Search Results (2,203)

Since 2014, a model of the individual response to ionizing radiation (IR), based on the radiation-induced nucleoshuttling of the ATM protein kinase (RIANS), has been developed by our lab: after irradiation, ATM dimers monomerize in cytoplasm and diffuse into the nucleus to trigger both recognition and repair of DNA double-strand breaks (DSB), the key-damage of IR response. Moderate radiosensitivity is generally caused by heterozygous mutations of ATM substrates (called X-proteins) that are over-expressed in cytoplasm and form complexes with ATM monomers, which reduces and/or delays the RIANS and DSB recognition. Here, we asked whether molecules, rather than X-proteins, can also influence RIANS. Caffeine was chosen as a potential “X-molecule” candidate. After incubation of cells with caffeine, cutaneous fibroblasts from an apparently healthy radioresistant donor, a patient suffering from Alzheimer’s disease (AD) and another suffering from neurofibromatosis type 1 (NF1) were exposed to X-rays. The functionality of ATM-dependent DSB repair and signaling was evaluated. We report here that caffeine molecule interaction with ATM leads to the inhibition of DSB recognition. This effect is significant in radioresistant cells. Conversely, in the AD and NF1 cells, the DSB recognition is already so low that caffeine does not provide any additional molecular effect. Full article

Fruit losses can occur during the storage of kiwifruit due to disorders such as chilling injury. A major factor influencing storage life is antioxidant metabolism. Antioxidants detoxify reactive oxygen species (ROS) and limit oxidative stress, which otherwise damages proteins, lipids, and DNA. Oxidative stress accelerates degradation and contributes to physiological disorders such as chilling injury during storage of kiwifruit. Regulation of antioxidant metabolism is complex, involving several biochemical pathways critical for maintaining kiwifruit integrity postharvest. The objective of this review is to critically evaluate current knowledge regarding oxidative stress and antioxidant metabolism and the development of postharvest disorders of kiwifruit during cold storage, with an emphasis on chilling injury. The review will provide an overview of current knowledge regarding oxidative stress and antioxidant metabolism in kiwifruit during cold storage, identifying gaps in our knowledge. The review will also discuss how an understanding of antioxidant metabolism can be used to design treatments that have the potential to increase the storability of kiwifruit and reduce chilling injury. Full article

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and the formation of immune complexes (ICs), which lead to widespread inflammation and tissue damage. Neutrophil extracellular traps (NETs), web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, play a crucial role in innate immunity by defending against pathogens. However, excessive NET formation and ineffective clearance of these structures contribute to the development of SLE. This review explores the mechanisms behind NET formation in SLE, their relationship with oxidative stress, and the potential role of antioxidants in treatment. Research indicates that SLE patients exhibit two key abnormalities: excessive NET formation and impaired NET clearance. Excessive NET formation is driven by proinflammatory low-density granulocytes (LDGs) and immune complexes (ICs). Impaired NET clearance stems from reduced DNase1/DNase1L3 activity or anti-nuclease autoantibodies. These two abnormalities lead to elevated circulating NETs. These NETs act as autoantigen reservoirs, forming pathogenic NET–ICs that amplify autoimmune responses. Oxidative stress drives NET formation by activating NADPH oxidase. In contrast, various antioxidants, including enzymatic and non-enzymatic types, can inhibit NET formation via scavenging reactive oxygen species (ROS) and blocking NADPH oxidase activation. Preclinical studies show that antioxidants such as curcumin, resveratrol, and mitochondrial-targeted MitoQ reduce NET formation and ameliorate lupus nephritis; clinical trials confirm that curcumin and N-acetylcysteine (NAC) lower SLE disease activity and reduce proteinuria, supporting their role as safe adjuvant therapies. However, high-dose vitamin E may exacerbate autoimmunity, highlighting the need for dose optimization. Future research should aim to clarify the mechanisms underlying NET formation in SLE and to optimize new antioxidant therapies, including assessments of their long-term efficacy and safety. Full article

Neutrophil extracellular traps (NETs)—webs of DNA and granular proteins expelled by neutrophils—have been implicated in hepatocellular carcinoma (HCC) progression. NETs promote tumor angiogenesis, facilitate invasion/metastasis, and enable immune evasion. Recent data suggest that perioperative factors, including anesthetic techniques, may modulate NET formation (NETosis), thus potentially influencing oncologic outcomes. We conducted a literature review of experimental and clinical studies on NETosis pathophysiology and involvement in HCC and how anesthetic techniques may modulate NET formation and, implicitly, cancer outcomes. NET biomarkers such as citrullinated histone H3 (CitH3), cell-free DNA (cfDNA), and myeloperoxidase–DNA complexes (MPO-DNA) are elevated in HCC patients and correlate with tumor spread, showing diagnostic and prognostic potential. Perioperative anesthetic choices may influence NET activity and immune function. Regional anesthesia and local anesthetics (e.g., lidocaine infusion) attenuate the surgical stress response and preserve anti-tumor immunity. Notably, lidocaine may modulate NET formation and, in a few studies published so far, was shown to reduce postoperative NET markers and other pro-metastatic factors (MMP-9, VEGF) in cancer surgery. In conclusion, NETosis is a process that is strongly implicated in HCC biology. Data published so far suggest that the clinical significance of NETosis may lie in its potential as a marker for disease evaluation and progression, including during the perioperative period. Preliminary results suggest that lidocaine may have a role in decreasing NETosis. Future large randomized trials are needed to exactly quantify these effects. Targeting NETs may be another way to influence HCC outcomes. Full article

Expansion of d(GGGGC)_n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer’s Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics. Full article

Egg quality is a critical economic trait in poultry production, influencing consumer preference and production efficiency. The genetic and epigenetic regulation of egg quality involves complex biological pathways across various traits such as shell quality, albumen composition, and yolk biochemistry. This review synthesizes recent advances in the genetic, molecular, and epigenetic mechanisms that determine poultry egg quality. Specifically, it focuses on external traits such as eggshell strength, color, and thickness, and internal traits including albumen height, yolk composition, and the Haugh unit. Through genome-wide association studies (GWAS), quantitative trait loci (QTL) mapping, whole-genome sequencing (WGS), and multi-omics approaches, key candidate genes such as OC-116, CALB1, CA2 (shell formation), OVAL, SPINK5, SERPINB14 (albumen quality), and FGF9, PIAS1, NOX5 (lipid metabolism) have been identified. These genes play a pivotal role in shell biomineralization, albumen protein regulation, and yolk lipid transport. This review also explores the heritability of these traits, emphasizing the challenges posed by polygenic architecture and the influence of environmental factors. Furthermore, it addresses the dynamic spatiotemporal regulation of egg quality traits, including epigenetic layers such as DNA methylation, histone modifications, RNA methylation, and post-translational protein modifications. This paper highlights the application of these findings to breeding programs via genomic selection, marker-assisted breeding, and epigenetic engineering approaches. Future directions for precision breeding and the development of functional eggs with enhanced quality are also discussed. Full article

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G₄C₂ repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G₄C₂ repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD. Full article

Silicon dioxide (SiO₂) nanoparticles approximately 5 nm in size have been obtained. A method has been developed for introducing SiO₂ nanoparticles into photolithographic resin at concentrations up to 0.1%. Composite resins can be used to manufacture parts with complex geometries with a maximum achievable resolution of 50 μm. Parts made from composite resin with SiO₂ nanoparticles polish well. After polishing, areas of approximately 100 μm² with height differences of less than 10 nm are revealed on the surface of the parts. A relatively uniform distribution of SiO₂ nanoparticles is observed within the parts, and no optical defects are detected. However, areas differing in the phase shift of electromagnetic radiation are observed within the parts. Importantly, the presence of nanoparticles in the resin during MSLA printing increases the degree of resin polymerization. SiO₂ nanoparticles have been shown to have prooxidant properties, leading to the formation of 8-oxoguanine in DNA and long-lived reactive protein species. Components made from photolithographic resins with SiO₂ nanoparticles have been shown to inhibit the growth and development of E. coli bacteria, with a significant loss of viability. Despite their antimicrobial properties, components made from photolithographic resins with SiO₂ nanoparticles do not affect the growth and development of mammalian cells. Full article

BRCC36, a member of the JAB1/MPN/Mov34 metalloenzymes family, exhibits distinct biochemical characteristics compared to other monomeric deubiquitinating enzymes. To function as a deubiquitinating enzyme, BRCC36 must assemble into a complex with other subunits that specifically cleaves K63-linked polyubiquitin chains. In the cytoplasm, BRCC36 forms the BRISC complex, which plays a crucial role in regulating various signaling pathways through modulating the K63-linked ubiquitination of substrate proteins. The BRISC complex can interact with the cytoplasmic SHMT2, thereby influencing diverse biological processes, including inflammation, mitosis, and hematopoiesis. Within the nucleolus, BRCC36 forms the BRCA1-A complex, which contributes to DNA damage repair. Growing evidence underscores the importance of the ubiquitin system, particularly deubiquitinating enzymes, in the initiation and progression of various diseases. In this review, we first provide a comprehensive overview of the localization, assembly, mutations, and functions of BRCC36 and its associated complexes. We then discuss recent advances in research on BRCC36 across various diseases and explore its potential as a therapeutic target. Full article

Background/Objectives: Systemic sclerosis (SSc) is a rare, complex autoimmune disease characterized by fibrosis of the skin and internal organs. While its pathogenesis is not fully understood, chromosomal instability and telomere attrition have emerged as significant areas of investigation. Methods: This review provides a historical narrative perspective and synthesizes current findings on the role of these genomic anomalies in SSc pathogenesis. We synthesized findings from foundational and recent research articles investigating genotoxic factors, chromosomal aberrations, and telomere biology in SSc. Results: There is a strong historical basis for chromosomal instability in SSc, manifesting as micronuclei, translocations, and breaks. This instability is driven by clastogenic factors and oxidative stress. SSc-specific autoantibodies are implicated; anti-centromere antibodies correlate with aneuploidy and micronuclei, while anti-topoisomerase I may inhibit DNA repair. SSc is also characterized by significant telomere attrition, first reported in 1996 and now confirmed by additional genetic studies. This telomere loss is associated with reduced telomerase activity and the presence of autoantibodies against telomere-associated proteins, including shelterin components. Conclusions: We conclude that inflammation, telomere attrition, and chromosomal instability are linked in a self-perpetuating cycle that drives SSc pathogenesis. We propose that an initial inflammatory stimulus leads to reactive oxygen species production, causing telomere damage and attrition. Critically short telomeres trigger faulty DNA repair mechanisms, such as breakage–fusion–bridge cycles, resulting in chromosomal instability. This genomic damage, in turn, acts as a danger signal, further activating inflammatory pathways and creating a feedback loop that perpetuates fibrosis. Full article

For decades, 8-oxoguanine (8-oxoG) has been recognized as a pervasive and pro-mutagenic oxidative DNA lesion. In human cells, 8-oxoG is removed from DNA via the base excision repair pathway initiated by 8-oxoguanine–DNA glycosylase (OGG1). However, emerging evidence over the past twenty years suggests a more complex, regulatory role for this DNA modification. Here, we discuss findings that 8-oxoG, particularly when present in gene promoters, can act as a signal to modulate transcription, establishing an 8-oxoG/OGG1 axis in the inflammatory response. Proposed mechanisms include the generation of 8-oxoG during chromatin remodeling processes involving histone demethylases, the recruitment of transcription factors (NF-κB, HIF1α, Myc, SMAD, etc.) by OGG1, and the lesion’s enrichment in guanine-rich sequences prone to forming G-quadruplex structures. The pro-mutagenic nature of 8-oxoG and the lack of dedicated, functionally separate writer and reader proteins challenge its classification as a true epigenetic DNA mark, distinguishing it from canonical epigenetic nucleobases like 5-methylcytosine and 5-hydroxymethylcytosine. On the other hand, 8-oxoG is well suited for the role of a regulatory signal localized to DNA and involved in the cellular response to oxidative stress and the associated physiological stimuli. Full article

Callicarpa americana L. is a member of the Lamiaceae family with important ornamental and medicinal value. Although the chloroplast genome of Lamiaceae has been extensively studied, its mitochondrial genome remains unreported, limiting a comprehensive understanding of the phylogeny and genome evolution of Lamiaceae. In this study, the complete mitochondrial genome of C. americana was successfully assembled for the first time. The genome is 499,565 bp in length, showing a complex multi-branched closed-loop structure that contains 37 protein-coding genes, 23 tRNA genes, and 4 rRNA genes. The difference in mitochondrial genome size is relatively large compared to Orobanchaceae species, but the difference in GC content is not obvious. The expansion of genome size was mainly due to the accumulation of non-coding regions and repetitive sequences. Meanwhile, two pairs of long repetitive sequences (LR3 and LR5) mediated homologous recombination. The mitogenome was also identified; there were a total of 494 C-to-U RNA editing sites in protein-coding genes. In addition, 42 mitochondrial plastid DNA fragments (MTPTs) were detected, with a total length of 21,464 bp, accounting for 4.30% of the genome. Repeat sequence analysis showed that tetranucleotide SSR was the most abundant repeat type in the mitochondria of Lamiaceae. Phylogenetic analysis based on the alignment of 32 protein-coding gene sequences showed that Callicarpa is sister to the other eight species of Lamiaceae. This work fills an important gap by presenting the first complete mitochondrial genome of C. americana, providing an important data resource for further understanding the structural evolution, dynamic recombination mechanism, and phylogeny of the mitochondrial genome of Lamiaceae. Full article

Eriobotrya and Rhaphiolepis are two closely related genera within the Maleae tribe of Rosaceae, and delineation of the boundary between these genera requires clarification. This study aims to reassess the phylogeny of two genera by integrating data from nuclear ribosomal DNA (nrDNA), mitochondrial DNA (mtDNA), and the micromorphological features of leaves, petioles, fruits, and fruit apical sepals from 53 accessions, including 16 nrDNA and one mtDNA sequences acquired from NCBI, representing 25 Eriobotrya, and 14 Rhaphiolepis species. Prior taxonomic investigations have often relied on either morphological or molecular methods; however, resolving the complex evolutionary background of these genera benefits from the application of molecular data with in-depth micromorphological analysis. Our findings indicate that molecular phylogeny derived from nrDNA sequences and leaf micromorphology elucidates the relationship between Eriobotrya and Rhaphiolepis, supporting the monophyly of Rhaphiolepis (with high support) and Eriobotrya (with moderate to low support). Supplementary micromorphological features (petioles, fruits, fruit apical sepals) support their classification as separate genera and aid in identification. Nevertheless, the mtDNA gene tree derived from 52 protein-coding genes offered restricted evolutionary insights due to low sequence variability, and displayed incongruence with the robust nuclear and morphological topologies. Furthermore, the mtDNA gene tree exhibited incongruent placements for four Eriobotrya species (E. hookeriana, E. laoshanica, E. deflexa, and E. fragrans) which clustered within the Rhaphiolepis clade, with support values ranging from low to high confidence. The observed topological incongruences, mito-nuclear discordance, and the congruent patterns of micromorphological and nrDNA sequences indicate a reticulate history. Further research employing whole genome sequencing may shed further light on the complex evolutionary history of this key clade. Full article

Chronic infections pose significant clinical challenges due to their persistent nature, heightened resistance to conventional therapies, and association with biofilm formation. Neutrophil extracellular traps (NETs), released through a unique form of cell death known as NETosis, serve as an innate immune defense mechanism by trapping and neutralizing pathogens. However, accumulating evidence reveals a complex and paradoxical relationship between NETs and microbial biofilms. While NETs can immobilize and kill planktonic microbes, the extracellular DNA and associated proteins often contribute to biofilm stability, immune evasion, and chronic infection persistence. This review explores the bidirectional interactions between NETosis and biofilm formation, with a focus on their synergistic roles in the pathogenesis of chronic infections such as cystic fibrosis lung disease, diabetic foot ulcers, periodontitis, and implant-associated infections. We outline the molecular mechanisms governing NETosis, the structural and functional dynamics of biofilms, and how these processes intersect to form recalcitrant infection niches. Emerging therapeutic strategies aimed at disrupting this pathogenic interplay including DNase-based treatments, PAD4 inhibitors, and combination therapies are critically evaluated. By illuminating the pathogenic synergy between NETs and biofilms, this review underscores the need for integrated immunomodulatory and anti-biofilm interventions to effectively manage chronic infectious diseases and improve patient outcomes. Full article

Ovarian tumors constitute a complex and heterogeneous group of neoplasms, encompassing both benign and highly malignant lesions. Accurate diagnosis and classification of ovarian tumor types are crucial for the personalization of therapeutic strategies and have a significant impact on patient prognosis. This review presents the current state of knowledge regarding both classical and novel biomarkers, with particular emphasis on their diagnostic, predictive, and prognostic value. Traditional markers, such as CA-125 and human epididymis protein 4 (HE4), remain central to clinical diagnostics; however, their limitations highlight the need for more sensitive and specific approaches. Emerging biomarkers, including microRNAs (miRNA), circulating tumor DNA (ctDNA), and advanced panels integrating transcriptomic, proteomic, and genomic data, offer the potential for earlier detection, improved disease monitoring, and assessment of treatment response. Despite these advances, major challenges persist, particularly those associated with the heterogeneity of ovarian tumors, the high costs of testing, lack of standardization, and unequal access to diagnostic methods. Full article