To investigate the therapeutic efficacy and potential regulatory mechanisms of human umbilical cord blood natural killer (NK) cell-derived exosomes (NK-Exos) in a lipopolysaccharide (LPS)-induced inflammatory model, as well as their impacts on cutaneous wound healing in mice, exosomes were isolated from the culture supernatant of human umbilical cord blood-derived NK cells by ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and Western-blot. Following co-culture of epidermal keratinocytes or LPS-stimulated ma-crophages with NK-Exo, the regulatory effects of NK-Exo on inflammatory cytokine expression were evaluated in vitro by Western-blot and real-time fluorescent quantitative PCR (RT-qPCR), and its impacts on the mig-ration and proliferation of epidermal keratinocytes were assessed using the scratch wound healing assay and Transwell assay. Furthermore, a full-thickness skin defect model was established on the dorsum of mice. Following topical administration of NK-Exo, histological analysis was performed by hematoxylin and eosin (HE) and Masson staining to evaluate wound healing status and collagen deposition, and immunohistochemis-try (IHC) was employed to detect the expression of F4/80 and Ki67 in wound tissue sections to assess inflam-matory infiltration and cell proliferation. The results demonstrated that NK-Exo could be effectively inter-nalized by recipient cells within 8 h, significantly downregulate the expression of pro-inflammatory cytokines (TNF-α, IL-6, iNOS, and IL-1β) in LPS-induced macrophages, and enhance the proliferation and migration of epidermal cells. In the mouse wound healing model, NK-Exo promoted cutaneous wound closure and col-lagen fiber deposition, while attenuating inflammatory cell infiltration and facilitating cell proliferation in the injured tissues. Collectively, these findings indicate that NK-Exo can alleviate inflammatory responses in in-jured skin tissues, promote cell proliferation and migration, and collagen formation. This study provides fun-damental experimental data for the development of NK-Exo as a potential cell-free therapeutic strategy for skin wound repair and healing.
Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a class of endogenous small RNAs ge-nerated from mature tRNAs or their precursor molecules. Increasing evidence indicates that tsRNAs are not random degradation products of tRNAs, but widely distributed, evolutionarily conserved, and expression-spe-cific functional small molecules. tsRNAs are broadly involved in important biological processes, including cellular stress responses, proliferation and differentiation, and are closely associated with the occurrence and progression of various diseases, especially cancer. At the mechanistic level, tsRNAs exert their functions through multiple layers of regulation, including transcriptional, post-transcriptional, and translational control. In recent years, with the rapid development of high-throughput sequencing technologies and bioinformatics approaches, research on tsRNAs has advanced substantially. This review systematically summarizes the bio-genesis, classification, nomenclature, and mechanisms of action of tsRNAs, as well as their relationships with human diseases, and further discusses their future prospects in basic research and disease diagnosis and therapy, with the aim of providing a reference for further studies in this field.
Circular RNAs (circRNAs) are a special class of non-coding RNA molecules, most of which are generated through backsplicing of exons from precursor mRNAs into covalently closed circular structures. The expression abundance of circRNAs is generally low, and they were initially regarded as negligible byproducts of RNA transcriptional splicing. In recent years, with the continuous development of bioinformatics and sequencing technologies, circRNAs have been found to play important roles in multiple aspects, inclu-ding regulating normal cellular physiological processes, immune responses, and especially serving as transla-tional templates to express proteins. Effective and efficient synthesis of circRNAs is the basis for understan-ding them and their biomedical applications, making the development of in vitro synthesis technologies a crucial step in circRNA-based drug development. At present, more and more research institutions and bio-medical companies are dedicating efforts to the design and application development of circRNAs. This re-view systematically elaborates the properties, in vitro cyclization methods and biomedical applications of circ-RNAs, aiming to offer insights for further research in this field.
Magnetoreceptor (MagR) is a conserved iron-sulfur cluster assembly protein which widely exists across species and forms a rod-like complex with the blue-light receptor cryptochrome (Cry). The MagR/Cry complex shows intrinsically magnetic property and may function as a “biological compass” to mediate animal magnetoreception. Although MagR oligomers play a crucial role in the biocompass model, the regulatory mechanism of MagR self-assembly and the electron transfer pathway within the MagR/Cry complex remain poorly understood. Herein, the conformational dynamics of MagR regulated by environmental factors was in-vestigated firstly, in which the MagR (clMagR) of domestic pigeon (Columba livia) was expressed and puri-fied. The results demonstrated that the self-assembly of clMagR is pH-dependent. The alkaline condition (pH 8.0), which mimics the mitochondrial physiological environment, can significantly promote the assembly of higher-order oligomerization of clMagR. Furthermore, clMagR exhibited DNA-binding capability, and DNA induced stepwise assembly in a length-and dose-dependent manner without altering its iron/iron-sul-fur cluster-binding properties. These findings reveal a dual regulatory mechanism for MagR assembly media-ted by environmental pH and nucleic acids, advancing the understanding of MagR assembly and providing new insights into the magnetosensing mechanism of the MagR/Cry complex.
To investigate the biological activity and antibacterial mechanism of L-amino acid oxidase (Bm-LAAO) from the venom of Bungarus multicinctus, Bm-LAAO was isolated and purified from the crude venom of B. multicinctus using Superdex G75 molecular sieve and cation exchange column, and its substrate speci-ficity, antibacterial activity and related antibacterial mechanism were explored. The results showed that the monomeric molecular weight of the enzyme was 59.116 kDa. The enzyme exhibited high specificity towards L-amino acids, with the optimal substrates being L-Leu, L-Met, L-Glu, L-Arg, L-Ala and L-Lys, followed by L-Ile and L-Trp. The enzyme activity of Bm-LAAO in the crude venom of B. multicinctus from three different habitats exhibited no significant difference. Moreover, the enzyme was relatively stable and showed better stability when stored at -20 °C. It also displayed antibacterial activity against both Gram-negative and Gram-positive bacteria, including Escherichia coli and Staphylococcus aureus. However, its inhibitory capacity against fungi such as Candida albicans was relatively weak. Additionally, catalase significantly at-tenuated the antibacterial effect of Bm-LAAO on E. coli and S. aureus. This study characterized the sub-strate specificity of Bm-LAAO and its inhibitory effects on various Gram-positive and Gram-negative bacteria, as well as the related mechanisms, thereby providing a theoretical basis for further revealing the anti-bacterial mechanism of Bm-LAAO and facilitating its application.
Insulin-like growth factors (IGFs), structurally homologous to insulin, are a class of anabolic peptide hormones with critical biological functions. The IGF family ligands include IGF-1, IGF-2, and insulin, and their secretory cells are widely distributed in tissues and organs such as the liver, kidney, lung, heart, brain, and intestine. The IGF system plays a pivotal regulatory role in mammalian embryonic development and neonatal growth. Studies have demonstrated that IGF binds to its specific receptors, activating two major signaling path-ways (PI3K/AKT and MAPK/ERK), which promote protein synthesis, inhibit protein degradation, and ultimately enhance protein deposition in the body. The binding process between IGF and its receptors is modulated by in-sulin-like growth factor-binding proteins (IGFBPs). This article outlines the components of the IGF system and highlights recent advances in IGF signal transduction mechanisms and their regulatory roles in growth and de-velopment. In-depth exploration of the IGF system not only contributes to elucidating molecular mechanisms underlying growth and development, but also offers novel insights and potential therapeutic targets for addres-sing major medical challenges, including metabolic disorders, tumorigenesis, and tissue regeneration.
Histones and their variants (such as H2A.Z, H2A.X, and H3.3), as fundamental structural compo-nents of chromatin, participate in the dynamic assembly of nucleosomes and play pivotal roles in gene ex-pression regulation and genome stability maintenance. A variety of histone post-translational modifications, such as phosphorylation, acetylation, methylation, ubiquitination and citrullination, can regulate chromatin structure, influence chromatin accessibility, and are involved in transcriptional activation, heterochromatin formation, and cell fate determination. Histone variants and histone post-translational modifications play cru-cial roles in individual growth and development. For instance, histone variants, such as H3.3 and H2B.E, are vital for neural development and cognitive function maintenance; γ-H2AX functions as a well-established molecular marker for DNA damage response in multiple cancer types, and H2A.Z overexpression can promote tumorigenesis; histone citrullination is associated with autoimmune diseases, particularly systemic lupus ery-thematosus (SLE) and rheumatoid arthritis (RA). Herein, the classification and expression regulation of his-tone variants, as well as their pathological roles in tumors, autoimmune diseases, and neurodegenerative disor-ders are systematically reviewed. It is anticipated to offer valuable insights for further research into the func-tions of histones in human diseases and for the development of novel therapeutic targets.
Mitochondria are the energy metabolic hub of eukaryotic cells, and their functional dynamic ba-lance is crucial for maintaining cell vitality. This characteristic is particularly prominent in neurons, which have extremely high energy demands. Mitophagy is a core mechanism for regulating mitochondrial quality, which maintains the homeostasis of mitochondrial function by selectively clearing damaged mitochondria. Dysregulation of mitophagy is closely related to the pathogenesis of various neurodegenerative diseases such as Parkinson disease (PD), Alzheimer’s disease (AD), and Huntington disease (HD). PTEN-induced kinase 1 (PINK1)/Parkin pathway is the core regulatory hub of mitophagy. PINK1 accumulates stably by sensing changes in mitochondrial membrane potential, thereby recruiting and activating Parkin, triggering a ubiqui-tination cascade, and ultimately promoting the clearance of damaged mitochondria. Abnormalities in this pathway can lead to mitochondrial dysfunction and the death of neurons, thereby accelerating the progres-sion of neurodegenerative diseases. This article reviews the molecular mechanisms of mitophagy mediated by the PINK1/Parkin pathway and explores its association with neurodegenerative diseases, aiming to pro-vide a theoretical basis and research directions for novel therapeutic strategies targeting mitochondrial quality control.
Proteins are fundamental to biological processes, and their dysregulation is closely associated with cancer. Aptamers, single-stranded DNA or RNA molecules that bind to targets with high affinity and specificity, have emerged as novel molecular ligands for disease diagnosis and therapy. As a distinct class of functional nucleic acids, bispecific aptamers enable simultaneous recognition of two targets, thereby modulating protein functions. Recent advances in bispecific aptamer-based therapeutics highlight their potential for targeted treatment of cancer. This review systematically summarizes the latest research progress in bispe-cific aptamers against tumors by regulating protein function, and discusses the key challenges and future de-velopment directions of bispecific aptamers, aiming to provide a theoretical basis and design strategies for the development of novel bispecific aptamer drugs.
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