Tiny animals known as tardigrades use a combination of DNA repair machinery and a novel protein to mend their genome after intense ionizing radiation.

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide\'s expediency in treating obesity and its associated complications.

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.
Izloženost ionizirajućem zračenju čak i pri niskim razinama može pridonijeti nastanku oštećenja oka. Međutim, osnovni molekulski mehanizmi i dalje nisu potpuno razjašnjeni. Cilj našega istraživanja bio je ispuniti tu nedostajuću kariku primjenom sveobuhvatnog in silico pristupa problemu. U tu svrhu, pomoću genomskih baza podataka, portala i poslužitelja (Comparative Toxicogenomics Database, ToppGene Suite portal, Cytoscape, GeneMANIA i Metascape), identificirano je šest ključnih regulacijskih gena koji su povezani s oštećenjem oka prouzročenog ionizirajućim zračenjem (ATM, CRYAB, SIRT1, TGFB1, TREX1 i YAP1) i koji su svi bili u fizičkoj interakciji. Neke od identificiranih molekulskih funkcija odnosile su se na mehanizme popravka oštećenja DNA, a druge su bile uključene u vezanje proteina, enzimsku aktivnost, metaboličke procese i posttranslacijske modifikacije proteina. Biološki procesi uglavnom su bili povezani s odgovorom na oštećenje DNA, pogotovo sa signalnim putem p53. Uočena je i značajna uloga nekoliko miRNA, poput hsa-miR-183 i hsa-miR-589, u mehanizmima povezanima s oštećenjem oka prouzročenog ionizirajućim zračenjem. Osim toga, u ovom je istraživanju opisana korisna metoda za ispitivanje štetnih učinaka izloženosti zračenju.

Traditional medicine has used sage (Salvia officinalis L.) preparations for centuries to prevent and treat various inflammatory and oxidative stress-induced conditions. The aim of this in vitro study was to determine the bioactive properties of a sage leave extract obtained with environmentally friendly aqueous extraction and lyophilisation in primary human peripheral blood cells. To that end we measured the total phenolic and flavonoid content (TPC and TFC, respectively) with gas chromatography-mass spectrometry (GC-MS). Non-cytotoxic concentrations determined with the trypan blue assay were used to assess the antioxidant (DPPH, ABTS, and PAB assay), antigenotoxic (CBMN assay), immunomodulatory (IL-1β and TNF-α), and neuroprotective effects (AChE inhibition). The extract contained high TPC (162 mg GAE/g of dry extract) and TFC (39.47 mg QE/g of dry extract) concentrations, while β-thujone content was unexpectedly low (below 0.9 %). Strong radical-scavenging activity combined with glutathione reductase activation led to a decrease in basal and H2O2-induced oxidative stress and DNA damage. A decrease in TNF-α and increase in IL-1β levels suggest complex immunomodulatory response that could contribute to antioxidant and, together with mild AChE inhibition, neuroprotective effects. Overall, this study has demonstrated that aqueous sage leave extract reduces the levels of thujone, 1,8-cineole, pinene, and terpene ketones that could be toxic in high concentrations, while maintaining high concentrations of biologically active protective compounds which have a potential to prevent and/or treat inflammatory and oxidative stress-related conditions.
Salvia officinalis L. stoljećima se koristi u tradicionalnoj medicini za prevenciju i liječenje raznih upalnih i oksidacijskim stresom izazvanih poremećaja. U ovoj studiji željeli smo ekstrahirati kaduljino lišće korištenjem ekološki prihvatljivog, “zelenog” pristupa vodenom ekstrakcijom i liofilizacijom te odrediti njegova bioaktivna svojstva u primarnim ljudskim perifernim krvnim stanicama. Ukupni sadržaj fenola i flavonoida i GC-MS korišteni su za karakterizaciju ekstrakta. Necitotoksične koncentracije, određene metodom bojenja s bojom tripan plavo, analizirane su za procjenu antioksidacijskih (DPPH, ABTS i PAB test), antigenotoksičnih (CBMN test), imunomodulacijskih (IL-1β i TNF-α) i neuroprotektivnih učinaka (AChE inhibicija). Ekstrakt je sadržavao visoku koncentraciju ukupnih fenola (162 mg GAE/g liofilizata) i flavonoida (39,47 mg QE/g liofilizata), dok je sadržaj β-tujona bio neočekivano nizak (niži od 0,9 %). Snažna aktivnost hvatanja radikala u kombinaciji s aktivacijom glutation reduktaze dovela je do smanjenja bazalnog i H2O2 induciranog oksidacijskog stresa i oštećenja DNA. Smanjenje TNF-α i povišenje razine IL-1β sugeriraju kompleksan imunomodulatorni odgovor koji bi mogao pridonijeti antioksidacijskim i, zajedno s blagom inhibicijom AChE, neuroprotektivnim učincima. Sveukupno, ova je studija pokazala da vodena ekstrakcija kaduljina lišća smanjuje toksične spojeve kao što su tujon, 1,8-cineol, pinen i terpenski ketoni, a održava visoku koncentraciju biološki aktivnih zaštitnih spojeva u ekstraktu, što bi moglo imati potencijal za prevenciju i/ili liječenje oksidacijskih i upalnih poremećaja.

This work examines the capacity of Naringin and Rutin to influence the DNA damage response (DDR) pathway by investigating their interactions with key DDR proteins, including PARP-1, ATM, ATR, CHK1, and WEE1. Through a combination of in silico molecular docking and in vitro evaluations, we investigated the cytotoxic and genotoxic effects of these compounds on MDA-MB-231 cells, comparing them to normal human fibroblast cells (2DD) and quiescent fibroblast cells (QFC). The research found that Naringin and Rutin had strong affinities for DDR pathway proteins, indicating their capacity to specifically regulate DDR pathways in cancer cells. Both compounds exhibited preferential cytotoxicity towards cancer cells while preserving the vitality of normal 2DD fibroblast cells, as demonstrated by cytotoxicity experiments conducted at a dose of 10 µM. The comet experiments performed particularly on QFC cells provide valuable information on the genotoxic impact of Naringin and Rutin, highlighting the targeted initiation of DNA damage in cancer cells. The need to use precise cell models to appropriately evaluate toxicity and genotoxicity is emphasized by this discrepancy. In addition, ADMET and drug-likeness investigations have emphasized the pharmacological potential of these compounds; however, they have also pointed out the necessity for optimization to improve their therapeutic profiles. The antioxidant capabilities of Naringin and Rutin were assessed using DPPH and free radical scavenging assays at a concentration of 10 µM. The results confirmed that both compounds have a role in reducing oxidative stress, hence enhancing their anticancer effects. Overall, Naringin and Rutin show potential as medicines for modulating the DDR in cancer treatment. They exhibit selective toxicity towards cancer cells while sparing normal cells and possess strong antioxidant properties. This analysis enhances our understanding of the therapeutic uses of natural chemicals in cancer treatment, supporting the need for more research on their mechanisms of action and clinical effectiveness.

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

BACKGROUND: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling.
METHODS: Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis.
RESULTS: Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified.
CONCLUSIONS: Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.

Naphthalene (NAP) was frequently detected in polycyclic aromatic hydrocarbons (PAHs)-contaminated soil, and its residues may pose an eco-toxicological threat to soil organisms. The toxic effects of NAP were closely tied to phenolic and quinone metabolites in biological metabolism. However, the present knowledge concerning the eco-toxicological impacts of NAP metabolites at the animal level is scanty. Here, we assessed the differences in the eco-toxicological responses of Eisenia fetida (E. fetida) in NAP, 1-naphthol (1-NAO) or 1,4-naphthoquinone (1,4-NQ) contaminated soils. NAP, 1-NAO, and 1,4-NQ exposure triggered the onset of oxidative stress as evidenced by the destruction of the antioxidant enzyme system. The lipid peroxidation and DNA oxidative damage levels induced by 1-NAO and 1,4-NQ were higher than those of NAP. The elevation of DNA damage varied considerably depending on differences in oxidative stress and the direct mode of action of NAP or its metabolites with DNA. All three toxicants induced different degrees of physiological damage to the body wall, but only 1, 4-NQ caused the shedding of intestinal epithelial cells. The integrated biomarker response for different exposure times illustrated that the comprehensive toxicity at the animal level was 1,4-NQ > 1-NAO > NAP, and the time-dependent trends of oxidative stress responses induced by the three toxicants were similar. At the initial stage, the antioxidant system of E. fetida responded positively to the provocation, but the ability of E. fetida to resist stimulation decreased with the prolongation of time resulting in provocation oxidative damage. This study would provide new insights into the toxicological effects and biohazard of PAHs on soil animals.

Triple-negative breast cancer (TNBC) could benefit from PARP inhibitors (PARPi) for their frequent defective homologous recombination repair (HR). However, the efficacy of PARPi is limited by their lower bioavailability and high susceptibility to drug resistance, so it often needs to be combined with other treatments. Herein, polydopamine nanoparticles (PDMN) were constructed to load Olaparib (AZD) as two-channel therapeutic nanoplatforms. The PDMN has a homogeneous spherical structure around 100 nm and exhibits a good photothermal conversion efficiency of 62.4%. The obtained AZD-loaded nanoplatform (PDMN-AZD) showed enhanced antitumor effects through the combination of photothermal therapy (PTT) and PARPi. By western blot and flow cytometry, we found that PTT and PARPi could exert synergistic antitumor effects by further increasing DNA double-strand damage (DSBs) and enhancing HR defects. The strongest therapeutic effect of PDMN-AZD was observed in a BRCA-deficient mouse tumor model. In conclusion, the PDMN-AZD nanoplatform designed in this study demonstrated the effectiveness of PTT and PARPi for synergistic treatment of TNBC and preliminarily explained the mechanism.

子宫颈癌的发病率居女性生殖系统恶性肿瘤的首位，放疗是其主要的治疗方法之一。放疗抵抗是导致子宫颈癌治疗失败及预后不良的主要原因，亟待解决。完善放疗技术并探索理想的增敏方法以改善预后已成为近年来子宫颈癌放疗领域的研究热点。本文综述了子宫颈癌放疗抵抗机制及常用增敏方法的进展，主要归纳总结了放疗抵抗与DNA损伤修复、细胞周期、肿瘤乏氧、代谢异常等机制的关系，并重点阐述化疗药物、热疗、抗血管生成、影响DNA损伤修复治疗、药物递送系统等放疗增敏方法在子宫颈癌治疗中的应用，以期为子宫颈癌放疗研究提供新的思路和方向。.