Search Results (4,761)

Lanthanide rare earth elements possess significant promise for material applications owing to their distinctive optical and magnetic characteristics, as well as their versatile coordination capabilities. This study introduced a lanthanide-functionalized magnetic nanocellulose composite (NNC@Fe₃O₄@La(OH)₃) for effective phosphorus/nitrogen (P/N) ligand separation. The hybrid material employs the adaptable coordination geometry and strong affinity for oxygen of La³⁺ ions to show enhanced DNA-binding capacity via multi-site coordination with phosphate backbones and bases. This study utilized cellulose as a carrier, which was modified through carboxylation and amination processes employing deep eutectic solvents (DES) and polyethyleneimine. Magnetic nanoparticles and La(OH)₃ were subsequently incorporated into the cellulose via in situ growth. NNC@Fe₃O₄@La(OH)₃ showed a specific surface area of 36.2 m²·g⁻¹ and a magnetic saturation intensity of 37 emu/g, facilitating the formation of ligands with accessible La³⁺ active sites, hence creating mesoporous interfaces that allow for fast separation. NNC@Fe₃O₄@La(OH)₃ showed a significant affinity for DNA, with adsorption capacities reaching 243 mg/g, mostly due to the multistage coordination binding of La³⁺ to the phosphate groups and bases of DNA. Simultaneously, kinetic experiments indicated that the binding process adhered to a pseudo-secondary kinetic model, predominantly dependent on chemisorption. This study developed a unique rare-earth coordination-driven functional hybrid material, which is highly significant for constructing selective separation platforms for P/N-containing ligands. Full article

The glucagon-like peptide-1 receptor (GLP-1R), which belongs to the class B1 G protein-coupled receptor (GPCR) family, is an important target for treatment of metabolic disorders, including type 2 diabetes and obesity. The growing interest in GLP-1R-based therapies is driven by the development of various functional agonists as well as the huge commercial market. Thus, understanding the structural details of ligand-induced signaling are important for developing improved GLP-1R drugs. Here, we investigated the conformational dynamics of the receptor in complex with a selection of prototypical functional agonists, including CHU-128 (small molecule-biased), danuglipron (small molecule balanced), and Peptide 19 (peptide balanced), which exhibit unique, distinct binding modes and induced helix packing. Furthermore, our all-atom molecular dynamics (MD) simulations revealed atomic feature how different those ligands led to signaling pathway preference. Our findings offer valuable insights into the mechanistic principle of GLP-1R activation, which are helpful for the rational design of next-generation GLP-1R drug molecules. Full article

Background: Response speed refers to an individual’s ability to perceive and react to harmful stimuli, which can vary due to genetics, neural regulation, and environmental factors. Our previous study demonstrated that whey protein hydrolysate was a potential means to enhance cognitive function. Methods: This study used a variety of behavioral methods to evaluate the functional effects of whey protein hydrolysate on improving reaction speed, and revealed its potential mechanisms through proteomics analysis. Results: The results showed that whey protein hydrolysate improved response speed in mice when tested against thermal pain, mechanical strength stimuli, and prepulse inhibition. Proteomic analysis of the hippocampus revealed changes in proteins related to arginine and proline metabolism, as well as neuroactive ligand–receptor interactions. Conclusions: These findings provide new insights into the neuromodulatory effects of whey protein hydrolysate and support its potential role in enhancing response speed and cognitive performance. Full article

The highly fluorescent fluorene group is of interest for its unique optical and electronic properties. By incorporating it into a metal complex, these properties are extended to the complex and are useful in a number of different applications. Four β-diketone ligands were synthesized containing the fluorene-functional group, where the varying substituent on the β-diketone was CF₃ (1), PhCF₃ (2), Ph (3) and PhCH₃ (4). The corresponding cyclooctadiene rhodium(I) complexes of the type [Rh(cod)((fluorene)COCHCOR)], with R = CF₃ (5), PhCF₃ (6), Ph (7) and PhCH₃ (8) were also synthesized. A crystal structure determination of 2 and 6 was performed, highlighting important changes in the ligand structure as a result of metal complexation. The structure of 2 also showed a hydrogen interaction between the hydroxy and carboxyl groups, forming a pseudo six-membered ring that stabilizes the enol form of the compound. Cyclic voltammetry (CV) of the β-diketones 1–4 showed a reduction wave for the reduction of the β-diketonato backbone between −1500 mV and −2100 mV as measured against ferrocene (FcH). CVs of rhodium(I) complexes 5–8 showed a reduction of the β-diketonato backbone between −1800 and −2000 mV, as well as an oxidation wave for the oxidation of the rhodium(I) metal centre at approximately 300 mV. Full article

Application of organic ligand 2-(3-ethyl-pyrazin-2-yl)quinoline-4-carboxylate with N/O donor atoms enabled solvothermal synthesis of a 2D Cu(II) coordination polymer, {Cu(L)BF₄}_n (L = deprotonated 2-(3-ethyl-pyrazin-2-yl)quinoline-4-carboxylate). Both the ligand and its coordination polymer have been characterized. The condensed ring system of the applied ligand promotes the formation of coordination polymers rather than mononuclear species. The obtained 2D coordination polymer is photoluminescent with bathochromic/hypsochromic shifts in ligand absorption bands leading to a single absorption band at 465 nm. Density Functional Theory was employed to provide a theoretical description of the possible conformational changes within the ligand, with emphasis on the difference between the ligand conformation in its hydrochloride salt and in the polymer. Two models of polymer fragments were constructed to describe the electronic structure and non-covalent interactions. The Quantum Theory of Atoms in Molecules (QTAIM) was applied for this purpose. Using the obtained results, we were able to develop potential energy profiles for various conformations of the ligand. For the set of the studied systems, we detected non-covalent interactions, which are responsible for the spatial conformation. Concerning the models of polymers, electron spin density distribution has been visualized and discussed. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression and are involved in diverse physiological and pathological processes, including carcinogenesis. In bladder cancer (BCa), dysregulation of NR signaling pathways has been linked to tumor initiation, progression, therapy resistance, and immune evasion. Recent evidence highlights the intricate crosstalk between NRs and microRNAs (miRNAs), which are small non-coding RNAs that posttranscriptionally modulate gene expression. This review provides an integrated overview of the molecular interactions between key NRs and miRNAs in BCa. We investigated how miRNAs regulate NR expression and function and, conversely, how NRs influence miRNA biogenesis, thereby forming regulatory feedback loops that shape tumor behavior. Specific miRNA–NR interactions affecting epithelial-to-mesenchymal transition, metabolic reprogramming, angiogenesis, and chemoresistance are discussed in detail. Additionally, we highlight therapeutic strategies targeting NR–miRNA networks, including selective NR modulators, miRNA mimics and inhibitors, as well as RNA-based combinatorial approaches focusing on their utility as diagnostic biomarkers and personalized treatment targets. Understanding the molecular complexity of NR–miRNA regulation in BCa may open new avenues for improving therapeutic outcomes and advancing precision oncology in urological cancers. Full article

In this study, three new terphenyl-substituted NPN ligands bearing pyridyl groups, two phosphonites and one diaminophosphine, were synthesized and fully characterized. Their coordination chemistry with copper(I) was investigated using CuBr and [Cu(NCMe)₄]PF₆ as metal precursors, affording six mononuclear Cu(I) complexes, which were characterized using NMR spectroscopy and, in selected cases, single-crystal X-ray diffraction (SCXRD) analysis. The NPN ligands adopt a κ³-coordination mode, stabilizing the copper centers in distorted tetrahedral geometries. The catalytic performance of these complexes in the S-arylation of thiols with aryl iodides was evaluated. Under optimized conditions, complexes 2a and 2b exhibited excellent activity and broad substrate scope, tolerating both electron-donating and electron-withdrawing groups, as well as sterically hindered and heteroaryl substrates. The methodology also proved effective for aliphatic thiols and demonstrated high chemoselectivity in the presence of potentially reactive functional groups. In contrast, aryl bromides and chlorides were poorly reactive under the same conditions. These findings highlight the potential of well-defined Cu(I)–NPN complexes as efficient and versatile precatalysts for C–S bond formation. Full article

The ZC4H2 gene is the site of congenital mutations linked to neurodevelopmental and musculoskeletal pathologies collectively termed ZARD (ZC4H2-Associated Rare Disorders). ZC4H2 consists of a coiled coil and a single novel zinc finger with four cysteines and two histidines, from which the protein obtains its name. Alpha Fold 3 confidently predicts a structure for the zinc finger but also for similarly sized random sequences, providing equivocal information on its folding status. We show using synthetic peptide fragments that the zinc finger of ZC4H2 is genuine and folds upon binding a zinc ion with picomolar affinity. NMR pH titration of histidines and UV–Vis of a cobalt complex of the peptide indicate its four cysteines coordinate zinc, while two histidines do not participate in binding. The experimental NMR structure of the zinc finger has a novel structural motif similar to RANBP2 zinc fingers, in which two orthogonal hairpins each contribute two cysteines to coordinate zinc. Most of the nine ZARD mutations that occur in the ZC4H2 zinc finger are likely to perturb this structure. While the ZC4H2 zinc finger shares the folding motif and cysteine-ligand spacing of the RANBP2 family, it is missing key substrate-binding residues. Unlike the NZF branch of the RANBP2 family, the ZC4H2 zinc finger does not bind ubiquitin. Since the ZC4H2 zinc finger occurs in a single copy, it is also unlikely to bind DNA. Based on sequence homology to the VAB-23 protein, the ZC4H2 zinc finger may bind RNA of a currently undetermined sequence or have alternative functions. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

We identified Murashka, a RING finger protein, in an oogenesis screen as a regulator of Drosophila ovary germline stem cell niche development. Mutant alleles of murashka exhibited an enlarged niche phenotype reminiscent of increased Notch signalling and displayed genetic interactions with Notch alleles, and with polychaetoid, a regulator of Notch during niche development. These interactions uncovered both positive and negative impacts on Notch in different genetic backgrounds. In S2 cells, Murashka formed a complex with Notch and colocalised with Notch in the secretory pathway. Murashka expression in S2 cells down-regulated Notch signalling levels but could result in increased fold induction due to the proportionally greater decrease in basal ligand-independent activity. In vivo Murashka expression had different outcomes on different Notch target genes. We observed a decrease in the expression of vestigial along the anterior/posterior boundary of the wing imaginal disc, but not of wingless at the dorsal/ventral boundary. Instead, weak ectopic wingless was observed, which was synergistically increased by the coexpression of Deltex, a positive regulator of ligand-independent signalling. Our results identify a novel developmental role for murashka, a gene previously only associated with a function in long-term memory, and indicate a regulatory role for Murashka through a physical interaction with Notch that has context-dependent outcomes. Murashka adds to a growing number of ubiquitin ligase regulators which interact with Notch at different locations within its secretory and endocytic trafficking pathways. Full article

The development of ceria (CeO_2−x)-based nanoantioxidants requires fine-tuning of structural and surface properties for enhancing antioxidant behavior in biological environments. In this contest, here ultrasmall water-dispersible CeO_2−x nanoparticles (NPs), characterized by a high Ce³⁺/Ce⁴⁺ ratio, were synthesized in a non-polar solvent and phase-transfer to an aqueous environment through ligand-exchange reactions using citric acid (CeO_2−x@Cit) and post-treatment with dopamine hydrochloride (CeO_2−x@Dopa). The concept behind this work is to enhance via surface engineering the intrinsic antioxidant properties of CeO_2−x NPs. For this purpose, thanks to electron transfer reactions between dopamine and CeO_2−x, the CeO_2−x@Dopa was obtained, characterized by increased surface Ce³⁺ sites and surface functionalized with polydopamine bearing o-quinone structures as demonstrated by complementary spectroscopic (UV–vis, FT-IR, and XPS) characterizations. To test the antioxidant properties of CeO_2−x NPs, the scavenging activity before and after dopamine treatment against artificial radical 1,1-diphenyl-2-picrylhydrazyl (DPPH^·) and the ability to reduce the reactive oxygen species in Diencephalic Immortalized Type Neural Cell line 1 were evaluated. CeO_2−x@Dopa demonstrated less efficiency in DPPH^· scavenging (%radical scavenging activity 13% versus 42% for CeO_2−x@Cit before dopamine treatment at 33 μM DPPH^· and 0.13 mg/mL loading of NPs), while it markedly reduced intracellular ROS levels (ROS production 35% compared to 66% of CeO_2−x@Cit before dopamine treatment with respect to control—p < 0.001 and p < 0.01, respectively). While steric hindrance from the dopamine-derived polymer layer limited direct electron transfer from CeO_2−x NP surface to DPPH^·, within cells the presence of o-quinone groups contributed with CeO_2−x NPs to break the autoxidation chain of organic substrates, enhancing the antioxidant activity. The functionalization of NPs with o-quinone structures represents a valuable approach to increase the inherent antioxidant properties of CeO_2−x NPs, enhancing their effectiveness in biological systems by promoting additional redox pathways. Full article

Background/Objectives: Asprosin is the endogenous ligand of the olfactory Olfr734 receptor linked to MASLD and glucose metabolism. Despite the involvement of asprosin in these processes, little has been published on the specific role of Olfr734 in liver function. The aim of this work is therefore to study the specific role of the olfactory Olfr734 receptor in MASLD and glucose metabolism. Methods: To achieve this objective, we performed a genetic inhibition specifically to inhibit Olfr734 in the livers of male mice. We then studied the progression of MASLD in DIO mice. In addition, we studied the glucose metabolism in hypoglycemia states and postprandial glucose production in standard diet-fed mice. Finally, analyses of liver biopsies from patients with obesity and with or without T2DM were conducted. Results: We found that hepatic Olfr734 levels vary according to changes in nutritional status and its knockdown effect in the liver is to increase the hepatic lipid content in DIO mice. Our results also showed that OLFR734 expression is involved in the adaptive response in terms of glucose production to nutrient availability. Finally, the hepatic human Olfr734 ortholog named OR4M1 has been observed to be at significantly higher levels in male patients with T2DM. Conclusions: This study increases understanding of the mechanisms by which the modulation of Olfr734 expression affects liver function. Full article

Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds 6, 9, 14, and 18) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure–activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds 9 and 14 toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target. Full article

Metastatic breast cancer (BC) spread underscores the need for novel prognostic biomarkers. This study investigated CCR4-NOT Transcription Complex Subunit 7 (CNOT7) and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in BC progression and natural killer (NK) cell resistance. In the current study, 90 female BC patients (46 non-metastatic, 44 metastatic) were analyzed. CNOT7 and LAIR-1 protein levels were measured in serum via ELISA and CNOT7 expression in tissue by immunohistochemistry (IHC). In silico tools explored related pathways. Computational analyses, including in silico bioinformatics and molecular docking, explored gene functions, interactions, and ligand binding to CNOT7 and LAIR-1. CNOT7 serum levels were significantly elevated in metastatic patients (mean 4.710) versus non-metastatic patients (mean 3.229, p < 0.0001). Conversely, LAIR-1 serum levels were significantly lower in metastatic (mean 56.779) versus non-metastatic patients (mean 67.544, p < 0.0001). High CNOT7 was found in 50% (45/90) of cases, correlating with higher tumor grade, hormone receptor negativity, and increased lymph node involvement. Elevated CNOT7 and lower LAIR-1 levels were associated with worse overall survival. Pathway analysis linked CNOT7 to the PI3K/AKT/mTOR pathway. Computational findings elucidated CNOT7′s cellular roles, gene/protein interaction networks for LAIR-1/CNOT7, and distinct ligand binding profiles. High CNOT7 levels are associated with advanced BC stages and poor clinical outcomes, which suggests its utility as a prognostic biomarker. The inverse relationship between CNOT7 and LAIR-1 provides mechanistic insights into BC progression and immune evasion, further supported by in silico investigations. Full article

Three-finger toxins (3FTxs) are the largest group of nonenzymatic toxins found in snake venoms. Among them, neurotoxins that target nicotinic acetylcholine receptors are the most well-studied ligands. In addition to the classical neurotoxins, several other new classes have been characterized for their structure, receptor subtype, and species selectivity. Here, we systematically analyzed over 700 amino acid sequences of three-finger neurotoxins that interact with nicotinic acetylcholine receptors. Based on the amino acid residue substitutions in the functional sites and structural features of various classes of neurotoxins, we have classified them into over 150 distinct subgroups. Currently, only a small number of typical examples representing these subgroups have been studied for their structure, function, and subtype selectivity. The functional site residues responsible for their interaction with specific receptor subtypes of several toxins are yet to be identified. The molecular details of each subgroup representative toxin with its target receptor will contribute towards the understanding of subtype- and/or interface-selectivity. Thus, this review will provide new impetus in the toxin research and pave the way for the design of potent, selective ligands for nicotinic acetylcholine receptors. Full article