The maintenance of the genome in eukaryotic cells is dependent on the proper maintenance of the structure and function of the nuclear envelope which encases the genome. The nuclear envelope in higher eukaryotic cells is composed of the outer nuclear membrane, the inner nuclear membrane, and the nuclear lamina which resides just inside of the inner nuclear membrane. The nuclear lamina provides mechanical support to the nuclear envelope, plays essential roles in transport of molecules between the cytoplasm and the nucleus, and is pivotal in regulating global chromatin structure and three-dimensional nuclear architecture. Proper functioning of the nuclear lamina plays roles in regulating the cell cycle, transcription, RNA splicing, chromatin organization, DNA replication, and DNA repair. The nuclear lamina is conserved in metazoans and is composed of a meshwork of interwoven proteins called lamins, as well as lamin associated proteins. The protein known as lamin A is a vital constituent of the nuclear lamina. Alterations in lamin A, particularly those associated with disruptions in posttranslational processing of lamin A by zinc metallopeptidase ste24, have been linked to a variety of genetic disorders that give rise to genome instability and accelerated aging. This review will concentrate primarily on what has been learned about the dependency of effective DNA repair and DNA replication on a functional nuclear lamina, with particular emphasis on how modifications in the protein lamin A may corrupt a cell's ability to maintain genome stability.

Wilson's disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, which impair cellular copper excretion and lead to toxic copper accumulation in the liver, brain, and other organs. Clinically, WD presents with a broad spectrum of hepatic and neurological manifestations. The pronounced phenotypic variability among patients harboring identical ATP7B mutations, including affected siblings, suggests the influence of additional genetic and/or epigenetic factors such as non-coding RNAs (ncRNAs), in modulating disease presentation. This review explores the potential involvement of ncRNAs in shaping the hepatic phenotype of WD. Although a few transcriptomic and network-based studies in mouse models have underscored the relevance of ncRNAs in WD pathogenesis, there remains a paucity of research investigating their role in the spectrum of hepatic severity observed in human patients. To address this gap, we collated existing evidence on ncRNAs implicated in WD and further sought to predict additional candidate ncRNAs by aligning hepatic severity categories in WD with general liver diseases that exhibit similar clinical features. Through a systematic literature review, we identified dysregulated ncRNAs in these liver diseases that may serve as surrogates for WD severity groups. Furthermore, our in silico analyses highlighted several microRNAs (miRNAs) that, if upregulated, could downregulate ATP7B or its putative modifier genes, raising the possibility that miRNA dysregulation may phenocopy certain pathogenic effects of ATP7B mutations, especially in WD cases exhibiting missing heritability.

Platinum nanoparticles (PtNP) have received considerable attention in the nanomedicine field due to their magnetic, catalytic, and optical properties. However, the potential toxicity of PtNP has not been properly evaluated yet, and current information on the possible risks related to their use is still limited. On this basis, the main objective of this systematic review was to gather available data on PtNP biological behaviour and potential harmful effects, as well as to highlight the gaps of knowledge that need to be filled in to progress in their use in clinical practice. A total of 441 studies were obtained and reviewed from the initial search; 108 fulfilled the selection criteria and were included in the revision. Mainly in vitro but also in vivo studies were reported using a variety of biological systems and animal models, with no data from human epidemiological studies published so far. All these studies were extensively evaluated to provide useful information on the PtNP biocompatibility and their potential to be employed for medical purposes. In particular, information on the physicochemical features of the PtNP influencing their biological behaviour, methods employed for toxicity evaluation, biological systems used, and outcomes addressed were analysed and discussed. In general, the results obtained showed a good biocompatibility of these NP, although some of them detected significant toxicity highly dependent of size, concentration/dose, coating, or exposed biological system. Furthermore, anticancer or protective effects were also described for PtNP in several revised studies. These findings encourage to continue exploring the benefits of PtNP for clinical practice.

Low-density lipoprotein receptor-related protein 1B (LRP1B) is one of the most frequently mutated genes across a wide range of malignancies and has garnered increasing attention owing to its crucial role in tumorigenesis and clinical outcomes. Emerging evidence suggests that LRP1B mutations not only disrupt essential cellular processes such as proliferation, migration, and genomic stability but also significantly impact antigen presentation, modulation of the tumor immune microenvironment, and responses to immunotherapy. These findings highlight its substantial biological and clinical significance. Notably, the mutational landscape of LRP1B exhibits marked tissue specificity and molecular subtype heterogeneity, which may influence the efficacy of immunotherapy, targeted therapies, and cytotoxic chemotherapy. In this review, we provide a comprehensive overview of the mutation patterns, mechanistic functions, immunological roles, and therapeutic predictive value of LRP1B across various cancer types, with the aim of supporting its development as a biomarker and therapeutic target in precision oncology.

Exposure to heavy metals such as lead, arsenic and chromium is associated with genotoxicity and increased risk of cancer. In this systematic review and meta-analysis, we have assessed effects of heavy metal exposure on levels of DNA strand breaks in leukocytes, measured by the comet assay, in human biomonitoring studies. We distinguish between traditional toxic metals (lead), semi-metals/metalloids (arsenic), transition metals (chromium), and other heavy metals. The literature search led to 66 studies, which were assessed by meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to lead (1.99, 95 % CI: 1.47, 2.51), arsenic (1.36, 95 % CI: 0.94, 1.77), chromium/welding fume (2.03, 95 % CI: 1.48, 2.57), and other heavy metals (0.81, 95 % CI: 0.45, 1.18). Subgroup analysis indicates that all studies combined from middle-income countries have higher effect size (1.99, 95 % CI: 1.63, 2.35) than have studies from high-income countries (0.81, 95 % CI: 0.37, 1.26). The lower effect size in high-income countries may be due to differences in exposure levels, related to stricter regulation of emissions or more awareness/use of personal protective equipment in the working environment. Sensitivity analysis does not unequivocally link effect size to comet assay measurement bias, inferred by insufficient information on comet assay procedures, missing assay controls, non-blinded analysis of samples, or exposure misclassification. In conclusion, this systematic review and meta-analysis shows that exposure to heavy metals - lead, arsenic and chromium - is associated with increased levels of DNA strand breaks in human leukocytes.

In 2022, an International Agency for Research on Cancer (IARC) Monographs Working Group assessed the carcinogenic hazard of occupational exposure as a firefighter. The working group concluded that occupational exposure as a firefighter is carcinogenic to humans and identified chronic inflammation as a contributing factor. This review therefore aimed to summarise the evidence of acute and chronic inflammation in firefighters. Acute and chronic (>2-6 weeks) levels inflammatory markers (Eg. Interleukin (IL) 1β, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNFα), C reactive protein (CRP)) were examined in firefighters following exposure to typical firefighting duties including structural and wildland fires. Experimental studies without exposure to combustion emissions were also reviewed to examine the specific contribution of heat exposure, physical exertion, cognitive load and restricted sleep to inflammation in firefighters. For chronic inflammation, the strongest evidence existed for elevated circulating IL-6 (n = 5 studies), followed by elevated IL-1β (n = 3), CRP (n = 3) and IL-8 (n = 2). Acute elevations in IL-6 (n = 8 studies), IL-8 (n = 7) and IL-1β (n=4) were also evident in firefighters in the hours and days following exposure to structural and wildland fires. Experimental studies provided evidence that physical exercise and heat contribute to acute elevations in IL-6 (n = 6) and TNFα (n = 3). In summary, the data reviewed provide strong support that typical firefighting duties can induce both acute and chronic inflammation. More work is needed to determine the prevalence of inflammation in firefighters and to identify mitigating strategies to lower the risk of firefighters developing inflammatory related-chronic disease.

Exposure to pesticides, most usually in occupational settings, is associated with different adverse health effects. In this systematic review and meta-analysis, we have assessed the effects of pesticide exposure on the level of DNA strand breaks in human peripheral blood cells, measured by the comet assay, in human biomonitoring studies. The literature search led to 80 studies included in the review. Of these, 66 studies met the criteria to be used in the meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show an increased level of DNA strand breaks in subjects exposed to pesticides (2.02, 95 % CI: 1.69, 2.35). Results originate mainly from studies on workers, with only a few studies on environmental pesticide exposure. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (2.22, CI: 1.84, 2.59, n = 55) than studies from high-income countries (1.09, CI: 0.41, 1.76, n = 11). This difference between middle- and high-income countries may be mostly due to legislative, economic, and socio-cultural aspects. It has to be pointed out that only 9 % of the studies were classified as having an overall low risk of bias, while 12 % of studies used exposure biomarkers. In conclusion, this systematic review and meta-analysis shows that exposure to pesticides is associated with increased levels of DNA strand breaks in human peripheral blood cells.

To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.

To assess the variations in Single Nucleotide Polymorphisms (SNPs) that affect susceptibility of CRC in Saudi patients.

Patients with inborn errors of immunity (IEI) experience severe infectious and non-infectious complications, leading to an increased risk of mortality. Delayed diagnosis or misdiagnosis significantly contributes to the heightened mortality rates observed in IEI patients.

Circulating cell-free DNA (cfDNA), particularly in blood, is emerging as a critical non-invasive biomarker for the prediction, diagnosis, and monitoring of human diseases. Additionally, cytoplasmic DNA has been implicated in promoting genetic aberrations, genome instability, and inflammation-factors that can contribute to the development of various diseases, including cancer. However, the heterogeneous nature of both intra- and extracellular DNA presents a significant challenge. This review synthesizes current evidence on the origin, composition, and fate of micronuclei (MN) and their derived DNA/chromatin, highlighting their potential as active participants in genomic instability and immune activation. We examine the molecular characteristics of MN, including their formation from acentric fragments, whole chromosomes, or double minutes, and their dynamic intracellular outcomes, such as reintegration, degradation, or extrusion. A major focus is placed on the consequences of micronuclear envelope rupture, including chromothripsis and cGAS-STING-mediated inflammation. We explore the emerging evidence for the extrusion of MN or MN-derived DNA via direct extrusion or packaging in extracellular vesicles, and discuss their implications for cfDNA composition, detection, and biomarker development. The review also underscores the relevance of MN in disease pathogenesis and senescence, and concludes by outlining critical knowledge gaps, particularly concerning the mechanisms of MN clearance, their tissue origin, and their survival and detectability in plasma. In conclusion, by elucidating the mechanistic link between MN biology and cfDNA, we propose that MN-derived DNA and chromatin may serve as informative indicators of genomic instability and disease progression, and offer valuable insights for future diagnostic and therapeutic strategies.

The success of Assisted Reproductive Technologies (ART), such as IVF and ICSI, relies heavily on the health of the oocyte, with abnormalities in oocyte morphology often leading to ART failure. The zona pellucida (ZP), an extracellular matrix surrounding the oocyte, plays a crucial role in sperm-egg recognition, species-specific fertilization, and protecting the embryo until implantation. This article investigates the impact of single nucleotide polymorphisms (SNPs) in the genes encoding ZP glycoproteins (hZP1, hZP2, hZP3, and hZP4) on fertility. Through a comprehensive meta-analysis of existing data, we identified 47 SNPs in hZP1, 17 in hZP2, 8 in hZP3, and 2 in hZP4 from female patients undergoing infertility treatment. Most of these SNPs are localized within the zona domain, which is crucial for the polymerization and structural integrity of the ZP. Functional predictions, based on in silico tools, suggest that these SNPs lead to impaired ZP glycoprotein secretion, crosslinking, and fibril formation; resulting in conditions like empty follicle syndrome (EFS) or oocytes with a thin or absent ZP. These deficiencies could significantly affect oocyte viability and reduce ART success rates. It could also affect folliculogenesis. Our results highlight the importance of genetic screening in women experiencing ART failure, especially those with ZP abnormalities. Additionally, the absence of reported SNPs in the N-terminal domain of ZP2 which is crucial for sperm interaction, suggests a potential area for further investigation, particularly in morphologically normal oocytes that may harbor undetected SNPs.

Epilepsy is a multifaceted and heterogenous neurological disorder that affects an estimated 70 million people worldwide and is identified by recurrent or unprovoked seizure activity. Although there have been advances in pharmacotherapeutic treatments, approximately one-third of patients with epilepsy remain drug resistant, highlighting the need for personalised and mechanism-based strategies. Neurogenetic biomarkers are emerging as valuable instruments for translating the genetic findings to the bedside and may provide new opportunities within a more precise treatment paradigm in epilepsy. Neurogenetic biomarkers include single-nucleotide polymorphisms (SNPs), copy number variants (CNVs), and mutations in disease-specific genes that inform our knowledge about the genetic architecture of seizure susceptibility, seizure progression and therapeutic response. The main genes, such as SCN1A, KCNQ2, GRIN2A, LGI1, GABRA1, and CHRNA4, impact neuronal excitability, ion channel dynamics, and synaptic interactions. Variations of mTOR signaling pathways (TSC1, TSC2, DEPDC5) and mutations in epigenetic regulators (MECP2, CDKL5) implicated a multilayered structure in the mechanistic underpinnings of epileptogenesis. Neurogenetic biomarkers are increasingly relevant to clinical practice for refining diagnosis, predicting seizure onset, guiding drug selection, and determining surgical intervention. The integration of neurogenetic sampling with neuroimaging, electrophysiological, inflammatory, and molecular signatures can improve diagnostic precision and provide an evidence-based framework towards therapeutic stratification. Although challenges remain-such as genetic heterogeneity, variant interpretation, cost barriers, and ethical considerations, advances in next-generation sequencing, pharmacogenomics, and artificial intelligence are rapidly transforming these limitations into opportunities. Neurogenetic biomarkers hold transformative potential to redefine epilepsy care, enabling earlier diagnosis, individualized therapy, and improved long-term outcomes. As the field advances, they are poised to shift epilepsy management from reactive to predictive, and from generalized to precision-driven, initiating a new era of neurology.

Methylglyoxal (MGO) is a highly reactive metabolite formed from glycolysis that can form advanced glycation endproducts (AGEs) on proteins and DNA. It has been well established that MGO induces DNA double strand breaks as a result of modifications on deoxyguanosine residues. However, recent studies shed new light on the genotoxic properties of MGO by its ability to cause chromosomal mis-segregation events, and other forms of chromosomal instability. These outcomes open a new avenue in which protein modifications, rather than DNA modifications, result in DNA damage. Herein, we present several hypotheses on how modification of proteins by MGO might cause these chromosome mis-segregation events based on identified protein modification sites from proteomic studies. These include various cell cycle proteins, such as those involved in sister chromatid cohesion, centrosome formation and histone proteins. Overall, recent studies implicate MGO in whole chromosome loss events, amongst other chromosomal instability events, suggesting it as a key player in cancer development and progression.

The FANCM gene is involved in the Fanconi Anemia (FA) DNA repair pathway. Although germline biallelic pathogenic variants in genes of this pathway cause the recessive FA syndrome, the role of FANCM in FA or FA-like has been questioned. Biallelic FANCM protein truncating variants (PTVs) have been primarily linked to infertility and cancer, suggesting the gene causes a clinically distinct phenotype. Four literature databases were systematically searched from inception to June 2024 to identify published articles describing individuals carrying biallelic PTVs in FANCM. Twenty articles describing 40 carriers of biallelic FANCM PTVs were identified. We established genotype-phenotype correlations and found that women carrying biallelic combinations of the C-terminal p.Gln1701* and p.Gly1906Alafs*12 PTVs showed infertility, chromosome fragility, breast cancer, and chemotoxicity. Men carrying the same PTVs combinations showed infertility only. Carriers of biallelic combinations including a single N-terminal PTV showed chromosome fragility, infertility, and early onset breast cancer and/or squamous cell carcinoma, and pediatric hematological cancers, often associated with severe chemotoxicity. Our findings indicate that FANCM biallelic PTVs may cause a novel recessive syndrome which is distinct from FA and characterized by infertility, chromosome fragility, cancer and chemotoxicity. While infertility is always observed, the severity of chromosome fragility, cancer predisposition and chemotoxicity seem to depend on FANCM PTVs position and the sex of the carrier. Larger analyses are warranted to consolidate these findings.

Non-coding RNAs (ncRNAs) have redefined the complexity of gene regulation, with the long non-coding (lncRNA) GAS5/miR-21 axis emerging as a critical determinant of cell fate across diverse pathological contexts. This review examines the molecular mechanisms by which GAS5 regulates miR-21 activity, thereby restoring tumor suppressor networks and controlling key pathways, including the PI3K/AKT, MAPK/ERK, and Wnt/β-catenin pathways. We detail how dysregulation of this axis fuels cancer progression, metastasis, therapy resistance, fibrosis, cardiovascular diseases, osteoporosis, osteoarthritis, and autoimmune conditions like systemic lupus erythematosus. Beyond its role as a master regulator of apoptosis, proliferation, and EMT, the GAS5/miR-21 interaction holds immense promise as a therapeutic target and a liquid biopsy biomarker. However, clinical translation demands solutions to major challenges, including RNA delivery barriers, context-dependent effects, and adaptive resistance. Leveraging multi-omics integration, gene-editing technologies, and personalized RNA therapeutics will be pivotal to overcoming these obstacles. By critically integrating current knowledge and outlining future directions, this review positions the GAS5/miR-21 axis at the forefront of next-generation ncRNA therapeutics. Harnessing its full potential could not only revolutionize treatment paradigms but also transform our understanding of RNA-driven disease networks.

Neutrophil extracellular traps (NETs) and the process of NETosis have emerged as critical participants in various pathological conditions. Resveratrol, a natural polyphenol found in several plants, has received significant attention due to its potential therapeutic properties. The purpose of this review is to investigate how resveratrol affects NETs and NETosis. The molecular mechanisms underlying NET formation and its role in disease pathogenesis are discussed, highlighting the involvement of various cellular and molecular factors. Moreover, the effects of resveratrol on NET formation, release, and stability are reported, focusing on its potential as a modulator of NET-associated diseases. Studies investigating the effect of resveratrol on NETosis in different disease models, including lung injury, COVID-19, cancer, and hepatic ischemia-reperfusion injury, are also summarized. Furthermore, the potential mechanisms through which resveratrol exerts its effects on NETosis, including anti-inflammatory, antioxidant, and immunomodulatory properties, are elucidated. The review also addresses the challenges and future perspectives in the field, emphasizing the need for further research to fully understand the therapeutic potential of resveratrol in targeting NET-associated disorders. Generally, this review provides a comprehensive analysis of the impact of resveratrol on NETs and NETosis, shedding light on its potential as a therapeutic intervention in various pathological conditions characterized by excessive NET formation. However, further research is essential to clarify the detailed mechanisms through which resveratrol exerts its effects on NETosis and to determine optimal dosages and treatment procedures.

The KRAS protein is a GTPase that plays a role in the MAPK/ERK signaling pathway and KRAS is one of the most frequently mutated proto-oncogenes in malignant neoplasms, including aggressive tumors such as lung, pancreatic, and colorectal cancer. Mutations in KRAS, previously considered oncogenic drivers and hallmarks of cancer, have been observed at a high frequency in benign sporadic tumors, including those with negligible potential for malignant transformation. In line with that, KRAS mutations have recently been shown to be highly prevalent in adenomatoid odontogenic tumor (AOT). In the present paper, we review the spectrum of KRAS mutations reported in AOT to date and discuss the context dependence of KRAS oncogenicity. KRAS p.G12V and p.G12R mutations have been reported in approximately 70 % of AOT cases. The fact that the same spectrum of KRAS mutations is found in tumors with diverse clinical behavior reinforces the tissue and context specificity of KRAS mutation effects. Genome-wide-based future studies may provide clarification on the molecular pathogenesis of the KRAS wild-type cases, and could potentially unravel additional genetic events in mutation-positive cases. In this scenario, the clarification of the molecular pathogenesis of AOT, a benign tumor of indolent behavior, sheds light into how KRAS oncogenic mutations exert distinct effects depending on the biological context.

Rett syndrome was first described over 50 years ago as an unusual clinical entity. Mutations in the X-linked MECP2 gene are the primary causes of Rett syndrome. The unstructured MeCP2 protein adopts various functional conformations, complicating its study. Researchers have investigated the pathogenicity and regulation of MECP2 through mechanisms such as apoptosis, mitophagy, the PI3K/AKT/mTOR pathway, BMP signaling, NF-kB, STAT3, and the Wnt/β-catenin pathway. These mechanisms have not been reviewed in such detail before. Summarizing these pathways is essential for facilitating further exploration by researchers; therefore, we have comprehensively summarized these pathways.

Trichothiodystrophy (TTD) is a rare hereditary disease characterized by brittle, sulphur deficient hair associated with a wide and varied spectrum of clinical features which include skin alterations, neurodevelopmental defects, and immune dysfunction. The presence of hypersensitivity to UV light defines the two main forms of TTD: photosensitive (PS-TTD) and non-photosensitive (NPS-TTD). The disease arises from mutations in a variety of genes involved in different biological processes. Affected processes include DNA repair, transcription as well as translation. This review provides the latest vision of TTD: from up-to-date mutational spectra and genotype-phenotype relationships to our current understanding of the pathogenic mechanisms that underlie the complex etiology of this multi-faceted disease.

The deficiency in breast cancer associated proteins 1 and 2 (BRCA1 and 2) causes an early and more frequent onset of tumor genesis and progression. Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively toxic towards BRCA1 and 2-deficient tumors, sparing the healthy cells from patients from side effects. In BRCA1 and 2 deficient tumors, PARPi-mediated cell death is characterized by the augmentation of replication stress (RS) and chromosome instability (CIN) including micronuclei (MN) accumulation, a source of swift genomic rearrangements. PARPi also cause resistance to treatments which indicates the need of treatment alternatives. In this review, we discuss potential options that, similarly to PARPi, selectively kill BRCA1 and/or 2 deficient tumors. Remarkably, while many of those alternatives also upregulate MN and other CIN variables, others cause a RS-independent and MN-independent cell killing. This is the case of the inhibitors of Rho-kinase (ROCK) and, potentially, mitotic kinase Polo like kinase 1 (PLK1). Such a mode of cell killing could be advantageous if attempting to either prevent or postpone the rise of resistance clones in the tumor population that survives the treatment.