Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment.

Ferroptosis is a novel type of regulated cell death (RCD) involving iron accumulation and lipid peroxidation. Since its discovery in 2012, various studies have shown that ferroptosis is associated with the pathogenesis of various diseases. Ferroptotic cell death has also been linked to intestinal dysfunction but can act as either a positive or negative regulator of intestinal disease, depending on the cell type and disease context. The continued investigation of mechanisms underlying ferroptosis provides a wealth of potential for developing novel treatments. Considering the growing prevalence of intestinal diseases, particularly colorectal cancer (CRC) and inflammatory bowel disease (IBD), this review article focuses on potential therapeutics targeting the ferroptotic pathway in relation to CRC and IBD.

Conjugated Polymer-Based Photo-Crosslinker for Efficient Photo-Patterning of Polymer Semiconductors.

Photo-patterning of polymer semiconductors using photo-crosslinkers has shown potential for organic circuit fabrication via solution processing techniques. However, the performance of patterning, including resolution (R), UV light exposure dose, sensitivity (S), and contrast (γ), remains unsatisfactory. In this study, a novel conjugated polymer based photo-crosslinker (PN3, Figure 1a) is reported for the first time, which entails phenyl-substituted azide groups in its side chains. Due to the potential π-π interactions between the conjugated backbone of PN3 and those of polymer semiconductors, PN3 exhibits superior miscibility with polymer semiconductors compared to the commonly used small molecule photo-crosslinker 4Bx (Figure 1a). Consequently, photo-patterning of polymer semiconductors with PN3 demonstrates improved performance with much lower UV light exposure dose, higher S and higher γ compared to 4Bx. By utilizing electron beam lithography, patterned arrays of polymer semiconductors with resolutions down to 500 nm and clearer edges are successfully fabricated using PN3. Furthermore, patterned arrays of PDPP4T, the p-type semiconductor (Figure 1b), after being doped, can function as source-drain electrodes for fabricating field-effect transistors (FETs) with comparable charge mobility and significantly lower sub-threshold swing value compared to those with gold electrodes.

Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking.

BACKGROUND: Hypertrophic scar (HTS) is dermal fibroproliferative disorder, which may cause physiological and psychological problems. Currently, the potential mechanism of WuFuYin (WFY) in the treatment of HTS remained to be elucidated. AIM: To explore the potential mechanism of WFY in treating HTS. METHODS: Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. HTS-related genes were obtained from the GeneCards, DisGeNET, and National Center for Biotechnology Information. The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome (KEGG) enrichment analysis. A protein + IBM-protein interaction (PPI) network was developed using STRING database and Cytoscape. To confirm the high affinity between compounds and targets, molecular docking was performed. RESULTS: A total of 65 core genes, which were both related to compounds and HTS, were selected from multiple databases. PPI analysis showed that CKD2, ABCC1, MMP2, MMP9, glycogen synthase kinase 3 beta (GSK3B), PRARG, MMP3, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the hub targets and MOL004941, MOL004935, MOL004866, MOL004993, and MOL004989 were the key compounds of WFY against HTS. The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway. Moreover, by performing molecular docking, we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity. CONCLUSION: The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941, MOL004989, and MOL004993 were the main compounds of WFY in HTS treatment.

Integrative transcriptome-proteome approach reveals key hypoxia-related features involved in the neuroprotective effects of Yang Xue oral liquid on Alzheimer's and Parkinson's disease.

Introduction: This study investigates the role of hypoxia-related genes in the neuroprotective efficacy of Yang Xue oral liquid (YXKFY) in Alzheimer's disease (AD) and Parkinson's disease (PD). Methods and results: Using differential expression and weighted gene co-expression network analysis (WGCNA), we identified 106 and 9 hypoxia-associated genes in AD and PD, respectively, that are implicated in the transcriptomic and proteomic profiles. An artificial intelligence-driven hypoxia signature (AIDHS), comprising 17 and 3 genes for AD and PD, was developed and validated across nine independent cohorts (n = 1713), integrating 10 machine learning algorithms and 113 algorithmic combinations. Significant associations were observed between AIDHS markers and immune cells in AD and PD, including naive CD4+ T cells, macrophages, and neutrophils. Interactions with miRNAs (hsa-miR-1, hsa-miR-124) and transcription factors (USF1) were also identified. Single-cell RNA sequencing (scRNA-seq) data highlighted distinct expression patterns of AIDHS genes in various cell types, such as high expression of TGM2 in endothelial cells, PDGFRB in endothelial and mesenchymal cells, and SYK in microglia. YXKFY treatment was shown to repair cellular damage and decrease reactive oxygen species (ROS) levels. Notably, genes with previously dysfunctional expression, including FKBPL, TGM2, PPIL1, BLVRB, and PDGFRB, exhibited significant recovery after YXKFY treatment, associated with riboflavin and lysicamine. Conclusion: The above genes are suggested to be central to hypoxia and neuroinflammation responses in AD and PD, and are potential key mediators of YXKFY's neuroprotective action.

Vanadium as a Ti-like mediator boosting electronic transmission in Fe-based MOFs for photocatalytic sterilization.

Efficient metal-organic frameworks (MOFs) photocatalytic bactericidal catalysts are urgently needed in water purification. Herein, a Fe-MOF (MIL-88B-NH2(V1Fe5) with promoted electron transport was achieved by vanadium (V) ions doping and V/Fe ratio optimization, showing excellent photocatalytic bactericidal activity againstE. coliunder visible light irradiation (99.92%). The efficient antibacterial mechanism, V as a Ti-like mediator boosting electronic transmission in MIL-88B-NH2(V1Fe5), was revealed by its band structure, transient photocurrent, electrochemical impedance spectroscopy, and scavenger quenching experiments. The enhancement of photocatalytic bactericidal performance of Fe-MOFs by V-ion-doping was confirmed by two other Fe-MOFs, MIL-53-NH2(V1Fe5) and MIL-101-NH2(V1Fe5), with the same metal ions and ligands, both of which have higher performance than the corresponding undoped MOFs. Among them, MIL-88B-NH2(V1Fe5) exhibits the highest photocatalytic bactericidal activity due to its suitable metal clusters ([M(µ3-O)] cluster) and topological structure (three-dimensional rhomboid network structure). This work demonstrated the amplification effect of V ion doping on electron transport in Fe-MOFs photocatalysts.

Engineering valence-mismatched Ti4+ into Fe-based metal-organic-frameworks for enhanced photocatalytic CO2 reduction.

A series of low-dose high-valence Ti4+ doped MIL-53-NH2(Fe) photocatalysts were synthesized for visible-light-driven CO2 reduction. The highest CO2-to-CO conversion rate of Ti4+ doped MIL-53-NH2(Fe) was 7.24 mmol g-1 h-1 and the highest CO selectivity was 94% in acetonitrile solvent using [Ru(bpy)3]2+ and triethanolamine.

Mitigating the influence of message features on health misinformation sharing intention in social media: Experimental evidence for accuracy-nudge intervention.

RATIONALE: The escalating dissemination of health misinformation on social media platforms poses a significant threat to users' well-being. It is imperative to identify the types of health misinformation that are more susceptible to widespread dissemination and to explore strategies to curb its spread. METHOD: This study designed a 2 (emotional appeal type: positive vs. negative) × 2 (fabricated source type: pseudo-common vs. pseudo-authoritative) × 2 (accuracy-nudge label: No vs. Yes) online between-subjects experiment controlling for factors such as e-health literacy, prior sharing experience, and personal involvement. A snowball sampling approach was used to recruit 1952 participants through social media, resulting in a final sample of 1393 valid responses. RESULTS: Compared to positive emotional appeal and pseudo-common sources, negative emotional appeal and pseudo-authoritative sources resulted in higher levels of sharing intention. Under the condition of negative emotional appeal, the promotion effect of pseudo-authoritative sources on sharing intention was intensified. The accuracy-nudge intervention could significantly mitigate this tendency. The underlying mechanisms revealed more details: both negative emotional appeals and pseudo-authoritative sources increased the perceived credibility of health misinformation, thereby increasing users' sharing intention. However, in contrast to pseudo-authoritative sources, excessive negative emotional appeal induced vigilant verification behavior among users, which reduced sharing to some extent. Adding an accuracy-nudge label to health misinformation reduced users' misguided trust in health misinformation features and stimulated information verification, ultimately reducing health misinformation sharing intention. CONCLUSIONS: Negative emotional appeal and pseudo-authoritative sources can enhance the perceived credibility of health misinformation, thereby strengthening the sharing intention of social media users. Therefore, health misinformation with negative emotional appeal and pseudo-authoritative sources is more likely to be widely shared. The accuracy nudge intervention can trigger users' information verification behavior, suppress the persuasive effects of the misinformation features mentioned above, and help prevent the spread of health misinformation on social media.

Development and application of a novel suspension concentrate for seed coating of rice for controlling bakanae disease and seedling rot disease.

The main rice planting areas in the middle and lower reaches of the Yangtze River are primarily affected by two types of rice seedling diseases: bakanae disease and seedling rot disease. These diseases lead to considerable losses. Seed coating technology effectively protects rice from these diseases and mitigates environmental pollution. We determined the antifungal activity of six fungicides, including phenamacril, azoxystrobin, fludioxonil, metconazole, thifluzamide and prothioconazole against Fusarium moniliforme Sheldon and Curvularia lunata in this study. In addition, the impact of fungicides and surfactants on rice seed germination were determined. Furthermore, phenamacril and fludioxonil were selected as the active components of suspension concentrate for seed coating. The antifungal activity of phenamacril against F. moniliforme Sheldon was 0.139 mg/L and fludioxonil against C. lunata was 0.110 mg/L. PEG-2000 was selected as the surfactant due to its promoting effect on rice seedling. Based on the above findings, 6% phenamacril fludioxonil FS was developed via the wet sand grinding method. The toxicity of 6% phenamacril fludioxonil FS to zebrafish was verified, and field experiments were conducted in five different regions of the Yangtze River Basin. The results indicated minimal toxicity of 6% phenamacril fludioxonil FS to zebrafish. Relative to the control agent consisting of 6.25% phenamacril metalaxyl-M FS, 6% phenamacril fludioxonil FS showed better control effect and exhibited superior efficacy in promoting growth and increasing yield in all five regions. Specifically, the control effect of 6% phenamacril fludioxonil FS on bakanae exceeded 84.83% with the highest yield increasing value recorded at 30.48%. Currently, the market offers a limited selection of suspension concentrate for seed coating of rice. The findings of this study may offer a viable alternative formulation and directions for further research concerning the application of suspension concentrate for seed coating of rice.

Sandwich-structured continuous ZIF-8/Ti3C2 MXene/ZIF-8 for efficient sterilization: Enhanced photocatalytic activity, photothermal effect, and environmental safety.

The development of effective water purification systems is crucial for controlling and remediating environmental pollution, especially in terms of sterilization. Herein, we demonstrate elaborately designed composite nanosheets with a sandwich structure, composed of two-dimensional (2D) Ti3C2 MXene nanosheet core and conformal ZIF-8 ultrathin outer layers, and their potential applications in photocatalytic sterilization. The study results indicate that the conformal ZIF-8-MXene nanosheet exhibits an expanded light absorption range (826 nm), improved photothermal conversion efficiency (6.2 °C s-1), and photocurrent response, thus boosting photocatalytic sterilization efficiency (6.63 log10 CFU mL-1) against Escherichia coli under simulated sunlight within 90 min. Interestingly, 2D ZIF-8 layers exhibit positive zeta potential (19 mV), good hydrophilicity (40.6°), and local photogenerated-hole accumulation, possessing efficient bacteria-trapping efficiency. Membrane filters fabricated from optimized composite nanosheets exhibit an outstanding bacteria-trapping and sterilization efficiency (almost 100 %) against Escherichia coli under simulated sunlight within 30 min of the flow photocatalytic experiments. This work not only presents a rational structural design of the conformal and ultrathin anchoring of ZIF-8 onto a 2D conductive material for bacteria-trapping and sterilization, but also opens new opportunities for using metal-organic frameworks in photocatalytic disinfection of drinking water.

Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice.

Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.

Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis.

BACKGROUND/OBJECTIVES: Hypoxia-inducible factor (HIF)-3α1's role in colorectal cancer (CRC) cells, especially its effects on epithelial-mesenchymal transition (EMT), zinc finger E-box binding homeobox 2 (ZEB2) gene expression, and iron metabolism, remains largely unstudied. This research sought to elucidate these relationships. METHODS: RNA-seq was conducted to investigate the impact of HIF-3α1 overexpression in CRC cells. Dual-luciferase reporter assays assessed the direct targeting of ZEB2 by HIF-3α1. Scratch assays measured changes in cell migration following HIF-3α1 overexpression and ZEB2 knockdown. The effects of HIF-3α1 overexpression on colon tumour growth and liver metastasis were examined in vivo. Iron chelation was used to explore the role of iron metabolism in HIF-3α1-mediated EMT and tumour growth. RESULTS: HIF-3α1 overexpression induced EMT and upregulated ZEB2 expression, enhancing cancer cell migration. ZEB2 knockdown reduced mesenchymal markers and cell migration. HIF-3α1 promoted colon tumour growth and liver metastasis, increased transferrin receptor (TFRC) expression and cellular iron levels, and downregulated HIF-1α, HIF-2α, and NDRG1. Iron chelation mitigated HIF-3α1-mediated EMT, tumour growth, and survival. CONCLUSIONS: HIF-3α1 plays a critical role in colon cancer progression by promoting EMT, iron accumulation, and metastasis through ZEB2 and TFRC regulation, suggesting potential therapeutic targets in CRC.

Nonhalogenated Solvent Processable and High-Density Photopatternable Polymer Semiconductors Enabled by Incorporating Hydroxyl Groups in the Side Chains.

Polymer semiconductors hold tremendous potential for applications in flexible devices, which is however hindered by the fact that they are usually processed by halogenated solvents rather than environmentally more friendly solvents. An effective strategy to boost the solubility of high-performance polymer semiconductors in nonhalogenated solvents such as tetrahydrofuran (THF) by appending hydroxyl groups in the side chains is herein presented. The results show that hydroxyl groups, which can be easily incorporated into the side chains, can significantly improve the solubility of typical p- and n-types as well as ambipolar polymer semiconductors in THF. Meanwhile, the thin films of these polymer semiconductors from the respective THF solutions show high charge mobilities. With THF as the processing and developing solvents these polymer semiconductors with hydroxyl groups in the side chains can be well photopatterned in the presence of the photo-crosslinker, and the charge mobilities of the patterned thin films are mostly maintained by comparing with those of the respective pristine thin films. Notably, THF is successfully utilized as the processing and developing solvent to achieve high-density photopatterning with ≈82 000 device arrays cm-2 for polymer semiconductors in which hydroxyl groups are appended in the side chains.

Dihydroartemisinin Protects Mice from CUMS-induced Depression-like Behaviors by Regulating Gut Microbes.

Depression is one of the most common forms of psychopathology, which is associated with gut microbiota dysfunction. Dihydroartemisinin (DHA) has been shown to regulate gut microbiota and ameliorate neuropathies, but whether it can be used to treat depression remains unclear. Our study found that DHA treatment raised the preference for sugar water in chronic unpredictable mild stress (CUMS)-induced mice and reduced the immobility time in open field, forced swimming and tail suspension experiments, and promoted doublecortin expression. Additionally, DHA up-regulated the diversity and richness of intestinal microbiota in depression-like mice, and restored the abnormal abundance of microbiota induced by CUMS, such as Turicibacter, Lachnospiraceae, Erysipelotrichaceae, Erysipelatoclostridium, Eubacterium, Psychrobacter, Atopostipes, Ileibacterium, Coriobacteriacea, Alistipes, Roseburia, Rikenella, Eggerthellaceae, Ruminococcus, Tyzzerella, and Clostridia. Furthermore, KEGG pathway analysis revealed that gut microbiota involved in the process of depression may be related to glucose metabolism, energy absorption and transport, and AMPK signaling pathway. These results indicated that DHA may play a protective role in CUMS-induced depression by mediating gut-microbiome.

Exosomes from senescent epithelial cells activate pulmonary fibroblasts via the miR-217-5p/Sirt1 axis in paraquat-induced pulmonary fibrosis.

BACKGROUND: Paraquat (PQ) is a widely used and highly toxic herbicide that poses a significant risk to human health. The main consequence of PQ poisoning is pulmonary fibrosis, which can result in respiratory failure and potentially death. Our research aims to uncover a crucial mechanism in which PQ poisoning induces senescence in epithelial cells, ultimately regulating the activation of pulmonary fibroblasts through the exosomal pathway. METHODS: Cellular senescence was determined by immunohistochemistry and SA-ß-Gal staining. The expression of miRNAs was measured by qPCR. Pulmonary fibroblasts treated with specific siRNA of SIRT1 or LV-SIRT1 were used to analysis senescent exosomes-mediated fibroblasts activation. Luciferase reporter assay and western blot were performed to elucidated the underlying molecular mechanisms. The effects of miR-217-5p antagomir on pulmonary fibrosis were assessed in PQ-poisoned mice models. RESULTS: Impairing the secretion of exosomes effectively mitigates the harmful effects of senescent epithelial cells on pulmonary fibroblasts, offering protection against PQ-induced pulmonary fibrosis in mice. Additionally, we have identified a remarkable elevation of miR-217-5p expression in the exosomes of PQ-treated epithelial cells, which specifically contributes to fibroblasts activation via targeted inhibition of SIRT1, a protein involved in cellular stress response. Remarkably, suppression of miR-217-5p effectively impaired senescent epithelial cells-induced fibroblasts activation. Further investigation has revealed that miR-217-5p attenuated SIRT1 expression and subsequently resulted in enhanced acetylation of ß-catenin and Wnt signaling activation. CONCLUSION: These findings highlight a potential strategy for the treatment of pulmonary fibrosis induced by PQ poisoning. Disrupting the communication between senescent epithelial cells and pulmonary fibroblasts, particularly by targeting the miR-217-5p/SIRT1/ß-catenin axis, may be able to alleviate the effects of PQ poisoning on the lungs.

Oct4 activates IL-17A to orchestrate M2 macrophage polarization and cervical cancer metastasis.

BACKGROUND: Cervical cancer is a common malignant tumor in the female. Interleukin (IL)-17A is a proinflammatory factor and exerts a vital function in inflammatory diseases and cancers. M2 macrophage has been confirmed to promote tumor development. Nevertheless, it is not yet known whether IL-17A facilitates cervical cancer development by inducing M2 macrophage polarization. Therefore, this study was conducted to investigate the regulatory effect of IL-17A on M2 macrophage polarization and the underlying mechanism in cervical cancer development. METHODS: RT-qPCR was utilized for testing IL-17A expression in cancer tissues and cells. Flow cytometry was applied to evaluate the M1 or M2 macrophage polarization. Cell proliferative, migratory, and invasive capabilities were measured through colony formation and transwell assays. ChIP and luciferase reporter assays were applied to determine the interaction between IL-17A and octamer-binding transcription factor 4 (OCT4). RESULTS: IL-17A expression and concentration were high in metastatic tissues and cells of cervical cancer. IL-17A was found to facilitate M2 macrophage polarization in cervical cancer. Furthermore, IL-17A facilitated the macrophage-mediated promotion of cervical cancer cell proliferative, migratory, and invasive capabilities. Mechanistic assays manifested that Oct4 binds to and transcriptionally activated IL-17A in cervical cancer cells. Furthermore, Oct4 promoted cervical cancer cell malignant phenotype and M2 macrophage polarization by activating the p38 pathway that, in turn, upregulated IL-17A. Additionally, in vivo experiments confirmed that Oct4 knockdown reduced tumor growth and metastasis. CONCLUSION: Oct4 triggers IL-17A to facilitate the polarization of M2 macrophages, which promotes cervical cancer cell metastasis.

Edge-sharing bi-octahedral diruthenium(IV,IV) compounds containing Ru-Ru bonds chelated and bridged by two carbonate and two oxo groups.

From paddle-wheel starting material Na3Ru2(CO3)4·6H2O, a family of edge-sharing bi-octahedral (ESBO) diruthenium(IV,IV) compounds formulated as Ru2O2(CO3)2(H2O)2L2·nH2O [L = piperazine (1) or 2-methylpiperazine (2), n = 4, and L = 2,2-dimethylpiperazine (3), n = 12] and Ru2O2(CO3)2(OH)4{M(H2O)4}2·nH2O [M = Mg (4), n = 4, and Ni (5), n = 2] were prepared and structurally characterized. The Ru28+ dimer is chelated and bridged by two CO32- and two µ-O in a trans manner, and the Ru-Ru distances fall in the range 2.3808(6)-2.4001(4) Å. Compound 2 shows the shortest Ru-Ru distance for all known ESBO Ru2 compounds reported thus far. Increasing -CH3 groups of terminal piperazine ligands coordinated to the Ru(µ-O)2(µ-O3C)2Ru core, and according to Raman spectra experiments combined with theoretical calculations, the intense bands of compounds 1-3 appearing at ∼360 cm-1 can be assigned to the stretching of Ru-Ru bonds.

The emerging role of hypoxia and environmental factors in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder characterized by inflammation of the gastrointestinal tract. Despite extensive research, the exact cause of IBD remains unknown, hampering the development of effective therapies. However, emerging evidence suggests that hypoxia, a condition resulting from inadequate oxygen supply, plays a crucial role in intestinal inflammation and tissue damage in IBD. Hypoxia-inducible factors (HIFs), transcription factors that regulate the cellular response to low oxygen levels, have gained attention for their involvement in modulating inflammatory processes and maintaining tissue homeostasis. The two most studied HIFs, HIF-1α and HIF-2α, have been implicated in the development and progression of IBD. Toxicological factors encompass a wide range of environmental and endogenous agents, including dietary components, microbial metabolites, and pollutants. These factors can profoundly influence the hypoxic microenvironment within the gut, thereby exacerbating the course of IBD and fostering the progression of colitis-associated colorectal cancer. This review explores the regulation of hypoxia signaling at the molecular, microenvironmental, and environmental levels, investigating the intricate interplay between toxicological factors and hypoxic signaling in the context of IBD, focusing on its most concerning outcomes: intestinal fibrosis and colorectal cancer.

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.

Effect of marital status on the survival outcomes of cervical cancer: a retrospective cohort study based on SEER database.

BACKGROUND: Cervical cancer is the fourth most common malignant tumor troubling women worldwide. Whether marital status affects the prognosis of cervical cancer is still unclear. Here, we investigate the prognostic value of marital status in patients with cervical cancer based on the seer database. MATERIAL/METHODS: The demographic and clinical data of patients with cervical cancer were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2017. Patients were divided into two groups (married and unmarried) according to marital status, and then the clinical characteristics of each group were compared using the chi-square test. Propensity score matching (PSM) was used to reduce differences in baseline characteristics. The overall survival (OS) and cervical cancer-specific survival (CCSS) were assessed by the Kaplan-Meier method, univariate and multivariate Cox regression models, and stratified analysis. Moreover, univariate and multivariate competing risk regression models were performed to calculate hazard ratios (HR) of death risk. RESULTS: A total of 21,148 patients were included in this study, including 10,603 married patients and 10,545 unmarried patients. Married patients had better OS(P < 0.05) and CCSS (P < 0.05) compared to unmarried patients, and marital status was an independent prognostic factor for both OS (HR: 0.830, 95% CI: 0.798-0.862) and CCSS (HR: 0.892, 95% CI: 0.850-0.937). Moreover, after eliminating the competing risk, married patients (CCSD: HR:0.723, 95% CI: 0.683-0.765, P < 0.001) had a significantly decreased risk of death compared to unmarried patients. In stratified analysis, the married patients showed better OS and CCSS than the unmarried patients diagnosed in 1975-2000 and 2001-2017. CONCLUSIONS: Being married was associated with a favorable prognosis of cervical cancer, and marital status was an independent prognostic factor for cervical cancer.

Identification of aging-related genes in diagnosing osteoarthritis via integrating bioinformatics analysis and machine learning.

BACKGROUND: Osteoarthritis (OA) is one of the main causes of pain and disability in the world, it may be caused by many factors. Aging plays a significant role in the onset and progression of OA. However, the mechanisms underlying it remain unknown. Our research aimed to uncover the role of aging-related genes in the progression of OA. METHODS: In Human OA datasets and aging-related genes were obtained from the GEO database and the HAGR website, respectively. Bioinformatics methods including Gene Ontology (GO), Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment, and Protein-protein interaction (PPI) network analysis were used to analyze differentially expressed aging-related genes (DEARGs) in the normal control group and the OA group. And then weighted gene coexpression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO) regression, and the Random Forest (RF) machine learning algorithms were used to find the hub genes. RESULTS: Four overlapping hub genes: HMGB2, CDKN1A, JUN, and DDIT3 were identified. According to the nomogram model and receiver operating characteristic (ROC) curve analysis, four hub DEARGs had good diagnostic value in distinguishing normal from OA. Furthermore, the qRT-PCR test demonstrated that HMGB2, CDKN1A, JUN, and DDIT3 mRNA expression levels were lower in OA group than in normal group. CONCLUSION: Finally, these four-hub aging-related genes may help us understand the underlying mechanism of aging in osteoarthritis and could be used as possible diagnostic and therapeutic targets.