Biophysical chemistry最新文献

{"title":"Relevance of ceramide 1-phosphate domain formation in activation of cytosolic phospholipase A2","authors":"Tomokazu Yasuda ,&nbsp;Daiki Ueura ,&nbsp;Madoka Nakagomi ,&nbsp;Shinya Hanashima ,&nbsp;Michio Murata","doi":"10.1016/j.bpc.2025.107433","DOIUrl":"10.1016/j.bpc.2025.107433","url":null,"abstract":"<div><div>Ceramide 1-phosphate (C1P), as a lipid mediator, specifically binds and activates cytosolic phospholipase A₂α (cPLA₂α). Previous findings revealed that modification of the specific hydrophobic moiety decreases the affinity with cPLA₂α. However, the possible biological role of the temporal C1P-enriched domains formed in biomembranes for the molecular recognition of cPLA₂α has not been fully elucidated. In this study we elucidated the properties of segregated domains formed by C1P (and its analogs) and the affinity of cPLA₂α for C1P in different co-lipid environments by fluorescence spectroscopy using <em>trans</em>-parinaric acid and surface plasmon resonance (SPR). Fluorescence measurements suggested that the formation of C1P ordered domains is strongly influenced by interfacial 3-OH and phosphate groups of C1P, such as hydrogen-bonding and electrostatic interactions, and depends on the co-lipid composition of the host bilayer. SPR indicated that C1P under the lipid environment favorable for the formation of C1P clusters has higher affinity for cPLA₂α. Thus, we speculate that C1P clusters formed under certain membrane conditions are important in specific binding with cPLA₂α by increasing the interaction between the C1P headgroup and basic residues of cPLA₂α. In conclusion, this study revealed that the local formation of lipid mediator-rich clusters in biomembranes likely has a significant effect on the interaction between the mediator and its receptor protein.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"322 ","pages":"Article 107433"},"PeriodicalIF":3.3,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling theranostic potential: Insights into cell-free microRNA-protein interactions","authors":"Vishal Kumar Sahu ,&nbsp;Subhayan Sur ,&nbsp;Sanjana Agarwal ,&nbsp;Harishkumar Madhyastha ,&nbsp;Amit Ranjan ,&nbsp;Soumya Basu","doi":"10.1016/j.bpc.2025.107421","DOIUrl":"10.1016/j.bpc.2025.107421","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) belong to a short endogenous class of non-coding RNAs which have been well studied for their crucial role in regulating cellular homeostasis. Their role in the modulation of diverse biological pathways by interacting with cellular proteins, genes, and RNAs through cellular communication projects them as promising biomarkers and therapeutic targets. However, studying miRNA-protein interactions specific to disease in the extracellular or cell-free environments for drug discovery and biomarker establishment is challenging and resource-intensive due to their structural complexities. In this study, we present a computational approach to uncover patterns in miRNA-protein interactions in the cell-free milieu leveraging existing experimental data. We employed motif discovery tools, extracted motifs from 3D protein and miRNA structures, and conducted molecular docking analyses to identify and rank these interactions. This <em>in silico</em>-based approach reveals 204 and 2874 consensus sequences in miRNAs and proteins, respectively, within the interactome highlighting their potential roles in the cardiovascular diseases, neurological disorders, and cancers. The role of proteins like METTL3 and AGO2 and miRNAs such as hsa-miR-484 and hsa-miR-30 families, hsa-mir-126-5p has been discussed contextually. Additionally, we discovered simple sequence repeats in the consensus patterns having unexplored functional roles. Our observations provide new insights into the extracellular miRNA-protein interactions that may drive disease initiation and progression offering potential avenues for overcoming challenges like therapy relapse and drug inefficacy. The results of our analysis are available in the miRPin database (<span><span>https://www.mirna.in/miRPin</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"322 ","pages":"Article 107421"},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the functional dynamics of glyceraldehyde-3-phosphate dehydrogenase upon ligand binding at the putative allosteric binding sites","authors":"Merve Yuce,&nbsp;Ozge Kurkcuoglu","doi":"10.1016/j.bpc.2025.107420","DOIUrl":"10.1016/j.bpc.2025.107420","url":null,"abstract":"<div><div>The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an attractive target to combat infection-related diseases as antibiotic resistance poses a global threat. Here, we investigated the functional dynamics of methicillin-resistant <em>S. aureus</em> GAPDH (<em>Sa</em>GAPDH) in apo-form and with ligands bound at two distinct potential allosteric binding sites in its tunnel-like region. AutoDock Vina was used for flexible docking with a library of 2447 FDA-approved drugs. After the interaction analysis and chemical fragment clustering, 5 compounds mutual to both sites were selected and subjected to independent 3 × 500 ns-long molecular dynamics (MD) simulations coupled with Molecular Mechanics Generalized Born Surface Area calculations to estimate their binding free energies. The ligand-protein dynamics pointed to either an increase or a decrease in the solvent accessibility of the co-factor NAD⁺ binding site as compared to apo-dynamics without an apparent change in residue fluctuations. Furthermore, dihedral angles of the co-factor binding site residues, particularly R12 and N316 changed upon ligand binding to the tunnel-like region. Residue network models based on the MD trajectories for each system revealed potential allosteric communication pathways linking putative allosteric binding sites to the co-factor binding sites. Favorable interactions between the ligands and the previously suggested hub residues T49-R53, E204 (S-loop) and/or Y180 seemed to affect the solvent accessibility of the binding sites that can either facilitate or prevent NAD⁺ binding. Dynamic coupling of NAD⁺ binding sites through correlated residue fluctuations was consistent in all investigated systems, revealing how cooperativity between the functional sites can be maintained by <em>Sa</em>GAPDH. All findings suggested hit compounds and the putative allosteric binding sites to change the NAD⁺ binding site dynamics that should be further evaluated by in vitro studies to assess their antibacterial activities.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107420"},"PeriodicalIF":3.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transmembrane clustering of short amyloid peptide fragments: A coarse grained molecular dynamics study","authors":"Aleksandra Drajkowska,&nbsp;Andrzej Molski","doi":"10.1016/j.bpc.2025.107418","DOIUrl":"10.1016/j.bpc.2025.107418","url":null,"abstract":"<div><div>Toxicity of amyloid peptides has been linked to peptide aggregation and interactions with lipid bilayers. In this work we use coarse-grained molecular dynamics simulations to study aggregation and transmembrane clustering of short amyloid peptide fragments, A<em>β</em>(25–35) and A<em>β</em>(29–42), in the presence of dipalmitoylphosphatidylcholine (DPPC) and palmitoylolyoilphosphatidylcholine (POPC) bilayers. First, we explored peptide aggregation starting from free monomers placed at the interface of preformed lipid membranes. At low peptide concentrations, no transmembrane clusters were formed in DPPC or POPC membranes. At high peptide concentration, the longer fragment, A<em>β</em>(29–42), showed strong peptide-peptide interactions that led to spontaneous formation of transmembrane clusters in POPC and DPPC. However, the shorter fragment, A<em>β</em>(25–35), did not form transmembrane clusters within the simulation time in either bilayer. To overcome the free-energy barriers to transmembrane clustering, we changed the simulation protocol and started simulations from random mixtures of peptides, lipids, and solvent. Using this system self-assembly approach, we found that both A<em>β</em>(25–35) and A<em>β</em>(29–42) can form stable transmembrane clusters in DPPC and POPC bilayers. Our study suggests that the cooperative effects induced by a localized increase in peptide density may be a mechanism of membrane disruption by short amyloid peptide fragments.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107418"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding SARS-CoV-2 variants: Mutations, viral stability, and breakthroughs in vaccines and therapies","authors":"Zainularifeen Abduljaleel","doi":"10.1016/j.bpc.2025.107413","DOIUrl":"10.1016/j.bpc.2025.107413","url":null,"abstract":"<div><div>This study investigates the infectivity of SARS-CoV-2 and its immune evasion mechanisms, particularly through mutations in the spike protein that enable the virus to escape host immune responses. As global vaccination efforts continue, understanding viral evolution and immune evasion strategies remains critical. This analysis focuses on fourteen key mutations (Arg346Lys, Lys417Asp, Leu452Glu, Leu452Arg, Phe456Leu, Ser477Asp, Thr478Lys, Glu484Ala, Glu484Lys, Glu484Gln, Gln493Arg, Gly496Ser, Glu498Arg, and His655Y) within the receptor-binding domain (RBD) of the spike protein. The results reveal consistent patterns of immune escape across various SARS-CoV-2 variants, with specific mutations influencing protein stability, binding affinity to the hACE2 receptor, and antibody recognition. These findings demonstrate how single-point mutations can destabilize the spike protein and reduce the efficacy of the immune response. By correlating expression levels and thermodynamic stability with immune evasion, this study provides valuable insights into the functional characteristics of the spike protein. The findings contribute to the understanding of immune escape variants and identify potential targets for enhancing vaccine efficacy and developing therapeutic approaches in response to the evolving SARS-CoV-2 landscape.</div></div><div><h3>Short summary</h3><div>The study investigates the infectivity of SARS-CoV-2 and its implications for immune evasion. It focuses on fourteen key mutations within the spike protein's Receptor-Binding Domain (S-RBD) and reveals consistent patterns associated with immune escape in various SARS-CoV-2 variants. The research highlights the influence of factors such as protein fold stability, hACE2 binding, and antibody evasion on spike protein evolution. Single-point immune escape variants alter virus stability, impacting antibody response success. The study provides valuable insights into immune escape variants and suggests avenues for enhancing vaccine efficacy. It also opens the way for novel therapeutic approaches in the context of SARS-CoV-2 variants.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107413"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating thyroid hormone transport proteins disruption by nitrophenols through computational and spectroscopic analysis","authors":"Yanhong Zheng,&nbsp;Zeyu Song,&nbsp;Muwei Huang,&nbsp;Cancan Li,&nbsp;Chunke Nong,&nbsp;Tinghao Jiang,&nbsp;Zhanji Li,&nbsp;Zhongsheng Yi","doi":"10.1016/j.bpc.2025.107415","DOIUrl":"10.1016/j.bpc.2025.107415","url":null,"abstract":"<div><div>Thyroxine (T4), as a type of thyroid hormone (TH), is a key hormone in regulating human metabolism, growth and development, central nervous system functions, and energy balance. It relies on TH transport proteins to reach cells and exert its biological actions. However, the binding of nitrophenol pollutants to TH transport proteins prevents the delivery of thyroid hormones to cells, thereby inhibiting the effects of the hormones. This study combines spectroscopic experiments and computational simulations to explore the mechanism of nitrophenols' interference with TH transport proteins. Detailed information on the quenching mechanism, binding parameters, interaction forces, binding models, and conformational changes of nitrophenols (PNP), chlorinated nitrophenols (CNP), and brominated nitrophenols (BNP) with TH transport proteins is obtained through spectroscopic experiments. Nitrophenols are found to form hydrogen bonds with residues Lys15, Arg378, and Arg381, respectively, thereby displacing T4 at the binding site in the TH transport proteins. With an increasing number of halogen atoms, the affinity of halogenated nitrophenols for TH transport proteins intensifies. Computational simulations are used to further understand the binding modes and binding sites, providing molecular-level insights into the binding of NPs in the cavity of TH transport proteins. Theoretical evidence from molecular docking and molecular dynamics (MD) simulations supports the experimental findings.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107415"},"PeriodicalIF":3.3,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Substitutions at rheostat position 52 of LacI have long-range effects on the LacI conformational landscape","authors":"Nilusha L. Kariyawasam ,&nbsp;Anastasiia Sivchenko ,&nbsp;Liskin Swint-Kruse ,&nbsp;Paul E. Smith","doi":"10.1016/j.bpc.2025.107414","DOIUrl":"10.1016/j.bpc.2025.107414","url":null,"abstract":"<div><div>In proteins, amino acid changes at “rheostat” positions exhibit functional changes that vary with the substitution chosen: some substitutions enhance function, some are like wild-type, some are partially detrimental, while others abolish function. One way that substitutions might exert their complex effects is by altering protein conformational landscapes. To test this, we studied five substitutions of V52 in <em>E. coli</em> LacI, an experimentally-known rheostat position. For each variant, we mapped the accessible conformational landscapes by performing molecular dynamics simulations at ambient conditions and under three perturbations: increased pressure, binding to allosteric ligand “ONPF”, and ONPF plus pressure. The simulated DNA binding domain landscapes were compared to published experimentally-measured parameters, and the results suggest that complex combinations of dynamic parameters and/or additional simulations in the presence of DNA are needed to predict DNA binding specificity. For the variants regulatory domains all landscapes displayed boundaries similar to wild-type, but changes within the boundaries were unique. Of these, V52A/ONPF was striking: The regulatory domains for ONPF-bound, wild-type LacI are in an “Open” conformation and, experimentally, ONPF enhances DNA binding. Four variants responded to ONPF like wild-type, but ONPF binding to V52A shifted these domains to a “Closed” conformation that is associated with diminished DNA binding for wild-type LacI. This finding predicted that ONPF's allosteric regulation of V52A would change from “anti-inducer” to “inducer”, which we experimentally validated <em>in vivo</em> and <em>in vitro</em>. This supports the hypothesis that substituting rheostat positions can alter function by altering the relative populations on protein conformational landscapes.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107414"},"PeriodicalIF":3.3,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting human prostaglandin reductase 1 with Licochalcone A: Insights from molecular dynamics and covalent docking studies","authors":"Sara Abigail Ramírez-Cortés ,&nbsp;Adrián Durán-Vargas ,&nbsp;Jesús Antonio Rauda-Ceja ,&nbsp;Paola Mendoza-Espinosa ,&nbsp;Luis Fernando Cofas-Vargas ,&nbsp;Armando Cruz-Rangel ,&nbsp;Julio Isael Pérez-Carreón ,&nbsp;Enrique García-Hernández","doi":"10.1016/j.bpc.2025.107410","DOIUrl":"10.1016/j.bpc.2025.107410","url":null,"abstract":"<div><div>Prostaglandin reductase 1 (PTGR1) is an NADPH-dependent enzyme critical to eicosanoid metabolism. Its elevated expression in malignant tumors often correlates with poor prognosis due to its role in protecting cells against reactive oxygen species. This study explores the inhibitory potential of licochalcone A, a flavonoid derived from Xinjiang licorice root, on human PTGR1. Using molecular dynamics simulations, we mapped the enzyme's conformational landscape, revealing a low-energy, rigid-body-like movement of the catalytic domain relative to the nucleotide-binding domain that governs PTGR1's transition between open and closed states. Simulations of NADPH-depleted dimer and NADPH-bound monomer highlighted the critical role of intersubunit interactions and coenzyme binding in defining PTGR1's conformational landscape, offering a deeper understanding of its functional adaptability as a holo-homodimer. Covalent docking, informed by prior chemoproteomic cross-linking data, revealed a highly favorable binding pose for licochalcone A at the NADPH-binding site. This pose aligned with a transient noncovalent binding pose inferred from solvent site-guided molecular docking, emphasizing the stereochemical complementarity of the coenzyme-binding site to licochalcone A. Sequence analysis across PTGR1 orthologs in vertebrates and exploration of 3D structures of human NADPH-binding proteins further underscore the potential of the coenzyme-binding site as a scaffold for developing PTGR1-specific inhibitors, positioning licochalcone A as a promising lead compound.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107410"},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of ergosterol or cholesterol on the morphology and dynamics of the POPC/sphingomyelin bilayer","authors":"Fernando Favela-Rosales ,&nbsp;Jorge Hernández-Cobos ,&nbsp;Arturo Galván-Hernández ,&nbsp;Omar Hernández-Villanueva ,&nbsp;Iván Ortega-Blake","doi":"10.1016/j.bpc.2025.107408","DOIUrl":"10.1016/j.bpc.2025.107408","url":null,"abstract":"<div><div>Phase segregation and domain formation in cell membranes and model lipid bilayers have become a relevant topic in the last decades due to their role in important cell functions such as signaling and molecule-membrane interactions. To date, the most accepted explanation for the formation of these domains in mammalian cells is that cholesterol-enriched sphingomyelin patches of membrane form because of the preferential interaction between them. However, detailed information on molecular interactions within cholesterol-containing bilayers and their comparison with other sterol-containing bilayers, such as those containing ergosterol, is needed to understand the role these molecules have. Recent experimental findings have shown sterol-dependent differences in the morphology of supported lipid bilayers, but the molecular basis for these differences remains unclear. This work provides a molecular explanation for these differences using atomistic Molecular Dynamics simulations of lipid bilayers composed of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and N-palmitoyl-D-erythro-sphingosylphosphorylcholine (PSM) with 20 mol% of cholesterol or ergosterol. Atomic force microscopy was used to validate the simulation. The simulation ran for 11 μs and revealed that both sterols affect the morphology of the membrane. Key findings include: ergosterol induces greater order in PSM domains compared to cholesterol, lipid diffusion constants are lower in ergosterol-containing membranes, sterol flip-flop rates are significantly reduced in ergosterol-containing membranes and ergosterol leads to greater PSM-sterol enrichment. These molecular-level differences provide insight into the experimentally observed variations in domain formation and membrane properties between cholesterol and ergosterol-containing bilayers. Our findings contribute to the understanding of sterol-specific effects on membrane organization and dynamics, with potential implications for cellular processes and drug interactions in different organisms.</div></div><div><h3>Statement of significance</h3><div>This study advances our understanding of how different sterols influence membrane properties through molecular dynamics simulations of three-component lipid membranes. Specifically, we investigate the effects of two major sterols: ergosterol, predominantly found in plants and fungi, and cholesterol, characteristic of mammalian cells. While extensive research has elucidated cholesterol's impact on lipid bilayers, studies on ergosterol's effects are comparatively limited. Our work provides a comprehensive comparison of these sterols, highlighting their similarities and differences. These insights not only enhance our knowledge of cell membrane structure and function, but also contribute to our understanding of selective drug permeability across membranes. This research has potential implications for both fundamental cell biology and pharmaceutical applications.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107408"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilirubin nanotechnology: An innovative approach in biomedicine","authors":"Alexander S. Tatikolov ,&nbsp;Pavel G. Pronkin ,&nbsp;Ina G. Panova","doi":"10.1016/j.bpc.2025.107412","DOIUrl":"10.1016/j.bpc.2025.107412","url":null,"abstract":"<div><div>Bilirubin, a product of heme catabolism, is toxic at elevated concentrations (&gt;250–300 μM in blood serum), whereas at therapeutic concentrations (∼20–200 μM) exerts potent antioxidant, anti-inflammatory, immunomodulatory, cytoprotective and neuroprotective effects. Despite the therapeutic potential, its use in clinical practice is hampered by poor aqueous solubility, instability, and rapid metabolism. Nanotechnology overcomes these limitations and additionally imparts to bilirubin the advantages characteristic of nanopreparations: targeted action on the desired organ/tissue, increased therapeutic efficacy by delaying drug elimination from the body, improved transportation over biological barriers, the ability to combine therapeutic and diagnostic properties in a single agent. The review analyses the chemical synthesis, therapeutic mechanisms, and preclinical applications of nanosystems comprising bilirubin. In particular, nanostructures obtained by the covalent binding of bilirubin to macromolecules, bilirubin encapsulation in nanocarriers, bilirubin conjugation with metal nanoparticles and nanofunctionalization of inorganic compounds are considered; the data on the therapeutic trials of nanobilirubin are summarized. While studies on animal models and in vitro systems demonstrate improved biodistribution, reduced toxicity, and enhanced efficacy, no clinical trials to date have validated nanobilirubin formulations. Key barriers may include unresolved challenges in scalable synthesis, long-term biocompatibility, reproducible dosing of nanoformulations. Hence, further development of nanotherapeutic bilirubin agents for clinical practice is urgent.</div></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"320 ","pages":"Article 107412"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}