Death Pathways Research Articles

Cross-talk between cuproptosis and ferroptosis to identify immune landscape in cervical cancer for mRNA vaccines development

Messenger RNA (mRNA)-based vaccines present a promising avenue for cancer immunotherapy; however, their application in cervical cancer remains unexplored. This study investigated the interplay between the regulated cell death pathways of cuproptosis and ferroptosis to advance the development of mRNA vaccines for cervical cancer. We identified key cuproptosis-related and ferroptosis-related genes (CFRGs) from public mRNA profiles and determined their prognostic significance, mutation frequencies, and effect on the immune landscape. Our analysis revealed two distinct subtypes of cervical cancer associated with CFRGs, with differences in prognosis and immune characteristics. Using LASSO, XGBoost, and SVM–RFE methods, we established a 4-gene prognostic signature (TSC22D3, SQLE, ZNF419, and TFRC) to stratify patients based on their risk and determine its correlation with immune microenvironment, mutation profiles, and treatment responses. RT-qPCR validation confirmed the differential expression of these genes in clinical samples. Our findings identify TSC22D3, SQLE, ZNF419, and TFRC as candidate targets for mRNA vaccine development and offer a potential prognostic tool for personalized cervical cancer treatment.

Synergistic enhancement of low-dose radiation therapy via cuproptosis and metabolic reprogramming for radiosensitization in in situ hepatocellular carcinoma

BackgroundRadiotherapy (RT) is a primary clinical approach for cancer treatment, but its efficacy is often hindered by various challenges, especially radiation resistance, which greatly compromises the therapeutic effectiveness of RT. Mitochondria, central to cellular energy metabolism and regulation of cell death, play a critical role in mechanisms of radioresistance. In this context, cuproptosis, a novel copper-induced mitochondria-respiratory-dependent cell death pathway, offers a promising avenue for radiosensitization.ResultsIn this study, an innovative theranostic nanoplatform was designed to induce cuproptosis in synergy with low-dose radiation therapy (LDRT, i.e., 0.5–2 Gy) for the treatment of in situ hepatocellular carcinoma (HCC). This approach aims to reverse the hypoxic tumor microenvironment, promoting a shift in cellular metabolism from glycolysis to oxidative phosphorylation (OXPHOS), thereby enhancing sensitivity to cuproptosis. Concurrently, the Fenton-like reaction ensures a sustained supply of copper and depletion of glutathione (GSH), inducing cuproptosis, disrupting mitochondrial function, and interrupting the energy supply. This strategy effectively overcomes radioresistance and enhances the therapeutic efficacy against tumors.ConclusionsIn conclusion, this study elucidates the intricate interactions among tumor hypoxia reversal, cuproptosis, metabolic reprogramming, and radiosensitization, particularly in the context of treating in situ hepatocellular carcinoma, thereby providing a novel paradigm for radiotherapy.Graphical abstract

Normothermic regional perfusion mobile teams in controlled donation after circulatory death pathway: Evidence and peculiarities.

To facilitate the implementation of controlled donation after circulatory death (cDCD) programs even in hospitals not equipped with a local Extracorporeal Membrane Oxygenation (ECMO) team (Spokes), some countries and Italian Regions have launched a local cDCD network with a ECMO mobile team who move from Hub hospitals to Spokes for normothermic regional perfusion (NRP) implantation in the setting of a cDCD pathway. While ECMO teams have been clearly defined by the Extracorporeal Life Support Organization, regarding composition, responsibilities and training programs, no clear, widely accepted indications are to date available for NRP teams. Although existing NRP mobile networks were developed due to the urgent need to increase the number of cDCDs, there is now the necessity for transplantation medicine to identify the peculiarities and responsibility of a NRP team for all those centers launching a cDCD pathway. Thus, in the present manuscript we summarized the characteristics of an ECMO mobile team, highlighting similarities and differences with the NRP mobile team. We also assessed existing evidence on NRP teams with the goal of identifying the characteristic and essential features of an NRP mobile team for a cDCD program, especially for those centers who are starting the program. Differences were identified between the mobile ECMO team and NRP mobile team. The common essential feature for both mobile teams is high skills and experience to reduce complications and, in the case of cDCD, to reduce the total warm ischemic time. Dedicated training programs should be developed for the launch of de novo NRP teams.

Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.

SENP1 promotes deacetylation of isocitrate dehydrogenase 2 to inhibit ferroptosis of breast cancer via enhancing SIRT3 stability.

Breast cancer, one of the most prevalent malignant tumors in women worldwide, is characterized by a poor prognosis and high susceptibility to recurrence and metastasis. Ferroptosis, a lipid peroxide-dependent programed cell death pathway, holds significant potential for breast cancer treatment. Therefore, investigating the regulatory targets and associated mechanisms of ferroptosis is crucial. In this study, we conducted proteomic screening and identified isocitrate dehydrogenase 2 (IDH2) as an important player in breast cancer progression. Our findings were further supported by CCK-8 assays, transwell experiments, and scratch assays, which demonstrated that the elevated expression of IDH2 promotes breast cancer progression. Through both in vitro and in vivo experiments along with the erastin treatment, we discovered that increased expression of IDH2 confers resistance to ferroptosis in breast cancer cells. By employing Western blot analysis, Co-IP techniques, and immunofluorescence staining methods, we elucidated the upstream molecular mechanism involving SENP1-mediated SIRT3 de-SUMOylatase, which enhances IDH2 enzyme activity through deacetylation, thereby regulating cell ferroptosis. In conclusion, our study highlights the role of the SENP1-SIRT3 axis in modulating ferroptosis via IDH2 in breast cancer cells, providing valuable insights for developing targeted therapies aimed at enhancing ferroptosis for improved management of breast cancer.

Integrated Single-Cell Analysis Revealed Novel Subpopulations of Foamy Macrophages in Human Atherosclerotic Plaques

Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high NR1H3 expression; (iv) mature foamy macrophages prone to programmed cell death; and (v) synthetic subset. Trajectory analysis elucidated a bifurcated differentiation cell fate from pro-foam macrophages toward either the programmed death (iv) or synthetic (v) phenotype. The existence of these foamy macrophage subsets was validated by immunostaining. Moreover, these foamy macrophage subsets exhibited strong potential ligand–receptor interactions. Finally, we conducted Mendelian randomization analyses to identify a possible causal relationship between key regulatory genes along the programmed death pathway in foamy macrophages and atherosclerotic diseases. This study provides a high-resolution map of foam cell diversity and a set of potential key regulatory genes in atherosclerotic plaques, offering novel insights into the multifaceted pathophysiology underlying human atherosclerosis.

Biological mechanism and functional verification of key genes related to major depressive disorder and type 2 diabetes mellitus.

Major depressive disorder (MDD) and type 2 diabetes (T2D) have been shown to be linked, but a comprehensive understanding of the underlying molecular mechanisms remains elusive. The purpose of this study was to explore the biological relationship between MDD and T2D and verify the functional roles of key genes. We used the Gene Expression Omnibus database to investigate the targets associated with MDD and T2D. Using linear models for microarray data, differentially expressed genes associated with MDD and T2D were identified in GSE76826 and GSE95849, respectively, and 126 shared genes were significantly upregulated. Weighted gene coexpression network analysis identified modules associated with MDD and T2D in the GSE38206 and GSE20966 datasets and identified 8 common genes. Functional enrichment analysis revealed that these genes were enriched in cell signaling, enzyme activity, cell structure and amino acid biosynthesis and involved in cell death pathways. Finally, combined with the CTD and GeneCards databases, lysophosphatidylglycerol acyltransferase 1 (LPGAT1) was identified as a key gene. LPGAT1 was validated in GSE201332 and GSE182117, and the subject operating characteristic curve showed good diagnostic potential for MDD and T2D. Additionally, we used an in vitro model of MDD related to T2D to verify the expression of LPGAT1. A subsequent gene knockdown assay revealed that the downregulation of LPGAT1 improved mitochondrial function and reduced apoptosis in damaged neurons. Taken together, our results highlight the role of LPGAT1 in the connection between MDD and T2D, and these findings provide new insights into potential therapeutic targets for depression associated with diabetes.

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies.

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc-/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

Nanoformula Design for Inducing Non-Apoptotic Cell Death Regulation: A Powerful Booster for Cancer Immunotherapy.

Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.

New Insights on Mechanisms and Therapeutic Targets of Cerebral Edema.

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to bloodbrain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

Gut microbiota in health and disease: advances and future prospects.

The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer's and Parkinson's). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome-gut-organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota's role in disease development.

Prediction of clinical prognosis and drug sensitivity in hepatocellular carcinoma through the combination of multiple cell death pathways.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, highlighting a significant need for reliable predictive models to assess clinical prognosis, disease progression, and drug sensitivity. Recent studies have highlighted the critical role of various programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, NETotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, in tumor development. Therefore, by investigating these pathways, we aimed to develop a predictive model for HCC prognosis and drug sensitivity. We analyzed transcriptome, single-cell transcriptome, genomic, and clinical information using data from the TCGA-LIHC, GSE14520, GSE45436, and GSE166635 datasets. Machine learning algorithms were used to establish a cell death index (CDI) with seven gene signatures, which was validated across three independent datasets, showing that high CDI correlates with poorer prognosis. Unsupervised clustering revealed three molecular subtypes of HCC with distinct biological processes. Furthermore, a nomogram integrating CDI and clinical information demonstrated good predictive performance. CDI was associated with immune checkpoint genes and tumor microenvironment components using single-cell transcriptome analysis. Drug sensitivity analysis indicated that patients with high CDI may be resistant to oxaliplatin and cisplatin but sensitive to axitinib and sorafenib. In summary, our model offers a precise prediction of clinical outcomes and drug sensitivity for patients with HCC, providing valuable insights for personalized treatment strategies.

A new perspective on targeting pulmonary arterial hypertension: Programmed cell death pathways (Autophagy, Pyroptosis, Ferroptosis).

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by elevated pulmonary vascular resistance, progressive increases in pulmonary artery pressures, ultimately leading to right-sided heart failure, and potentially mortality. Pulmonary vascular remodeling is pivotal in PAH onset and progression. While targeted drug therapies have notably ameliorated PAH prognosis, current medications primarily focus on vascular vasodilation, with limited ability to reverse pulmonary vascular remodeling fundamentally, resulting in suboptimal patient prognoses. Cellular death in pulmonary vasculature, once thought to be confined to apoptosis and necrosis, has evolved with the identification of pyroptosis, autophagy, and ferroptosis, revealing their association with vascular injury in PAH. These novel forms of regulated cellular death impact reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, leading to pulmonary vascular cell loss, exacerbating vascular injury, and mediating adverse remodeling, inflammation, immune anomalies, and current emerging mechanisms (such as endothelial-mesenchymal transition, abnormal energy metabolism, and epigenetic regulation) in the pathogenesis of PAH. This review comprehensively delineates the roles of autophagy, pyroptosis, and ferroptosis in PAH, elucidating recent advances in their involvement and regulation of vascular injury. It juxtaposes their distinct functions in PAH and discusses the interplay of these programmed cell deaths in pulmonary vascular injury, highlighting the benefits of combined targeted therapies in mitigating pulmonary arterial hypertension-induced vascular injury, providing novel insights into targeted treatments for pulmonary arterial hypertension.

Apigenin attenuates cisplatin-induced hair cell damage in the zebrafish lateral line

Cisplatin, a widely used chemotherapy drug, is notorious for causing ototoxicity, which leads to irreversible sensorineural hearing loss by damaging cochlear sensory hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV). Mechanisms include DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammation, ultimately triggering cell death pathways like apoptosis, necroptosis, pyroptosis, or ferroptosis. Apigenin, a natural flavonoid found in various foods and beverages, possesses antioxidant, anti-inflammatory, and anti-tumor properties. Despite these benefits, its potential to mitigate cisplatin-induced ototoxicity remains unexplored. To investigate, we administered varying concentrations of apigenin (1 μM, 20 μM, 100 μM, and 250 μM) alongside cisplatin (200 μM) to zebrafish larvae at 5 days post fertilization. Cisplatin significantly reduced lateral line HCs, impacting auditory function as shown in startle response tests. However, co-administration with apigenin preserved lateral line HCs and mitigated cisplatin-induced hearing loss. In larvae exposed to cisplatin, TUNEL assay confirmed significant HCs apoptosis, which apigenin effectively countered by suppressing reactive oxygen species accumulation in lateral line HCs. RNA-seq analysis highlighted apigenin's role in modulating apoptosis-related pathways, supporting its protective effects against cisplatin-induced ototoxicity. These findings underscore apigenin's potential as a crucial protective agent against cisplatin-induced ototoxicity, meriting further investigation for clinical applications.

Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance.

Caspase-8 and the kinase RIPK1 are at focal points of several inflammation and cell death pathways. Thus, a careful regulation of their actions is needed. Our work identifies the RNA splicing factor Raver1 as a critical factor directing the splicing of Ripk1 in order to modulate RIPK1/caspase-8-driven pyroptosis, apoptosis and inflammation. Raver1 is central for macrophage responses to Yersinia bacteria, initiated after blockade of kinases TAK1 and IKK, measured as activation of RIPK1, caspase-8, Gasdermin D, caspase-3, IL-1ß and IL-18. Importantly, Raver1 is necessary for host resistance to Yersinia infection in vivo . We propose that Raver1 is key for correct tuning of RIPK1-caspase-8 dependent processes.

PTPN23-dependent ESCRT machinery functions as a cell death checkpoint

Cell death plasticity is crucial for modulating tissue homeostasis and immune responses, but our understanding of the molecular components that regulate cell death pathways to determine cell fate remains limited. Here, a CRISPR screen of acute myeloid leukemia cells identifies protein tyrosine phosphatase non-receptor type 23 (PTPN23) as essential for survival. Loss of PTPN23 activates nuclear factor-kappa B, apoptotic, necroptotic, and pyroptotic pathways by causing the accumulation of death receptors and toll-like receptors (TLRs) in endosomes. These effects are recapitulated by depletion of PTPN23 co-dependent genes in the endosomal sorting complex required for transport (ESCRT) pathway. Through proximity-dependent biotin labeling, we show that NAK-associated protein 1 interacts with PTPN23 to facilitate endosomal sorting of tumor necrosis factor receptor 1 (TNFR1), sensitizing cells to TNF-α-induced cytotoxicity. Our findings reveal PTPN23-dependent ESCRT machinery as a cell death checkpoint that regulates the spatiotemporal distribution of death receptors and TLRs to restrain multiple cell death pathways.

Evaluation of the Chemotherapeutic Potential of Medicinal Plant Mespilus germanica Fruit Extract: Cell Death Pathways and DNA Damage Mechanism

Plant extracts are a mixture of natural complex compounds containing various biological activities, including anticancer properties. The fact that they have fewer side effects than synthetic drugs has made plant extracts an important strategy in cancer treatment The purpose of this study was to explore the chemotherapeutic potential of Mespilus germanica (medlar) fruit extract. The compound content of the extract was determined by HPLC. The proliferative concentration (PRO) and the concentration inhibiting the proliferation of half of the cells (IC50) were determined by the MTT viability test. PRO and IC50 concentrations were treated to A549 lung cancer cells for 48 hours. The study groups were determined as 3 groups: control, PRO, and IC50. Total mRNA was obtained from the cells by using the Trizol Reagent-chloroform method. cDNA synthesis was performed from total mRNA. mRNA gene expression levels of programmed cell death markers were detected by RT-qPCR. For all group studies, p

Green manure plants enhance atrazine degradation in agriculture soil through modulating rhizosphere microbial communities

The widespread use of atrazine in agriculture threatens soil health and the safety of agricultural products. In this study, the removal and mechanism of green manure plants (GMPs) hairy vetch (Vicia villosa Roth, VV) and ryegrass (Lolium perenne L., LP) to atrazine were investigated. The results showed that VV and LP show a certain tolerance to 5–25 mg/kg atrazine contamination compared to VV and LP without atrazine (VV0 and LP0), with LP exhibiting higher tolerance. Moreover, compared to CK, VV and LP significantly promoted the removal of atrazine by 13.49%∼26.41% and 13.98%∼23.42%, respectively. VV was more effective at lower concentrations (5–10 mg/kg), while LP showed better results at 25 mg/kg. Soil enzyme activities (catalase and urease), as well as bacterial abundance and diversity, were significantly increased by VV and LP treatments. LP had a stronger effect. The function analysis revealed that VV enhances the Cell growth and death pathway in the rhizosphere soil, while LP primarily boosts the Replication and repair pathway to cope with atrazine stress. This difference likely results from the distinct root structures of the two plants, which create varying rhizosphere environments. Additionally, VV and LP upregulate the Atrazine degradation pathway by enriching atrazine-degrading bacteria, thereby promoting atrazine removal. VV growth was affected under 25 mg/kg atrazine treatment, which may lead to lower Atrazine degradation pathway abundance in the rhizosphere compared to LP. This study provides a theoretical basis for selecting plant species for the remediation of atrazine-contaminated soils.

Circular RNAs as multifaceted molecular regulators of vital activity and potential biomarkers of aging.

Aging presents a significant challenge to health and social care systems due to the increasing proportion of the elderly population. The identification of reliable biomarkers to assess the progression of aging remains an unresolved question. Circular RNAs (circRNAs) are single-stranded covalently closed RNAs. They have been found to regulate various biological processes. CircRNAs are present in human biological fluids, are relatively stable, and accumulate with age, making them promising as biomarkers of aging. Current information on the expression of circRNAs in aging was analyzed using scientific databases. In this review, we have identified key stages in the study of circRNAs during aging and summarized the current understanding of their biogenesis. By focusing on the role of circRNAs in processes that contribute to aging - such as genomic stability, metabolism, cell death, and signaling pathways - we hypothesize that circRNAs may drive the aging process through their age-related accumulation and resultant deregulation. Examples of age-related differential expression of circRNAs in various species, including humans, are provided. This review highlights the importance of finding novel epigenetic biomarkers of aging, beyond the already identified molecules (circFOXO3, circRNA100783, circPVT1), and highlights circRNAs as a potential therapeutic target for the treatment of age-associated diseases.

Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumour in children. The Sonic Hedgehog (SHH)-medulloblastoma subtype arises from the cerebellar granule neuron lineage. Terminally differentiated neurons are incapable of undergoing further cell division, so an effective treatment for this tumour could be to force neuronal differentiation. Differentiation therapy provides a potential alternative for patients with medulloblastoma who harbor mutations that impair cell death pathways (TP53), which is associated a with high mortality. To this end, our goal was to explore epigenetic regulation of cerebellar granule neuron differentiation in medulloblastoma cells. Key regulators were discovered using chromatin immunoprecipitation with high-throughput sequencing. DNA-bound protein and chromatin protein modifications were investigated across all genes. We discovered that Ezh2-mediated tri-methylation of the H3 histone (H3K27me3), occurred on more than half of the 787 genes whose transcription normally increases as granule neurons terminally differentiate. Conditional knockout of Ezh2 led to early initiation of differentiation in granule neuron precursors (GNPs), but only after cell cycle exit had occurred. Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.