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Genes & Diseases Sep 2024Protein lysine crotonylation (Kcr) is one conserved form of posttranslational modifications of proteins, which plays an important role in a series of cellular... (Review)
Review
Protein lysine crotonylation (Kcr) is one conserved form of posttranslational modifications of proteins, which plays an important role in a series of cellular physiological and pathological processes. Lysine ε-amino groups are the primary sites of such modification, resulting in four-carbon planar lysine crotonylation that is structurally and functionally distinct from the acetylation of these residues. High levels of Kcr modifications have been identified on both histone and non-histone proteins. The present review offers an update on the research progression regarding protein Kcr modifications in biomedical contexts and provides a discussion of the mechanisms whereby Kcr modification governs a range of biological processes. In addition, given the importance of protein Kcr modification in disease onset and progression, the potential viability of Kcr regulators as therapeutic targets is elucidated.
PubMed: 38957707
DOI: 10.1016/j.gendis.2023.06.029 -
The Science of the Total Environment Jun 2024The ionizing radiation (IR) represents a formidable challenge as an environmental factor to mitochondria, leading to disrupt cellular energy metabolism and posing health...
The ionizing radiation (IR) represents a formidable challenge as an environmental factor to mitochondria, leading to disrupt cellular energy metabolism and posing health risks. Although the deleterious impacts of IR on mitochondrial function are recognized, the specific molecular targets remain incompletely elucidated. In this study, HeLa cells subjected to γ-rays exhibited concomitant oxidative stress, mitochondrial structural alterations, and diminished ATP production capacity. The γ-rays induced a dose-dependent induction of mitochondrial fission, simultaneously manifested by an elevated S616/S637 phosphorylation ratio of the dynamin-related protein 1 (DRP1) and a reduction in the expression of the mitochondrial fusion protein mitofusin 2 (MFN2). Knockdown of DRP1 effectively mitigated γ-rays-induced mitochondrial network damage, implying that DRP1 phosphorylation may act as an effector of radiation-induced mitochondrial damage. The mitochondrial outer membrane protein voltage-dependent anion channel 1 (VDAC1) was identified as a crucial player in IR-induced mitochondrial damage. The VDAC1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), counteracts the excessive mitochondrial fission induced by γ-rays, consequently rebalancing the glycolytic and oxidative phosphorylation equilibrium. This metabolic shift was uncovered to enhance glycolytic capacity, thus fortifying cellular resilience and elevating the radiosensitivity of cancer cells. These findings elucidate the intricate regulatory mechanisms governing mitochondrial morphology under radiation response. It is anticipated that the development of targeted drugs directed against VDAC1 may hold promise in augmenting the sensitivity of tumor cells to radiotherapy and chemotherapy.
PubMed: 38955266
DOI: 10.1016/j.scitotenv.2024.174246 -
International Journal of Radiation... Jul 2024Radiation-induced alterations in gene expression show great promise for dose reconstruction and for severity prediction of acute health effects. Among several genes...
PURPOSE
Radiation-induced alterations in gene expression show great promise for dose reconstruction and for severity prediction of acute health effects. Among several genes explored as potential biomarkers, FDXR is widely used due to high upregulation in white blood cells following radiation exposure. Nonetheless, the absence of a standardized protocols for gene expression-based biodosimetry is a notable gap that warrants attention to enhance the accuracy, reproducibility and reliability. The objective of this study was to evaluate the sensitivity of transcriptional biodosimetry to differences in protocols used by different laboratories and establish guidelines for the calculation of calibration curve using FDXR expression data.
MATERIAL AND METHODS
Two sets of irradiated blood samples generated during RENEB exercise were used. The first included samples irradiated with known doses including: 0, 0.25, 0.5, 1, 2, 3 and 4 Gy. The second set consisted of three 'blind' samples irradiated with 1.8 Gy, 0.4 Gy and a sham-irradiated sample. After irradiation, samples were incubated at 37 °C over 24 h and sent to participating laboratories, where RNA isolation and FDXR expression analysis by qPCR were performed using sets of primers/probes and reference genes specific for each laboratory. Calibration curves based on FDXR expression data were generated using non-linear and linear regression and used for dose estimation of 'blind' samples.
RESULTS
Dose estimates for sham-irradiated sample (0.020-0.024 Gy) and sample irradiated with 0.4 Gy (0.369-0.381 Gy) showed remarkable consistency across all laboratories, closely approximating the true doses regardless variation in primers/probes and reference genes used. For sample irradiated with 1.8 Gy the dose estimates were less precise (1.198-2.011 Gy) but remained within an acceptable margin for triage within the context of high dose range.
CONCLUSION
Methodological differences in reference genes and primers/probes used for FDXR expression measurement do not have a significant impact on the dose estimates generated, provided that all reference genes performed as expected and the primers/probes target a similar set of transcript variants. The preferred method for constructing a calibration curve based on FDXR expression data involves employing linear regression to establish a function that describes the relationship between the logarithm of absorbed dose and FDXR ΔCt values. However, one should be careful with using non-irradiated sample data as these cannot be accurately represented on a logarithmic scale. A standard curve generated using this approach can give reliable dose estimations in a dose range from 50 mGy to 4 Gy at least.
PubMed: 38953870
DOI: 10.1080/09553002.2024.2373751 -
Cancer Immunology Research Jul 2024Antitumor immune responses are predominantly mediated by CD8+ cytotoxic T cells (CTLs). But immune-modulatory factors in the tumor microenvironment determine the...
Antitumor immune responses are predominantly mediated by CD8+ cytotoxic T cells (CTLs). But immune-modulatory factors in the tumor microenvironment determine the effectiveness of these responses. In this issue, Wei and colleagues report a new role for CTL-derived IL3 in stimulating basophilic granulocytes to produce IL4, which, in turn, activates, reprograms, and stabilizes CTLs. These findings stress the importance of the crosstalk between the innate and adaptive immune systems to elicit efficient antitumor immunity. See related article by Wei et al., p. 822 (3).
Topics: Humans; Granulocytes; Neoplasms; Animals; Tumor Microenvironment; T-Lymphocytes, Cytotoxic; Immunity, Cellular
PubMed: 38952273
DOI: 10.1158/2326-6066.CIR-24-0395 -
Nature Communications Jun 2024Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy to overcome immune evasion...
Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy to overcome immune evasion and to improve treatment response. However, clinical benefits of radiotherapy-immunotherapy combinations have been modest. Routine concomitant tumor-draining lymph node irradiation (DLN IR) might be the culprit. As crucial sites for generating anti-tumor immunity, DLNs are indispensable for the in situ vaccination effect of radiotherapy. Simultaneously, DLN sparing is often not feasible due to metastatic spread. Using murine models of metastatic disease in female mice, here we demonstrate that delayed (adjuvant), but not neoadjuvant, DLN IR overcomes the detrimental effect of concomitant DLN IR on the efficacy of radio-immunotherapy. Moreover, we identify IR-induced disruption of the CCR7-CCL19/CCL21 homing axis as a key mechanism for the detrimental effect of DLN IR. Our study proposes delayed DLN IR as a strategy to maximize the efficacy of radio-immunotherapy across different tumor types and disease stages.
Topics: Animals; Immune Checkpoint Inhibitors; Female; Mice; Lymph Nodes; Cell Line, Tumor; Immunotherapy; Mice, Inbred C57BL; Lymphatic Irradiation; Disease Models, Animal; Combined Modality Therapy; Humans; Receptors, CCR7; Neoplasm Metastasis
PubMed: 38951172
DOI: 10.1038/s41467-024-49873-y -
Journal of Veterinary Research Jun 2024This study focuses on perfluoroalkyl substance (PFAS) content in chickens' eggs and the livers of farm animals.
INTRODUCTION
This study focuses on perfluoroalkyl substance (PFAS) content in chickens' eggs and the livers of farm animals.
MATERIAL AND METHODS
Chickens' eggs (n = 25) and the livers of cows (n = 10), chickens (n = 7) and horses (n = 3) were collected from various regions of Poland. Samples were analysed using the isotope dilution technique with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS).
RESULTS
The mean lower bound (LB) sum of four PFAS (∑4 PFAS) concentrations (perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexanesulfonic acid (PFHxS)) were the highest in cows' livers (0.52 μg/kg) and much lower in chickens' (0.17 μg/kg) and horses' livers (0.13 μg/kg) and chickens' eggs (0.096 μg/kg). The ratio of ∑4 PFASs to the limits set by Commission Regulation (EU) 2023/915 was <7% for liver and <6% for eggs. Linear PFOS was the compound with the highest detection frequency (8% in eggs and 48% in all livers). In cows' livers it was detected in 80% of samples. The estimated exposure to LB ∑4 PFASs consumption of liver tissue from farm animals (assuming 50 g and 100 g portions) was <52% of the tolerable weekly intake (TWI) for children and <17% of the TWI for adults. Dietary intake the average portion of three eggs led to low exposure of <15% for children and <5% for adults.
CONCLUSION
Neither eggs nor the livers of chickens or horses as analysed in this study are significant sources of PFASs, while cows' livers might contribute significantly to a child's overall dietary intake. Further investigation of PFOS in farm animal livers should be conducted.
PubMed: 38947157
DOI: 10.2478/jvetres-2024-0034 -
Journal of Veterinary Research Jun 2024Radioactive caesium-137 occurring in the environment may be taken up by plants and animals and pose a trophic threat to humans. Game animals living in forest ecosystems...
INTRODUCTION
Radioactive caesium-137 occurring in the environment may be taken up by plants and animals and pose a trophic threat to humans. Game animals living in forest ecosystems are very good bioindicators of the level of environmental contamination by ionising radiation. The main species measurably exposed to caesium-137 are the wild boar (), the roe deer (), and the red deer (). The study determined the levels of Cs-137 in muscle samples of these game animals in 2015-2022.
MATERIAL AND METHODS
Using gamma radiation spectrometry, 858 samples of game animal muscle tissue were examined: 508 wild boar, 145 roe deer and 205 red deer samples.
RESULTS
Concentrations of Cs-137 varied widely (from minimum detectable activity (MDA) values to over 4,000 Bq/kg). In 63.4% of cases, the obtained concentrations exceeded the MDA. The permissible limit (600 Bq/kg for food) was exceeded in nine wild boar muscle samples, whereas it was not even exceeded once in roe or red deer muscle. The average concentration in wild boar was three times higher than in roe and red deer and amounted to 42.84 Bq/kg. The highest concentration of Cs-137 in wild boar muscle was 4,195 ± 372.0 Bq/kg, in roe deer muscle it was 111.5 ± 12.50 Bq/kg, and in red deer muscle was 86.70 ± 3.470 Bq/kg.
CONCLUSION
The seven years' data indicate that wild boar absorb the most caesium-137 among game animals. The concentrations of Cs-137 in the muscle of game animals in the years 2015-2022 were at a nearly constant level, a very slow diminution being noticeable over time in roe and red deer muscle.
PubMed: 38947154
DOI: 10.2478/jvetres-2024-0026 -
Food and Chemical Toxicology : An... Jun 2024Nanosilver (AgNPs) is popular nanomaterials used in food industry that makes gastrointestinal tract an essential route of its uptake. The aim of the presented study was...
Nanosilver (AgNPs) is popular nanomaterials used in food industry that makes gastrointestinal tract an essential route of its uptake. The aim of the presented study was to assess the effects of intragastric exposure to AgNPs on redox balance and steroid receptors in the testes of adult Fisher 344 rats. The animals were exposed to 20 nm AgNPs (30 mg/kg bw/day, by gavage) for 7 and 28 days compared to saline (control groups). It was demonstrated that 7-day AgNPs administration resulted in increased level of total antioxidant status (TAS), glutathione reductase (GR) activity, lower superoxide dismutase activity (SOD), decreased glutathione (GSH) level and GSH/GSSG ratio, as well as higher estrogen receptor (ESR2) and aromatase (Aro) protein expression in Leydig cells compared to the 28-day AgNPs esposure. The longer-time effects of AgNPs exposition were associated with increased lipid hydroperoxidation (LOOHs) and decreased SOD activity and androgen receptor protein level. In conclusion, the present study demonstrated the adverse gastrointestinally-mediated AgNPs effects in male gonads. In particular, the short-term AgNPs exposure impaired antioxidant defence with concurrent effects on the stimulation of estrogen signaling, while the sub-chronic AgNPs exposition revealed the increased testicle oxidative stress that attenuated androgens signaling.
PubMed: 38944145
DOI: 10.1016/j.fct.2024.114841 -
Biomacromolecules Jun 2024Hyaluronic acid is an excellent biocompatible material for applications. Its ability to bind CD44, a cell receptor involved in numerous biological processes,...
Hyaluronic acid is an excellent biocompatible material for applications. Its ability to bind CD44, a cell receptor involved in numerous biological processes, predetermines HA-based nanomaterials as unique carrier for therapeutic and theranostic applications. Although numerous methods for the synthesis of hyaluronic acid nanoparticles (HANPs) are available today, their low reproducibility and wide size distribution hinder the precise assessment of the effect on the organism. A robust and reproducible approach for producing HANPs that meet strict criteria for applications (, to lung parenchyma) remains challenging. We designed and evaluated four protocols for the preparation of HANPs with those required parameters. The HA molecule was cross-linked by novel combinations of carbodiimide, and four different amine-containing compounds resulted in monodisperse HANPs with a low polydispersity index. By a complex postsynthetic characterization, we confirmed that the prepared HANPs meet the criteria for inhaled therapeutic delivery and other applications.
PubMed: 38943654
DOI: 10.1021/acs.biomac.4c00370 -
Life Science Alliance Sep 2024This work presents a novel consensus molecular subtype (CMS) classifier for colorectal cancer (CRC), optimized for RNA-sequencing data stemming from degraded RNA of...
This work presents a novel consensus molecular subtype (CMS) classifier for colorectal cancer (CRC), optimized for RNA-sequencing data stemming from degraded RNA of clinical formalin-fixed paraffin-embedded (FFPE) tissue samples (the CMSFFPE classifier).
PubMed: 38936972
DOI: 10.26508/lsa.202402889