Search Results (289)

(1) Background: The naked mole-rat (Heterocephalus glaber) survives hypoxia–reoxygenation stresses by utilizing metabolic rate depression, achieved in part by downregulating nonessential genes and processes to conserve endogenous cellular resources and prevent buildup of toxic waste byproducts. Tight molecular control of protein degradation (specifically the ubiquitin–proteasome system) is a potent regulatory tool for maintaining muscle integrity during hypoxia, but how this system is regulated in the heart of hypoxia-tolerant species is poorly understood. (2) Methods: The protein expression levels of cullin-RING E3 ligases (specifically CRL4 architecture), deubiquitinating enzymes, and proteasomal activity were assayed in cardiac tissues from H. glaber exposed to 24 h of normoxia or hypoxia in vivo. (3) Results: Overall, the protein expression of E3 ligases decreased, whereas expression of deubiquitinating enzymes increased during hypoxia, all of which play roles in themes of oxidative stress, heightened DNA damage repair, and the HIF-1-VHL-NFκB axis. Proteasomal activity was elevated during hypoxia, which conceivably links to the oxidative stress theory of aging and longevity of H. glaber. (4) Conclusions: Taken together, our results expand current research into protein degradation and extreme environmental stress responses, with a specific focus on cardiac mechanisms related to oxidative stress resistance along the hypoxia-longevity axis. Full article

This narrative review aims to systematize the current knowledge on the dual role of reactive oxygen species and reactive nitrogen species in cancer processes, from their physiological function in redox signaling to their pathological impact in oxidative distress. The mechanisms of biomolecule damage, particularly DNA, and deregulation of signaling pathways induced by excessive ROS/RNS concentrations, which promote neoplastic transformation, are presented. The importance of diet and endogenous antioxidants in cancer prevention is also discussed, emphasizing the role of natural antioxidants in prevention and adjunctive therapy. In this context, oleanolic acid emerges as a promising compound with dual action modulating oxidative stress, capable of balancing cellular redox responses. We discuss the most important antioxidant mechanisms of oleanolic acid, the interconnection of oxidative stress with carcinogenesis-related pathways, anticancer mechanisms mediated by oxidative stress modulation, and structural modifications and modern application techniques that improve its bioavailability, as well as future perspectives on oleanolic acid research in the context of its antioxidant and anticancer activity. Overall, available experimental and preclinical data indicate that oleanolic acid, through pleiotropic modulation of oxidative stress and signaling networks, holds promise as an adjuvant agent in cancer prevention and therapy. Full article

Mitochondrial dysfunction plays a central role in cardiac aging. Damaged mitochondria release excessive free radicals from the electron transport chain (ETC), leading to an increased production of reactive oxygen species (ROS). The accumulation of ROS, together with impaired ROS clearance mechanisms, results in oxidative stress, further disrupts mitochondrial dynamics, and diminishes bioenergetic capacity. Furthermore, the dysfunctional mitochondria exhibit an impaired endogenous antioxidant system, exacerbating this imbalance. These alterations drive the structural and functional deterioration of the aging heart, positioning mitochondria at the center of mechanisms underlying age-associated cardiovascular decline. In this review, we summarize the current evidence on how mitochondrial oxidative stress, mutations on mitochondrial DNA (mtDNA), and disruptions in the fission—fusion balance contribute to cardiomyocyte aging. This review also explores ways to mitigate oxidative stress, particularly with mitochondria-targeted antioxidants, and discusses the emerging potential of mitochondrial transplantation to replace dysfunctional mitochondria. Full article

Oxidative stress arises from an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms and disrupts the structural integrity of macromolecules such as lipids, proteins, and DNA. This biochemical imbalance triggers the pathogenesis of cardiovascular and neurodegenerative diseases and leads to lipid oxidation and quality degradation in food systems. Plant-derived bioactive compounds (BACs) such as polyphenols and terpenes develop versatile molecular strategies to mitigate this oxidative damage. In addition to their direct radical scavenging effects, polyphenols stimulate the synthesis of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) by activating the Nrf2–Keap1 signaling pathway. Terpenes, on the other hand, create a specialized protective shield in lipid-based matrices through “chain-breaking” reactions and a “slingshot” mechanism that externally halts the oxidation of γ-terpinene. In food engineering applications, these compounds meet the demand for “clean-label” products by providing alternatives to synthetic antioxidants such as BHA and BHT. Specific terpenes, such as carnosic acid, demonstrate higher performance in inhibiting lipid oxidation compared to their synthetic counterparts. Although BAC use extends the shelf life of products while maintaining color and flavor stability, potential interactions with protein digestibility necessitate dosage management. From a clinical perspective, these compounds suppress inflammatory responses by inhibiting the NF-κB pathway and contribute to the prevention of chronic diseases by modulating the gut microbiota. This review evaluates the capacity of BACs to manage oxidative stress in food preservation technologies and human health through a mechanistic and application-based approach. Full article

Leuconostoc mesenteroides is a key microorganism in food biotechnology, valued for its production of flavor-forming metabolites and exopolysaccharides, and its inclusion in starter cultures and biocatalytic systems. However, the application of advanced genetic tools to L. mesenteroides remains hindered by multiple barriers, including inefficient DNA transfer, elevated endogenous nuclease activity, and restriction–modification systems sensitive to plasmid methylation patterns. As a result, even widely accepted electroporation methodologies often yield inconsistent or irreproducible transformation results, limiting the strain’s amenability to metabolic engineering and synthetic biology applications. In this study, a reproducible electroporation protocol for the L. mesenteroides strain H32-02 Ksu is developed and experimentally validated. The protocol concept relies on the sequential optimization of key process steps: targeted weakening of the cell wall followed by osmotic protection, the development of a gentle electrical stimulus that ensures membrane permeability without critical damage, and the creation of recovery conditions that minimize loss of viability and degradation of incoming DNA. Matching plasmid methylation to the recipient’s restriction profile proved critical: choosing a source for plasmid DNA production with a compatible methylation pattern dramatically increased the likelihood of successful transformation. In our case, the selection of an E. coli strain with a more suitable methylation profile increased the yield of transformants by 3.5 times. It was also shown that reducing the pulse voltage increase transformant number by 3 times. The combined optimization resulted in an approximately 40-fold increase in transformation efficiency compared to the baseline level and, for the first time, provided consistently reproducible access to transformants of this strain. The highest transformation efficiency was achieved: 8 × 10² CFU µg⁻¹ DNA. The presented approach highlights the strain-specificity of barriers in Leuconostoc and forms a technological basis for constructing strains with desired properties, expressing heterologous enzymes, and subsequently scaling up bioprocesses in food and related industries. The methodological principles embodied in the protocol are potentially transferable to other lactic acid bacteria with similar limitations. Full article

The controlled pro-inflammatory immune response is critical for fighting against external and endogenous threats, such as microbes/pathogens, allergens, xenobiotics, various antigens, and dying host cells and their mediators (DNA, RNA, and nuclear proteins) released into the circulation and cytosol (PAMPs, MAMPs, and DAMPs). Several pattern recognition receptors (PRRs) and their downstream adaptor molecules, expressed by innate and adaptive immune cells, are critical in generating the inflammatory immune response by recognizing PAMPs, MAMPs, and DAMPs. However, their dysregulation may predispose the host to develop inflammation-associated organ damage, neurodegeneration, autoimmunity, cancer, and even death due to the absence of the inflammation resolution phase. The cytosolic calcium (Ca²⁺) level regulates the survival, proliferation, and immunological functions of immune cells. Cysteine-rich proteases, specifically calpains, are Ca²⁺-dependent proteases that become activated during inflammatory conditions, playing a critical role in the inflammatory process and associated organ damage. Therefore, this article discusses the expression and function of calpain-1 and calpain-2 (ubiquitous calpains) in various innate (epithelial, endothelial, dendritic, mast, and NK cells, as well as macrophages) and adaptive (T and B cells) immune cells, affecting inflammation and immune regulation. As inflammatory diseases are on the rise due to several factors, such as environment, lifestyle, and an aging population, we must not just investigate but strive for a deeper understanding of the inflammation and immunoregulation under the calpain system (calpain-1 and calpain-2 and their endogenous negative regulator calpastatin) lens, which is ubiquitous and senses cytosolic Ca²⁺ changes to impact immune response. Full article

DNA is continuously exposed to endogenous and exogenous factors that induce oxidative modifications leading to mutations and genomic instability. Oxidative DNA damage plays a dual role, contributing to physiological signaling at low levels while promoting mutagenesis, carcinogenesis and degenerative diseases when unpaired. Among various lesions, an oxidized base, such as 8-oxo-2′-deoxyguanosine (8-oxodG), is one of the major biomarkers of oxidative stress and genomic damage. Cells have evolved sophisticated repair processes, including base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR), to maintain genomic integrity. Dysregulation or polymorphism of these repair genes has been linked with cancer, neurologic, and cardiovascular disorders. This review discusses an overview of what is presently known concerning oxidative DNA damage and repair mechanisms, particularly emphasizing their molecular players, signaling routes, and human disease implications. It further refers to the latest advances in CRISPR-based technologies and multi-omics approaches that are redefining our understanding of DNA damage response (DDR) networks and creating new frontiers for therapeutic interventions. Full article

Background: Non-small cell lung cancer (NSCLC) progression is driven by dysregulated competing endogenous RNA (ceRNA) networks, where non-coding RNAs sequester miRNAs to modulate oncogene expression. The tumor-suppressor miR-145 is frequently downregulated in NSCLC, but its lncRNA-mediated regulation remains incompletely characterized. Methods: Integrated transcriptomic analysis of NSCLC datasets (GSE135304: blood RNA from 712 patients; GSE203510: plasma miRNAs) was used to identify dysregulated genes (|log2FC| > 0.1, p < 0.05) and miRNAs (|log2FC| > 1, p < 0.05). Experimentally validated targets from miRTarBase/TarBase were intersected with dysregulated genes, followed by WikiPathways/GO enrichment. ceRNA networks were constructed via co-expression analysis. RT-qPCR validated miR-145-3p expression in A549/MRC-5 cells and NSCLC tissues. GEPIA assessed FN1/CCND1 clinical relevance. Results: We identified 8271 dysregulated genes and 52 miRNAs. miR-145-3p, critical in immune regulation, was significantly downregulated (log2FC = −1.24, p = 0.036). Intersection analysis revealed 27 miR-145-3p targets (e.g., FN1, CCND1, SMAD3) enriched in immune pathways (FDR < 0.05) and TGF-β-mediated EMT within the dysregulated geneset. Six immune-linked hub genes emerged. LncRNAs LOC729919 and LOC100134412 showed strong co-expression with hub genes and competitively bind miR-145-3p, derepressing the expression of the metastasis drivers FN1 (ECM regulator) and CCND1 (cell cycle controller). This ceRNA axis operates within a broader dysregulation of ATM-dependent DNA damage, Hippo signaling, and cell cycle pathways. RT-qPCR confirmed significant miR-145-3p suppression in NSCLC models (p < 0.05). GEPIA revealed a significant FN1-CCND1 co-expression (p = 0.0017). Conclusions: We characterize a novel LOC729919/LOC100134412–miR-145–FN1/CCND1 ceRNA axis in NSCLC pathogenesis. FN1’s prognostic value and functional linkage to CCND1 underscores its potential clinical relevance for therapeutic disruption. Full article

Cancer immunotherapy has redefined oncology’s goals, aiming for durable systemic immunity rather than mere cytoreduction. However, many solid tumors remain refractory due to immunosuppressive microenvironments and antigenic heterogeneity. Local tumor ablation techniques—including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, irreversible electroporation (IRE), and high-intensity focused ultrasound (HIFU)—are being re-evaluated beyond their historic cytoreductive role. This comprehensive review synthesizes the paradigm of tumor ablation as an in situ vaccination strategy, a concept that leverages the tumor itself as a source of antigens and the ablation process to generate endogenous adjuvants. We detail the mechanistic underpinnings, highlighting how ablation induces immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) such as calreticulin, ATP, HMGB1, and cytosolic DNA. These signals activate innate immunity via pathways like cGAS-STING, promote dendritic cell maturation, and facilitate epitope spreading. We critically examine the determinants of efficacy, including the critical impact of ablation modality on the “DAMP signature,” the necessity of complete ablation, and the pivotal role of the host’s immune contexture. Furthermore, we explore the induction of tertiary lymphoid structures (TLS) as a key anatomical site for sustained immune priming. Translational strategies are extensively discussed, focusing on optimizing procedural techniques, rationally combining ablation with immune checkpoint inhibitors (ICIs) and innate immune agonists, and developing a robust biomarker framework. By adopting the core principles of vaccinology—meticulous attention to antigen, adjuvant, route, and schedule—ablation can be engineered into a reproducible platform for systemic immunotherapy. This review concludes by addressing current limitations and outlining a roadmap for clinical translation, positioning interventional oncology as a central discipline in the future of immuno-oncology. Full article

The DNA Damage Response (DDR) network is an essential machinery for maintaining genomic integrity, with DDR defects being implicated in cancer initiation, progression, and treatment resistance. Moreover, oxidative stress, an imbalance between reactive oxygen species production and antioxidant defense, can significantly impact cell viability, leading to cell death or survival. Herein, we tested the hypothesis that DDR-related signals and redox status measured in multiple myeloma (MM) cell lines correlate with the sensitivity to genotoxic insults. At baseline and following irradiation with Ultraviolet C (UVC; 50 J/m²) or treatment with melphalan (100 μg/mL for 5 min) DDR-related parameters, redox status expressed as GSH/GSSG ratio and apurinic/apyrimidinic sites were evaluated in a panel of eleven human MM cell lines and one healthy B lymphoblastoid cell line. We found that MM cell lines with increased apoptosis rates displayed significantly higher levels of endogenous/baseline DNA damage, reduced GSH/GSSG ratio, augmented apurinic/apyrimidinic lesions, decreased nucleotide excision repair and interstrand crosslinks repair capacities, and highly condensed chromatin structure. Taken together, these findings demonstrate that DDR-related parameters and redox status correlate with the sensitivity of MM cells to DNA-damaging agents, specifically melphalan, and, if further validated, may be exploited as novel sensitive/effective biomarkers. Full article

Human DNA is continuously exposed to endogenous and exogenous agents that generate over 100,000 lesions per cell each day. In addition to damage to nucleobases, deoxyribose, and phosphate groups, a particularly harmful class of lesions involves non-canonical DNA termini—structures deviating from the canonical 3′-hydroxyl and 5′-phosphate ends. These aberrant DNA ends can obstruct essential DNA transactions and, if left unrepaired, contribute to cytotoxicity and mutagenesis. Their biological significance is further highlighted by the severe pathologies linked to deficiencies in DNA end-processing enzymes, including inflammation, cancer predisposition syndromes, neurodegeneration, and aging. This review highlights recent advances in our understanding of the formation, prevalence, and repair mechanisms of several key non-canonical DNA end structures, including 3′-phosphate, 3′-phosphoglycolate, 3′-α,β-unsaturated aldehyde and its glutathione derivative, 5′-deoxyribose-5-phosphate, 2′-deoxyribonucleoside-5′-aldehyde, and 5′-adenosine monophosphate. These non-canonical DNA terminal structures arise from various sources, such as radical-induced oxidation of the 2-deoxyribose moiety and DNA repair pathways. While this review does not cover the full spectrum of non-canonical termini, the selected structures are emphasized based on quantitative data supporting their biological relevance. The review also discusses their broader implications in mitochondrial DNA maintenance and inflammatory signaling and highlights key knowledge gaps that warrant further investigation. Full article

Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and the antioxidant defense system, plays a central role in the pathophysiology of numerous diseases, including cardiovascular, neurodegenerative, and inflammatory disorders. This review explores the biochemical mechanisms of ROS-induced damage to lipids, proteins, cholesterol, and DNA, and analyzes both endogenous (enzymatic and non-enzymatic) and exogenous (nutritional) antioxidant systems that counteract oxidative damage. Key enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, alongside dietary antioxidants like vitamins C and E, polyphenols, and carotenoids, are highlighted for their protective roles. The dual antioxidant/pro-oxidant behavior of these compounds under varying physiological conditions is discussed. Furthermore, this paper reviews the cellular repair systems activated in response to oxidative injury and the biomarkers used to assess oxidative stress in clinical settings. Special attention is given to the implications of oxidative stress in cardiovascular and autoimmune diseases and the potential of antioxidant strategies in disease prevention and therapy. The findings underscore the importance of maintaining redox homeostasis and support further research into antioxidant-based interventions. Full article

The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology. Full article

Ultraviolet radiation (UVR) is a major contributor to skin aging and carcinogenesis, primarily through the induction of DNA damage. While conventional sunscreens provide passive protection by blocking UVR, active photoprotection using DNA repair enzymes offers a strategy to reverse UV-induced DNA lesions at the molecular level. Enzymes such as photolyase, T4 endonuclease V, and 8-oxoguanine glycosylase address distinct types of DNA damage through light-dependent and -independent mechanisms, complementing the skin’s endogenous repair systems. Advances in nanocarrier technologies and encapsulation methods have improved the stability and delivery of these enzymes in topical formulations. Emerging evidence from clinical studies indicates their potential in reducing actinic keratoses, pigmentation disorders, and photoaging signs, although challenges in regulatory approval, long-term efficacy validation, and formulation optimization remain. This review provides a comprehensive synthesis of the mechanistic, clinical, and formulation aspects of enzyme-based photoprotection, outlines regulatory and ethical considerations, and highlights future directions, including CRISPR-based repair and personalized photoprotection strategies, establishing enzyme-assisted sunscreens as a next-generation approach to comprehensive skin care. Full article

The whitefly Bemisia tabaci (Hemiptera: Aleyrodoidea) causes direct feeding damage to crop plants and transmits pathogenic plant viruses, thereby threatening global food security. Although whitefly-infecting RNA viruses are known and proposed as biocontrol agents, no insect DNA virus has been found in any member of Aleyrodoidea. Using rolling circle amplification (RCA) of viral DNA from whiteflies collected from crop fields in Morocco, followed by Illumina sequencing of the RCA products, we found a novel insect single-stranded (ss) DNA parvovirus (family Parvoviridae) in addition to plant ssDNA geminiviruses transmitted by whiteflies. Based on its genome organization with inverted terminal repeats and evolutionarily conserved proteins mediating viral DNA replication (NS1/Rep) and encapsidation (VP), encoded on the forward and reverse strands, respectively, we named this virus Bemisia tabaci ambidensovirus (BtaDV) and classified it as a founding member of a new genus within the subfamily Densovirinae. This subfamily also contains three distinct genera of ambisense densoviruses of other hemipteran insects (Aphidoidea, Coccoidea, and Psylloidea). Furthermore, we provide evidence for the genetic variants of BtaDV circulating in whitefly populations and for its partial sequences integrated into the B. tabaci genome, with one integrant locus potentially expressing a fusion protein composed of viral Rep endonuclease and host DNA-binding domains. This suggests a long-term virus-host interaction and neofunctionalization of BtaDV-derived endogenous viral elements. Full article