Search Results (32)

Epigenetic mechanisms, including DNA methylation and hydroxymethylation, contribute to inflammation, cardiac remodelling and progression of heart failure. Ten–Eleven Translocation (TET) dioxygenases are key regulators of these processes, but the impact of statins on TET proteins in human heart failure is not well characterised. We investigated how statin therapy relates to TET1, TET2 and TET3 expression in circulating immune cells in heart failure with reduced ejection fraction (HFrEF). In this cross-sectional study, 106 patients with HFrEF were enrolled; 84 were receiving statins and 22 were not. Intracellular TET1/2/3 protein levels were measured by multiparameter flow cytometry in granulocytes, monocytes and lymphocytes, and clinical and laboratory characteristics were compared between groups. Statin-treated patients had lower NT-proBNP concentrations and lower neutrophil, lymphocyte and monocyte counts, and more often received guideline-directed medical therapy. Statin therapy was associated with a distinct TET expression profile, characterised by higher TET1 and TET3 indices in monocytes and lymphocytes and lower TET2 indices in granulocytes and monocytes. This pattern is compatible with a distinct immune-cell TET expression profile aligned with the anti-inflammatory and reparative profile attributed to statins, and the course of disease. These associations do not establish causality and require prospective validation. TET proteins may form part of an epigenetic signature associated with statin treatment in heart failure and warrant further study as potential biomarkers in larger, prospective cohorts. Full article

Multiple sclerosis (MS) pathogenesis involves not only immune-mediated myelin injury but also glial responses. We examined how three charge isomers of myelin basic protein (MBP)—native (C1), phosphorylated (C4), and citrullinated (C8)—modulate rat astrocytes. Cytokines were quantified and grouped (pro/anti-inflammatory, chemotactic, neurotrophic, angiogenic, tissue remodeling), and regulatory markers assessed. C1 strongly upregulated the lipid-sensing receptor LXR, and reduced global DNA methylation; C4 moderately enhanced LXR; C8 failed to activate LXR or alter methylation. Functionally, C1 attenuated IL-1β, IL-6 and GM-CSF while increasing IL-10 and certain chemokines. C4 elicited an intermediate pattern, inducing CX3CL1 (fractalkine), CCL20, VEGF-A and TIMP-1 with minor effects on classical cytokines. In contrast, C8 triggered a robust pro-inflammatory phenotype, increasing IL-1α/β, TNF-α and GM-CSF, with higher IL-10, fractalkine, CCL20, VEGF-A and TIMP-1. All isomers suppressed IFN-γ, IL-4 and CNTF. These data indicate that MBP post-translational modifications drive distinct astrocyte phenotypes through integrated cytokine, metabolic and epigenetic pathways: C1 favors immune regulation and repair, C4 blends inflammatory and reparative cues, and C8 amplifies neuroinflammation. Understanding how modified MBP shapes astrocyte behavior provides mechanistic insight into lesion evolution in MS and suggests astrocyte-directed strategies to modulate neuroinflammation and promote remyelination. Full article

Zinc oxide nanoparticles (ZnO NPs) are increasingly applied in medicine, cosmetics, and environmental technologies, yet their interactions with blood cells remain poorly understood, raising cross-species safety concerns. Using frog (nucleated) and human (anucleate) erythrocytes as comparative models, we show that cellular architecture fundamentally shapes responses to ZnO NPs exposure. Human erythrocytes exhibited a dose-dependent progression from membrane deformation to eryptosis and hemolysis, reflecting the pronounced vulnerability of anucleate cells. In contrast, frog erythrocytes sustained nuclear DNA damage while largely preserving membrane integrity, highlighting the protective or reparative role of the nucleus. Molecular docking revealed energetically favorable interactions of ZnO NPs with ERα-LBD and DNA (ΔG = −4.28 and −5.68 kcal/mol, respectively), while quantum chemical analyses indicated electron-accepting properties and a narrow HOMO–LUMO gap, suggesting efficient macromolecular interactions and intracellular ROS generation. Together, these findings demonstrate that the presence of a nucleus shifts the primary target of nanoparticle toxicity from membrane to genome, providing novel mechanistic insights. This comparative study offers a robust framework for understanding nanomaterial reactivity across taxa and informs One Health-oriented risk assessments. Full article

The advancement of Vital Pulp Therapy (VPT) in dentistry has shown remarkable progress, with a focus on innovative materials and scaffolds to facilitate reparative dentin formation and tissue regeneration. A comprehensive search strategy was performed across PubMed, Scopus, and Web of Science using keywords such as “vital pulp therapy”, “biomaterials”, “dentin regeneration”, and “growth factors”, with filters for English language studies published in the last 10 years. The inclusion criteria focused on in vitro, in vivo, and clinical studies evaluating traditional and next-generation biomaterials for pulp capping and tissue regeneration. Due to the limitations of calcium-based cements in tissue regeneration, next-generation biomaterials like gelatin, chitosan, alginate, platelet-rich fibrins (PRF), demineralized dentin matrix (DDM), self-assembling peptides, and DNA-based nanomaterials were explored for their enhanced biocompatibility, antibacterial properties, and regenerative potential. These biomaterials hold great potential in enhancing VPT outcomes, but further research is required to understand their efficacy and impact on dentin reparative properties. This review explores the mechanisms and properties of biomaterials in dentin tissue regeneration, emphasizing key features that enhance tissue regeneration. These features include biomaterial sources, physicochemical properties, and biological characteristics that support cells and functions. The discussion also covers the biomaterials’ capability to encapsulate growth factors for dentin repair. The development of innovative biomaterials and next-generation scaffold materials presents exciting opportunities for advancing VPT in dentistry, with the potential to improve clinical outcomes and promote tissue regeneration in a safe and effective manner. Full article

A cross-disciplinary rapid scoping review was carried out, generally following the PRISMA-SCR protocol to examine historical racial and caste-based discrimination as structural determinants of health disparities in the 21st century. We selected 48 peer-reviewed full-text articles available from the University of Memphis Libraries database search, focusing on three selected case-study countries: the United States (US), Canada, and Nepal. The authors read each article, extracted highlights, and tabulated the thematic contents on structural health disparities attributed to racism or casteism. The results link historical racism/casteism to health disparities occurring in Black and African American, Native American, and other ethnic groups in the US; in Indigenous peoples and other visible minorities in Canada; and in the Dalits of Nepal, a population racialized by caste, grounded on at least four foundational theories explaining structural determinants of health disparities. The evidence from the literature indicates that genetic variations and biological differences (e.g., disease prevalence) occur within and between races/castes for various reasons (e.g., random gene mutations, geographic isolation, and endogamy). However, historical races/castes as socio-cultural constructs have no inherently exclusive basis of biological differences. Disregarding genetic discrimination based on pseudo-scientific theories, genetic testing is a valuable scientific means to achieve the better health of the populations. Epigenetic changes (e.g., weathering—the early aging of racialized women) due to the DNA methylation of genes among racialized populations are markers of intergenerational trauma due to racial/caste discrimination. Likewise, chronic stresses resulting from intergenerational racial/caste discrimination cause an “allostatic load”, characterized by an imbalance of neuronal and hormonal dysfunction, leading to occurrences of chronic diseases (e.g., hypertension, diabetes, and mental health) at disproportionate rates among racialized populations. Major areas identified for reparative policy changes and interventions for eliminating the health impacts of racism/casteism include areas of issues on health disparity research, organizational structures, programs and processes, racial justice in population health, cultural trauma, equitable healthcare system, and genetic discrimination. Full article

Ionizing radiation-induced damage in cancer and normal cells leads to apoptosis and cell death, through the intracellular oxidative stress, DNA damage and disorders of their metabolism. Irradiation doses that do not lead to the death of tumor cells can result in the emergence of radioresistant clones of these cells due to the rearrangement of metabolism and the emergence of new mutations, including those in the genes responsible for DNA repair. The search for the substances capable of modulating the functioning of the tumor cell repair system is an urgent task. Here we analyzed the effect of cerium(III) fluoride nanoparticles (CeF₃ NPs) on normal (human mesenchymal stem cells–hMSC) and cancer (MCF-7 line) human cells after X-ray radiation. CeF₃ NPs effectively prevent the formation of hydrogen peroxide and hydroxyl radicals in an irradiated aqueous solution, showing pronounced antioxidant properties. CeF₃ NPs are able to protect hMSC from radiation-induced proliferation arrest, increasing their viability and mitochondrial membrane potential, and, conversely, inducing the cell death of MCF-7 cancer cells, causing radiation-induced mitochondrial hyperpolarization. CeF₃ NPs provided a significant decrease in the number of double-strand breaks (DSBs) in hMSC, while in MCF-7 cells the number of γ-H2AX foci dramatically increased in the presence of CeF₃ 4 h after irradiation. In the presence of CeF₃ NPs, there was a tendency to modulate the expression of most analyzed genes associated with the development of intracellular oxidative stress, cell redox status and the DNA-repair system after X-ray irradiation. Cerium-containing nanoparticles are capable of providing selective protection of hMSC from radiation-induced injuries and are considered as a platform for the development of promising clinical radioprotectors. Full article

The ends of human chromosomes are defended by DNA–protein complexes named telomeres, which inhibit the chromosomes from fusing with each other and from being known as a double-strand break by DNA reparation proteins. Telomere length is a marker of biological aging, and disfunction of telomeres is related to age-related syndromes. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Telomere length has been proven to be positively linked with nutritional status in human and animal scientific research as several nutrients influence it through mechanisms that imitate their function in cellular roles including oxidative stress and inflammation. Data reported in this article support the idea that following a low-in-fat and rich-plant polyphenols food diet seems to be able to slow down the shortening of telomeres. Full article

(1) Background: The human MutS homolog, hMSH2, is known to be involved in DNA mismatch repair and is responsible for maintaining the stability of the genome. When DNA damage occurs, MSH2 promotes cell apoptosis via the regulation of ATR/Chk2/p53 signal transduction, and MSH2 deficiency is also related to accelerated telomere shortening in humans. MSH2 missense mutations are involved in a defective DNA reparation process, and it can be implied in carcinogenesis, as it is already involved in well-known cancer-related syndromes such as Lynch syndrome. Human MSH6, which stands for mutS homolog 6, is a member of the MMR family that is responsible for the repair of post-replicative mismatched DNA bases. It is also one of the proteins with gene mutations that are associated with a high risk of developing Lynch syndrome, leading to a large series of tumors. (2) Methods: Patients and their clinical and pathological features were selected from the database of the project GRAPHSENSGASTROINTES and used accordingly, with ethics committee approval no. 32647/2018 awarded by the County Emergency Hospital from Targu-Mures. Analyses were conducted on whole blood, saliva, urine, and tumoral tissue samples using a stochastic method with stochastic microsensors. (3) Results: The results obtained using stochastic sensors were correlated with a series of macroscopic and microscopic pathological features for each sample type. Criteria or relationships were established for tumor location, vascular and perineural invasions, lymph node metastases, the presence of tumor deposits, and the presence of a mucus compound in the tumor mass. (4) Conclusions: The correlation between the concentrations of MSH2 in the four types of samples and the pathological features allowed for the fast characterization of a tumor, which can help surgeons and oncologists choose personalized treatments. Also, the colorectal tumor location was correlated with the concentration of MSH2 in whole blood, urine, and saliva. MSH6, which stands for mutS homolog 6, is not only useful in immunohistochemistry but in pathology practice as well. In this paper, the relationships between MSH6 levels in four biological fluids—whole blood, saliva, urine, and tissues—and tumor locations among the colorectal area, gross features, presence of a mucinous compound, molecular subtype, stroma features, and vascular invasions are presented. Full article

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor therapy by the generation of excessive highly cytotoxic ROS. However, the poor water solubility of the photosensitizer, reactive oxygen species (ROS) depleting by high concentrations of glutathione (GSH) in the tumor microenvironment and the activation of DNA repair pathways to combat the oxidative damage, will significantly limit the therapeutic effect of PDT. Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Ola nanoparticles (NPs)) together with DSPE-PEG₂₀₀₀ and PARP inhibitor Olaparib (Ola). The CSP/Ola NPs features excellent physiological stability, efficient loading capacity, much better cellular uptake behavior and photodynamic performance. Specifically, the nanoplatform could induce elevated intracellular ROS levels upon the in situ generation of ROS during PDT, and decrease ROS consumption by reducing intracellular GSH level. Moreover, the CSP/Ola NPs could amplify DNA damage by released Cb and inhibit the activation of Poly(ADP-ribose) polymerase (PARP), promote the upregulation of γ-H2AX, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. In vitro investigations revealed that CSP/Ola NPs showed excellent phototoxicity and the IC₅₀ values of CSP/Ola NPs against MDA-MB-231 breast cancer cells were as low as 0.05–01 μM after PDT. As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair. Full article

The intraspecific genetic diversity of freshwater fish inhabiting hydro-systems of the macrogeographic area spreading from the Black to Baltic Seas requires comprehensive investigation from fundamental and practical perspectives. The current study focused on the involvement of the mtDNA ATP6 region in the adaptability and microevolution of Perca fluviatilis within phylogeographic and anthropogenic contexts. We sequenced a 627 bp fragment encompassing the ATP6 region and used it for genetic analysis of 193 perch caught in Latvia, Lithuania, Belarus, and Ukraine, representing natural and anthropogenically impacted populations. We evaluated patterns of intraspecific genetic diversity in the ATP6 region and phylogeographic trends within the studied area compared with previously established D-loop trends. Evaluation of ATP6 coding sequence variability revealed that among 13 newly detected haplotypes, only two were caused by non-synonymous substitutions of amino acids of the protein. PCoA revealed three genetic groups (I–III) based on the ATP6 region that encompassed four previously described genetic groups established based on the mtDNA D-loop. The two mtDNA regions (D-loop and ATP6) have microevolved at least partially independently. Prolonged anthropogenic impacts may generate new point mutations at the ATP6 locus, but this phenomenon could be mainly concealed by natural selection and reparation processes. Full article

We are not entirely able to understand, assess, and modulate the functioning of the immune system in clinical situations that lead to a systemic inflammatory response. In the search for diagnostic and treatment strategies (which are still far from perfect), it became very important to study the pathogenesis and participation of endogenous inflammation mediators. This study attempts to more precisely establish the role of neutrophils in individual phenomena occurring during an inflammatory and anti-inflammatory reaction, taking into account their cidal, immunoregulatory, and reparative abilities. Pro- and anticoagulatory properties of endothelium in systemic inflammatory response syndrome (SIRS) are emphasised, along with the resulting clinical implications (the application of immunotherapy using mesenchymal stem/stromal cells (MSCs) or IL-6 antagonists in sepsis and COVID-19 treatment, among others). Special attention is paid to reactive oxygen species (ROS), produced by neutrophils activated during “respiratory burst” in the course of SIRS; the protective and pathogenic role of these endogenous mediators is highlighted. Moreover, clinically useful biomarkers of SIRS (neutrophil extracellular traps, cell-free DNA, DAMP, TREMs, NGAL, miRNA, selected cytokines, ROS, and recognised markers of endothelial damage from the group of adhesins by means of immunohistochemical techniques) related to the neutrophils are presented, and their role in the diagnosing and forecasting of sepsis, burn disease, and COVID-19 is emphasised. Finally, examples of immunomodulation of sepsis and antioxidative thermal injury therapy are presented. Full article

The problem of low-dose irradiation has been discussed in the scientific literature for several decades, but it is impossible to come to a generally accepted conclusion about the presence of any specific features of low-dose irradiation in contrast to acute irradiation. We were interested in the effect of low doses of UV radiation on the physiological processes, including repair processes in cells of the yeast Saccharomyces cerevisiae, in contrast to high doses of radiation. Cells utilize excision repair and DNA damage tolerance pathways without significant delay of the cell cycle to address low levels of DNA damage (such as spontaneous base lesions). For genotoxic agents, there is a dose threshold below which checkpoint activation is minimal despite the measurable activity of the DNA repair pathways. Here we report that at ultra-low levels of DNA damage, the role of the error-free branch of post-replicative repair in protection against induced mutagenesis is key. However, with an increase in the levels of DNA damage, the role of the error-free repair branch is rapidly decreasing. We demonstrate that with an increase in the amount of DNA damage from ultra-small to high, asf1Δ-specific mutagenesis decreases catastrophically. A similar dependence is observed for mutants of gene-encoding subunits of the NuB4 complex. Elevated levels of dNTPs caused by the inactivation of the SML1 gene are responsible for high spontaneous reparative mutagenesis. The Rad53 kinase plays a key role in reparative UV mutagenesis at high doses, as well as in spontaneous repair mutagenesis at ultra-low DNA damage levels. Full article

Within regenerative endodontics, exciting opportunities exist for the development of next-generation targeted biomaterials that harness epigenetic machinery, including microRNAs (miRNAs), histone acetylation, and DNA methylation, which are used to control pulpitis and to stimulate repair. Although histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) induce mineralisation in dental pulp cell (DPC) populations, their interaction with miRNAs during DPC mineralisation is not known. Here, small RNA sequencing and bioinformatic analysis were used to establish a miRNA expression profile for mineralising DPCs in culture. Additionally, the effects of a HDACi, suberoylanilide hydroxamic acid (SAHA), and a DNMTi, 5-aza-2′-deoxycytidine (5-AZA-CdR), on miRNA expression, as well as DPC mineralisation and proliferation, were analysed. Both inhibitors increased mineralisation. However, they reduced cell growth. Epigenetically-enhanced mineralisation was accompanied by widespread changes in miRNA expression. Bioinformatic analysis identified many differentially expressed mature miRNAs that were suggested to have roles in mineralisation and stem cell differentiation, including regulation of the Wnt and MAPK pathways. Selected candidate miRNAs were demonstrated by qRT-PCR to be differentially regulated at various time points in mineralising DPC cultures treated with SAHA or 5-AZA-CdR. These data validated the RNA sequencing analysis and highlighted an increased and dynamic interaction between miRNA and epigenetic modifiers during the DPC reparative processes. Full article

Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed that the exposure of mitochondria to cisplatin increased the level of lipid peroxidation products in the in vitro experiment. Cisplatin caused strong damage to renal mtDNA, both in the in vivo and in vitro experiments. Cisplatin injections induced oxidative stress by depleting renal antioxidants at the transcriptome level but did not increase the rate of H₂O₂ production in isolated mitochondria. Methylene blue, on the contrary, induced mitochondrial H₂O₂ production. We supposed that methylene blue-induced H₂O₂ production led to activation of the Nrf2/ARE signaling pathway. The consequences of activation of this signaling pathway were manifested in an increase in the expression of some antioxidant genes, which likely caused a decrease in the amount of mtDNA damage. Methylene blue treatment induced an increase in the expression of genes that were involved in the base excision repair (BER) pathway: the main pathway for mtDNA reparation. It is known that the expression of these genes can also be regulated by the Nrf2/ARE signaling pathway. We can assume that the protective effect of methylene blue is related to the activation of Nrf2/ARE signaling pathways, which can activate the expression of genes related to antioxidant defense and mtDNA reparation. Thus, the protection of kidney mitochondria from cisplatin-induced damage using methylene blue can significantly expand its application in medicine. Full article

DNA polymerase β (Polβ) expression is essential for the cell’s response to DNA damage that occurs during natural cellular processes. Polβ is considered the main reparative DNA polymerase, whose role is to fill the DNA gaps arising in the base excision repair pathway. Mutations in Polβ can lead to cancer, neurodegenerative diseases, or premature aging. Many single-nucleotide polymorphisms have been identified in the POLB gene, but the consequences of these polymorphisms are not always clear. It is known that some polymorphic variants in the Polβ sequence reduce the efficiency of DNA repair, thereby raising the frequency of mutations in the genome. In the current work, we studied two polymorphic variants (G118V and R149I separately) of human Polβ that affect its DNA-binding region. It was found that each amino acid substitution alters Polβ’s affinity for gapped DNA. Each polymorphic variant also weakens its binding affinity for dATP. The G118V variant was found to greatly affect Polβ’s ability to fill gapped DNA and slowed the catalytic rate as compared to the wild-type enzyme. Thus, these polymorphic variants seem to decrease the ability of Polβ to maintain base excision repair efficiency. Full article