prevents the onset of type 2 diabetes. Given the growing interest in food-derived DPP-4 inhibitory peptides as potential functional ingredients, buckwheat (Fagopyrum esculentum) represents a promising source; however, few studies have investigated the bioactivity of peptides derived from buckwheat flour hydrolysates. In this study, two DPP-4 inhibitory peptides, Ile-Pro-Trp and Ile-Pro-Leu, were identified through purification of buckwheat flour hydrolysate and liquid chromatography–tandem mass spectrometry analysis. In a rat oral glucose tolerance test (OGTT), a fraction of buckwheat flour hydrolysate, crudely purified by reverse-phase column chromatography, showed a non-significant trend toward reducing increases in blood glucose. To our knowledge, this study is the first to show that Ile-Pro-Trp isolated from food protein hydrolysates exhibits considerable DPP-4 inhibitory activity. Moreover, this is the first study identifying Ile-Pro-Ile as a DPP-4 inhibitor from a plant source. Full article

Currently, there is no report on prediction models of standardized ileal amino acid digestibilities (SIAADs) in soybean meals (SBMs) for medium-growing yellow-feathered chickens. This study firstly analyzed the chemical compositions of 10 SBMs, then determined their SIAADs in chickens, and finally established and verified prediction models for SBM SIAADs based on their chemical compositions and amino acid (AA) profiles. A total of 276 55 d-old Tianluma roosters were selected and randomly divided by body weight into 11 treatment groups. On d 63, chickens were fed either a nitrogen-free diet (NFD) or one of 10 SBM diets for 5 d. On d 67, ileal chyme samples were collected to determine SIAADs. Data from nine SBM samples and stepwise regressions were employed to build prediction models, while one SBM sample was randomly selected to validate model accuracy. Different SBM sources affected (p ≤ 0.007) SIAADs in medium-growing yellow-feathered chickens. The standardized ileal digestibility (SID) of glutamic acid (Glu) was the highest (93.9%), whereas that of cysteine (Cys) was the lowest (81.7%). Fifteen prediction models (R² = 0.567–0.993, p < 0.03) for the SIDs of methionine (Met), isoleucine (Ile), leucine (Leu), phenylalanine (Phe), lysine (Lys), histidine (His), arginine (Arg), aspartic acid (Asp), serine (Ser), Glu, glycine (Gly), alanine (Ala), Cys, tyrosine (Tyr), and proline (Pro) in SBMs for medium-growing yellow-feathered chickens were effectively established based on chemical compositions and AA profiles. Among them, the prediction model for the SID of Cys showed the best fit (R² = 0.993, p = 0.002), while the model for the SID of Ala had the lowest fit (R² = 0.567, p = 0.019). Except for His and Pro, which exhibited poor predictive accuracy, all other models showed good accuracy. These prediction models thus provide a valuable reference for rapidly estimating the SIDs of key AAs in SBMs for medium-growing yellow-feathered chickens. Full article

Background/Objectives: Thyroid hormones (THs) regulate almost all physiological processes in vertebrates via specific mechanisms exercised spatiotemporally throughout the lifespan. The TH signalling can be impaired by thyroid-disrupting chemicals (TDCs) capable of disrupting the hypothalamic–pituitary–thyroid (HPT) axis. Octyl methoxycinnamate (OMC) (also designated octinoxate), one of the most widely used ultraviolet (UV) filters, has emerged as an environmental contaminant and has raised significant concerns recently due to its disruptive effects as TDC on humans and animals. Although the disruption of TH homeostasis has been reported, its exact modes of action (MoA) remain largely unknown. Our study aimed to provide a comparative information on the molecular interactions of OMC on TH signalling in humans and zebrafish. Methods: In silico approaches were performed comparing OMC with endogenous thyroid hormone T3 and the anti-thyroid drug propylthiouracil (PTU). Results: Our findings suggested a key role of OMC on the corticotrophin-releasing hormone receptor (crhr2), thyrotropin receptor (TSHR/tshr), and thyroid nuclear receptors (TR/tr-α and -β). At the hypothalamic level, a favourable binding of OMC to zebrafish crhr2 was found, involving ALA86, CYS44, HIS89, ILE63, ILE64, LEU92, PRO87, PRO88, SER48, and THR47. At the pituitary level, OMC was bound to human TSHR by the amino acid residues ASN590, GLU506, ILE583, ILE640, LEU570, MET572, PRO571, SER505, TYR667, VAL502, VAL586, ALA644, LEU587, MET637, SER641, and TYR582 and to zebrafish tsrh by ASN589, ILE639, MET636, ILE582, LEU569, LEU586, VAL501, and VAL585. Concerning nuclear receptors, OMC showed a more favourable binding energy of T3, involving the shared residues PHE218 and MET259 with T3 in both species. For human TRβ, OMC shared T3 with residues ILE 275, ILE276, LEU346, PHE269, PHE272, THR273, ALA279, ASN331, HIS435, LEU330, MET310, MET313, and PHE455. No similar residues were obtained for zebrafish trβ compared with the humans. Conclusions: Overall, the action of OMC seems to agree with primary hypothyroidism (anti-thyroid action) mimicking the T3 hormone. This investigation demonstrates that OMC acts as a potential TDC and provides new insights into its disruptive action on the HPT axis. Full article

This research sought to analyze the nutritional composition of red-fleshed dragon fruit cultivated in various regions of Guizhou, focusing on samples obtained from three distinct production areas: Guanling (GL), Zhenfeng (ZF), and Luodian (LD). The findings revealed notable regional variations in nutritional constituents. Specifically, the GL samples exhibited the highest concentrations of betacyanin, vitamin C, total phenolics, and flavonoids; ZF samples demonstrated the greatest levels of soluble sugars alongside the lowest titratable acidity, whereas LD samples presented the opposite trend. Through non-targeted metabolomic profiling, a total of 4515 metabolites were identified. Multivariate analyses, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), indicated that metabolic differences corresponded with geographical origin. Furthermore, the OPLS-DA S-plot identified L-Histidine, Glu-Leu, Uridine, Leu-Glu, (2S)-2-Isopropylmalate, 2-amino-4-({1-[(carboxymethyl)-C-hydroxycarbonimidoyl]-2-[(3-hydroxy-2-methyl-4-oxobutan-2-yl}sulfanyl]ethyl)-C-hydroxycarbonimidoyl)butanoic acid, Leu-Leu-Ser-Pro-Tyr, 1,1′-bis(iso-13-carbon saturated acyl)-2-(iso-12-carbon saturated acyl)-3-[(9Z,11Z)-octadecadienoyl] cardiolipin. The eight characteristic metabolites under scrutiny can evidently differentiate dragon fruits from disparate regions and thus serve as potential markers for distinguishing their origins. This study offers a theoretical foundation for quality assessment, investigations into health benefits, and the sustainable advancement of the dragon fruit industry. Full article

Watermelon soy sauce (WSS) is a liquid condiment usually prepared using watermelon juice, soybeans, and wheat flour through the process of making koji and natural fermentation. It is widely used in Chinese culinary art, despite the lack of knowledge about its aromatic compound content. Here, we characterized the physicochemical properties, free amino acid composition, and volatile compounds of WSS using SPME-GC/MS and E-nose. We noticed that WSS had the highest total acid content but the lowest amino nitrogen and reducing sugar contents compared with commercial soy sauce. Moreover, the highest amounts of Glu and Pro were observed in WSS. A total of 173 volatile compounds were identified in WSS, including alcohols, hydrocarbons, esters, ketones and aldehydes. The E-nose analysis showed a good capacity of differentiating braised samples mainly through W5S, W1S, W1W, W2W, and W3S sensors. The analysis of relationships between flavor components and free amino acids in soy sauce samples showed that Ser, Gly, Val, Ile, Leu, Ph,e and Lys had a strong positive correlation with alcohol and acidic compounds. Moreover, Pro was found to be correlated with aldehyde, ketone, heterocyclic compounds, sulfur compounds, and benzene, while Glu was correlated with hydrocarbons, aldehyde, and benzene. This study could provide important information regarding WSS quality control, characterization, and aroma improvement. Full article

Skin aging is primarily driven by oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. This study investigated the anti-senescence effects of fermented porcine placenta (FPP) and its dipeptides, leucine–glycine (LG) and proline–hydroxyproline (PH), in human epidermal keratinocytes (HEKs), using nicotinamide mononucleotide (NMN) as a reference for nicotinamide adenine dinucleotide (NAD⁺)-related pathways. FPP suppressed senescence-associated β-galactosidase (SA-β-gal) activity and Cyclin-dependent kinase inhibitor 2A (p16) expression while enhancing adenosine triphosphate (ATP) production and sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling. LG and PH exhibited distinct actions: LG improved redox balance by increasing the NAD⁺/NADH ratio and NAD(P)H quinone oxidoreductase 1 (NQO1) activity, whereas PH modulated cell cycle regulators and upregulated sirtuin 3 (SIRT3) expression. Although both peptides contributed to FPP’s effects, their combination did not fully replicate its overall activity, suggesting synergistic roles of multiple bioactive constituents. These findings highlight FPP as a multifactorial modulator of keratinocyte senescence, acting via mitochondrial and redox-related mechanisms. Full article

Background: Multiple Sclerosis (MS) is a chronic, autoimmune, multifactorial, and complex disorder of the central nervous system (CNS), affecting more than 2 million individuals globally. Genome-wide association studies (GWAS) have explained only a small fraction of its high heritability, highlighting the need for alternative approaches to identify rare genetic variants that contribute to its etiology. To address this, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: WES was performed in a MS multigenerational family comprising two affected sisters, their two healthy brothers, and one affected son. Results: Bioinformatics analysis identified 47 co-segregating rare variants. Three missense variants in genes involved in inflammation, autoimmunity, and demyelinization were identified as the most promising candidates: c.443 C>T, p.Pro148Leu in the RTN4 gene, c.1678 T>G, p.Phe560Val in the JAK2 gene, and c.3449 A>G, p.Tyr1150Cys in the DUOX2 gene. Protein modeling and in silico tools suggest that the three selected variants may have a significant impact on protein function. Conclusions: We identified novel candidate genes for MS in a multiplex family, providing evidence for an oligogenic model of disease susceptibility. Further replication and functional studies are required to validate these preliminary results. Full article

We developed and validated a capillary electrophoresis (CE) method for the separation of two opioid–neurotensin hybrid peptides, recently presented as potent analgesics being decapeptides with a hybridic nature (i.e., H-Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH; PK20 and its structural analogue H-Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Ile-Leu-OH; [Ile9]PK20). As these two chimeras differ by only one amino acid, Tle→Ile, and are characterized by possessing the same molecular weight while having different spatial conformations, the aim of the study was to determine their potential separation in terms of the presence of any differences resulting from this structural modification. The separation process was performed using an eCAP fused silica capillary at a detection wavelength of 200 nm in 25 mM phosphate buffer at pH 2.5. The analysis was performed at 25 °C and 10 kV. The developed method was validated by assessing linearity in the concentration range from 50 to 5000 ng/mL. Very good linearity was obtained, with the coefficient of determination (R²) ranging from 0.9991 to 0.9999 for both analyzed derivatives. The method demonstrated baseline resolution (Rs = 1.4). The limit of quantification ranged from 34.72 ng/mL to 34.98 ng/mL. The recoveries of all derivatives ranged from 94.8% to 100%. The total analysis time was only 6 min. The developed method enables the determination of PK20 and [Ile9]PK20 derivatives both in aqueous solutions and in serum. Full article

RNA editing is a crucial mechanism regulating gene expression in plant organellar genomes, which optimizes protein structures through base substitution and plays a vital role in plant growth, development, and stress adaptation. This study revises the conventional understanding restricting MORF proteins to seed plants by reporting their first identification in ferns, an early vascular plant lineage. We sequenced chloroplast genomes of O. japonica and P. vachellii, revealing one MORF9 homolog in O. japonica and three homologs (MORF1/8/9) in P. vachellii through comparative transcriptomics and structural validation. All identified MORF proteins harbor conserved MORF-box domains, suggesting structural and potentially functional conservation with angiosperms. Crucially, MORF members differentially regulate organellar RNA editing: chloroplast editing frequencies are predicted to show dose-dependent enhancement (0.7–1.0 in conserved sites), potentially influenced by MORF presence or copy number. In O. japonica, chloroplast editing exhibits tissue-specific patterns (conserved sites 0.7–1.0; tissue-specific sites lower efficiency at 0.1–0.2), while this study’s mitochondrial editing results show a balanced frequency distribution (0–1 range). Amino acid substitution analysis demonstrates MORF-mediated hydrophobic optimization (Ser→Leu > 30%, Pro→Leu > 18%), likely underpinning fern adaptability. This work provides crucial initial evidence for a conserved MORF-mediated RNA editing module shared between these early vascular plants (ferns) and angiosperms, offering fundamental insights into the evolutionary trajectory of plant organellar gene regulation. Full article

This study investigated the interaction between cannabidiol (CBD) derivatives and the GPR55 receptor using a bioinformatics-driven molecular docking approach. GPR55, implicated in central nervous system (CNS) pathologies, represents a promising target for novel therapeutics. Drug-likeness evaluation via SwissADME confirmed that all selected derivatives complied with Lipinski′s Rule of Five, exhibiting favorable physicochemical properties with molecular weights below 500 Da and acceptable logP values. Molecular docking simulations, performed using AutoDock Vina through PyRx, revealed strong binding affinities, with docking scores ranging from −9.2 to −7.2 kcal/mol, indicating thermodynamically feasible interactions. Visualization and interaction analysis identified a conserved binding pocket involving key residues, including TYR101, PHE102, TYR106, ILE156, PHE169, MET172, TRP177, PRO184, LEU185, LEU270 and MET274. Ligand clustering in this region further supports the presence of a structurally defined binding site. Molecular dynamics simulations of GPR55 in complex with the three top-scoring ligands (3″-HOCBD, THC, and CBL) revealed that all ligands remained stably bound within the cavity over 100 ns, with ligand-specific rearrangements. Predicted oral bioavailability was moderate (0.55), consistent with the need for optimized formulations to enhance systemic absorption. These findings suggest that CBD derivatives may act as potential modulators of GPR55, offering a basis for the development of novel CNS-targeted therapeutics. Full article

Diketopiperazines (DKPs) are biologically important cyclic dipeptides widespread in nature, associated primarily with microorganisms. This is the case for the 2,5-DKP derivative cyclo(L-Leu-L-Pro) (cLP), also known as gancidin W or PPDHMP, identified from a variety of bacteria and fungi, and occasionally found in food products. The present review retraces the discovery of cLP, its identification in living species, its chemical syntheses, and its biochemical properties. In bacteria, cLP is often associated with other DKPs to serve as a defense element against other microorganisms and/or as a regulator of bacterial growth. cLP plays a role in quorum-sensing and functions as an anticariogenic and antifungal agent. The antimicrobial mechanism of action and molecular targets of cLP are evoked. The interest in cLP for combatting certain parasitic diseases, such as malaria, and cancers is discussed. The capacity of cLP to interact with CD151 and to down-regulate the expression of this tetraspanin can be exploited to reduce tumor dissemination and metastases. The review sheds light on the pharmacology and specific properties of cyclo(L-Leu-L-Pro), which can be useful for the development of a novel therapeutic approach for different human pathologies. It is also of interest to help define the bioactivity and mechanisms of action of closely related DKP-based natural products. Full article

Metatropic dysplasia is an autosomal dominant skeletal disorder characterized by progressive kyphoscoliosis, severe platyspondyly, pronounced metaphyseal enlargement, and shortening of the long bones. This condition is caused by pathogenic variants in the TRPV4 (Transient Receptor Potential Vanilloid 4) gene, which encodes a non-selective calcium channel involved in bone homeostasis. Variants in TRPV4 have been associated with two major disease groups: skeletal dysplasias and neuropathies, with recent findings indicating an overlap in their clinical features. We report three patients with metatropic dysplasia, each presenting a distinct severity profile. All exhibited a bell-shaped thorax, significant platyspondyly, and shortened long bones with broad metaphyses. Notably, patients 1 and 3 had more complex clinical courses, including seizures and global developmental delay. Genetic analysis revealed two different TRPV4 variants: p.Asn796del (patient 1) and p.Pro799Leu (patients 2 and 3). These cases illustrate variability in extra-skeletal manifestations, complications, and prognosis. In our patients with TRPV4-related disorders, the co-occurrence of neurological symptoms and skeletal abnormalities suggests a clinically heterogeneous spectrum consistent with a single disease rather than distinct entities. A comprehensive, multidisciplinary approach is essential to optimize management and improve the quality of life for patients. Full article