TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA-PKcs.

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-ß-carboline derivatives as potential antibacterial agents.

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-ß-carboline (THßC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THßC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THßC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.

Prognostic relevance of ventricular arrhythmias in surgical patients with gastrointestinal tumors.

BACKGROUND: Individuals diagnosed with gastrointestinal tumors are at an increased risk of developing cardiovascular diseases. Among which, ventricular arrhythmia is a prevalent clinical concern. This suggests that ventricular arrhythmias may have predictive value in the prognosis of patients with gastrointestinal tumors. AIM: To explore the prognostic value of ventricular arrhythmias in patients with gastrointestinal tumors receiving surgery. METHODS: We retrospectively analyzed data from 130 patients undergoing gastrointestinal tumor resection. These patients were evaluated by a 24-h ambulatory electrocardiogram (ECG) at the Sixth Affiliated Hospital of Sun Yat-sen University from January 2018 to June 2020. Additionally, 41 general healthy age-matched and sex-matched controls were included. Patients were categorized into survival and non-survival groups. The primary endpoint was all-cause mortality, and secondary endpoints included major adverse cardiovascular events (MACEs). RESULTS: Colorectal tumors comprised 90% of cases. Preoperative ambulatory ECG monitoring revealed that among the 130 patients with gastrointestinal tumors, 100 (76.92%) exhibited varying degrees of premature ventricular contractions (PVCs). Ten patients (7.69%) manifested non-sustained ventricular tachycardia (NSVT). The patients with gastrointestinal tumors exhibited higher PVCs compared to the healthy controls on both conventional ECG [27 (21.3) vs 1 (2.5), P = 0.012] and 24-h ambulatory ECG [14 (1.0, 405) vs 1 (0, 6.5), P < 0.001]. Non-survivors had a higher PVC count than survivors [150.50 (7.25, 1690.50) vs 9 (0, 229.25), P = 0.020]. During the follow-up period, 24 patients died and 11 patients experienced MACEs. Univariate analysis linked PVC > 35/24 h to all-cause mortality, and NSVT was associated with MACE. However, neither PVC burden nor NSVT independently predicted outcomes according to multivariate analysis. CONCLUSION: Patients with gastrointestinal tumors exhibited elevated PVCs. PVCs > 35/24 h and NSVT detected by 24-h ambulatory ECG were prognostically significant but were not found to be independent predictors.

Key molecules regulating the blood meals of Rhipicephalus sanguineus (Acari: Ixodidae) revealed by transcriptomics.

Rhipicephalus sanguineus, a repulsive obligate blood feeder, is a three-host tick inflicting tremendous damage. Blood-sucking initiates tick-pathogen-host interactions along with alterations in the expression levels of numerous bioactive ingredients. Key molecules regulating blood meals were identified using the transcriptomic approach. A total number of 744 transcripts showed statistically significantly differential expression including 309 significantly upregulated transcripts and 435 significantly downregulated transcripts in semiengorged female ticks compared to unfed ticks, all collected in 2021. The top 10 differentially upregulated transcripts with explicit functional annotations included turripeptide OL55-like protein, valine tRNA ligase-like protein and ice-structuring glycoprotein-like protein. The top 10 differentially down-regulated transcripts were uncharacterized proteins. Gene Ontology (GO) enrichment analysis revealed four associated terms in the cellular component category and 16 in the molecular function category among the top 20 terms. Differentially expressed genes (DEGs) were enriched in GO terms ID 0000323 (lytic vacuole) and ID 0005773 (vacuole). The top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included metabolism, cellular processes, organismal systems and human diseases. The DEGs were enriched in the KEGG term ID: ko-04142 (lysosome pathway) associated with intracellular digestion in the tick midgut epithelium. Molecular markers annotated via comparative transcriptomic profiling were expected to be candidate markers for the purpose of tick control.

Impact of Adverse Childhood Experiences and Mental Health on School Success in Autistic Children: Findings from the 2016-2021 National Survey of Children's Health.

PURPOSE: School is an important developmental setting for children. Adverse childhood experiences (ACEs) are linked to overall lower educational attainment and are more prevalent in children with Autism Spectrum Disorder (ASD) than in their neurotypical peers. The aim of this study is to test the association between ACEs and school outcomes among autistic children and whether mental health conditions explain this association. METHODS: We combined 2016-2021 data from the National Surveys of Children's Health for children, ages 6-17, identified by parents as having ASD (N = 4,997), to examine the relationship between ACEs and school outcomes (grade progression, school attendance, and engagement). We analyzed depression and anxiety variables to investigate the extent to which mental health can explain the relationships between ACEs and school outcomes. RESULTS: ACEs were significantly associated with school outcomes. With increased ACEs, autistic children experienced a significant decrease in the odds of school attendance, grade progression and school engagement (p < .05). Furthermore, although depression and anxiety symptoms were significantly associated with school outcomes, they cannot explain away the enduring, strong relationship between ACEs and level of grade progression, engagement, and school success index. CONCLUSION: Our findings suggest ACEs predict school success among autistic children, with mental health conditions appearing to mediate the relationship between ACEs and key factors in school success. Efforts should be made to proactively identify and address the impact of ACEs and associated mental health conditions among autistic students.

[Mechanism of Ganke Granules intervening acute lung injury based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of action in the intervention of acute lung injury(ALI) based on the blood entry components of Ganke Granules in rats and in conjunction with network pharmacology, molecular docking, and animal experimental validation. The blood entry components of Ganke Granules in rats were imported into the SwissTargetPrediction platform to predict drug targets, and ALI-related targets were collected from the disease database. Intersections were taken, and protein-protein interaction(PPI) networks were constructed to screen the core targets, followed by Gene Ontology(GO) functional and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analyses. A "blood entry components-target-pathway-disease" network was constructed, and the core components for disease intervention based on their topological parameters were screened. Molecular docking was used to predict the binding ability of the core components to key targets. The key targets of Ganke Granules in the intervention of ALI were verified by the lipopolysaccharide(LPS)-induced ALI mouse model. Through PPI topological parameter analysis, the top six key targets of STAT3, SRC, HSP90AA1, MAPK3, HRAS, and MAPK1 related to ALI were obtained. GO functional analysis showed that it was mainly related to ERK1 and ERK2 cascade, inflammatory response, and response to LPS. KEGG analysis showed that the main enrichment pathways were MAPK, neutrophil extracellular trap(NET) formation, and so on. Six core components(schizantherin B, schisandrin, besigomsin, harpagoside, isotectorigenin, and trachelanthamine) were filtered out by the "blood entry components-target-pathway-disease" network based on the analysis of topological parameters. Molecular docking results showed that the six core components and Tectoridin with the highest content in the granules had a high affinity with the key targets of MAPK3, SRC, MAPK1, and STAT3. In vivo experiment results showed that compared with the model group, Ganke Granules could effectively alleviate LPS-induced histopathological injury in the lungs of mice and reduce the percentage of inflammatory infiltration. The total protein content, nitric oxide(NO) level, myeloperoxidase(MPO) content, tumor necrosis factor-α(TNF-α), gamma interferon(IFN-γ), interleukin-1ß(IL-1ß), interleukin-6(IL-6), vascular endothelial growth factor(VEGF), and chemokine(C-X-C motif) ligand 1(CXCL1) chemokines in bronchoalveolar lavage fluid(BALF) were decreased, and the expression levels of lymphocyte antigen 6G(Ly6G), citrullinated histones 3(Cit-H3), and phosphorylated proteins SRC, ERK1/2, and STAT3 in lung tissue were significantly down-regulated. In conclusion, Ganke Granules could effectively inhibit the inflammatory response of ALI induced by LPS, protect lung tissue, regulate the release of inflammatory factors, and inhibit neutrophil infiltration and NET formation, and the mechanism of action may be related to inhibiting the activation of SRC/ERK1/2/STAT3 signaling pathway.

Multi-strategy learning-based particle swarm optimization algorithm for COVID-19 threshold segmentation.

With advancements in science and technology, the depth of human research on COVID-19 is increasing, making the investigation of medical images a focal point. Image segmentation, a crucial step preceding image processing, holds significance in the realm of medical image analysis. Traditional threshold image segmentation proves to be less efficient, posing challenges in selecting an appropriate threshold value. In response to these issues, this paper introduces Inner-based multi-strategy particle swarm optimization (IPSOsono) for conducting numerical experiments and enhancing threshold image segmentation in COVID-19 medical images. A novel dynamic oscillatory weight, derived from the PSO variant for single-objective numerical optimization (PSOsono) is incorporated. Simultaneously, the historical optimal positions of individuals in the particle swarm undergo random updates, diminishing the likelihood of algorithm stagnation and local optima. Moreover, an inner selection learning mechanism is proposed in the update of optimal positions, dynamically refining the global optimal solution. In the CEC 2013 benchmark test, PSOsono demonstrates a certain advantage in optimization capability compared to algorithms proposed in recent years, proving the effectiveness and feasibility of PSOsono. In the Minimum Cross Entropy threshold segmentation experiments for COVID-19, PSOsono exhibits a more prominent segmentation capability compared to other algorithms, showing good generalization across 6 CT images and further validating the practicality of the algorithm.

Efficacy of botulinum toxin A combined with extracorporeal shockwave therapy in post-stroke spasticity: a systematic review.

Objectives: In recent years, there has been an increase in the number of randomized clinical trials of BTX-A combined with ESWT for the treatment of post-stroke spasticity. This has made it possible to observe the benefits of combination therapy in clinical practice. Therefore, this paper reviews the effectiveness of BTX-A in combination with ESWT for the treatment of post-stroke spasticity. Methods: By October 2023, a systematic review was conducted in the databases PubMed, Cochrane, Embase, Medline, Web of Science, China National Knowledge Infrastructure, Wan Fang Database, China Biology Medicine disc and China Science and Technology Journal Database were systematically searched. We included randomized controlled trials that reported outcome metrics such as MAS, FMA, and MBI score. Studies were excluded if MAS was not reported. The quality of the included studies was assessed by the Cochrane Collaboration's tool for assessing risk of bias, and the AMSTAR quality rating scale was selected for self-assessment. Results: A total of 70 articles were included in the initial search, and six were ultimately included. The results of the included studies showed that the combination therapy was effective in reducing MAS scores and improving FMA and MBI scores in patients with spasticity compared to the control group. Combination therapy has also been shown to improve joint mobility and reduce pain in spastic limbs. Conclusion: Cumulative evidence from clinical randomized controlled trial studies suggests that the combination therapy is effective in reducing lower limb spasticity and improving mobility after stroke. However, more clinical trials are still needed to corroborate the evidence regarding the efficacy of BTX-A combined with shockwave therapy. Systematic Review Registration: The system review can be searched in the PROSPERO database (CRD42023476654).

Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.

Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring p53 and ATRX loss of function mutations. In this study, RNA-seq and ChIP-seq data revealed human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies related to mitochondrial metabolism and upregulated autophagy. Further analysis revealed that the decreased mitochondrial metabolism was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy in mIDH1 glioma cells. Analysis of autophagy pathways showed that mIDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy activity. This dependence is reflected by increased sensitivity of mIDH1 glioma cells to autophagy inhibition. Blocking autophagy selectively impairs the growth of cultured mIDH1 glioma cells but not wild-type IDH1 (wtIDH1) glioma cells. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 (SPNP-siRNA-Atg7) sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory, when used in combination with IR. Our results indicate autophagy as a critical pathway for survival and maintenance of mIDH1 glioma cells, a strategy that has significant potential for future clinical translation. One Sentence Summary: The inhibition of autophagy sensitizes mIDH1 glioma cells to radiation, thus creating a promising therapeutic strategy for mIDH1 glioma patients. Graphical abstract: Our genetically engineered mIDH1 mouse glioma model harbors IDH1 R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies.

Effect of Rare Earth Elements on Microstructure and Tensile Behavior of Nb-Containing Microalloyed Steels.

The present investigation endeavors to explore the influence of rare earth elements on the strength and plasticity characteristics of low-carbon microalloyed steel under tensile loading conditions. The findings from the conducted tensile tests indicate that the incorporation of rare earths leads to a notable enhancement in the yield strength, ultimate tensile strength, and ductility properties of the steel. A comparative analysis of the microstructures reveals that the presence of rare earths significantly refines and optimizes the microstructure of the microalloyed steel. This optimization is manifested through a reduction in grain size, diminution of inclusion sizes, and a concomitant rise in their number density. Moreover, the addition of rare earths is observed to foster an increase in the volumetric fraction of carbides within the steel matrix. These multifaceted microstructural alterations collectively contribute to a substantial strengthening of the microalloyed steel. Furthermore, it is elucidated that the synergistic interaction between rare earth elements and both carbon (C) and niobium (Nb) in the steel matrix augments the extent of the Lüders strain region during the tensile deformation of specimens. This phenomenon is accompanied by the effective modification of inclusions by the rare earths, which serves to mitigate stress concentrations at the interfaces between the inclusions and the surrounding matrix. This article systematically evaluates the modification mechanism of rare earth microalloying, which provides a basis for broadening the application of rare earth microalloying in microalloyed steel.

Spiritual Needs and Influencing Factors of Postoperative Breast Cancer Women Undergoing Chemotherapy: A Cross-Sectional Study.

Purpose: The purpose of the study was to determine the status of spiritual needs and influencing factors of postoperative breast cancer (BC) women undergoing chemotherapy. Participants and Methods: This study is a cross-sectional study. A total of 173 participants completed a general information questionnaire and a Chinese version of the Spiritual Needs Scale at the Guangxi Medical University Cancer Hospital. Data were collected by purposive sampling from December 2022 to April 2023. Data were analyzed by descriptive statistics, independent t-test, ANOVA, non-parametric test, and logistic regression analysis. Results: The spiritual needs of postoperative BC women undergoing chemotherapy were at a high level (84.20 ± 12.86). The need for "hope and peace" was considered paramount and the need for a "relationship with transcendence" was considered the least important. Significant differences were found in the following: spiritual needs total score (P=0.040) and "hope and peace" (P=0.021) in education level; "love and connection" in disease stage (P=0.021); "meaning and purpose" in education level (P=0.013), household income (P=0.012), and payment method (P=0.015); "relationship with transcendence" in religion (P<0.001); and "acceptance of dying" in marital status (P=0.023). The level of education was the influencing factor of spiritual needs (OR=1.50, P=0.005), especially for "hope and peace" (OR=1.50, P=0.012). Conclusion: The spiritual need of postoperative BC Chinese women undergoing chemotherapy is at a high level and should receive more attention. In clinical work, nurses should fully assess the spiritual needs of patients and meet their specific needs. Results may help nurses to develop targeted and comprehensive spiritual intervention strategies according to the characteristics of patients.

Design, synthesis, and evaluation of novel ferrostatin derivatives for the prevention of HG-induced VEC ferroptosis.

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases.

Brief discussion of the differences in the acupoint location between Meridians and Acupoints and Acupuncture and Moxibustion. / æµ è®®ã€Šç»ç»œè §ç©´å­¦ã€‹å’Œã€Šé’ˆç¸å­¦ã€‹"十四五"规划教材经穴定位差异.

There are the differences in the location of some acupoints between textbooks Meridians and Acupoints and Acupuncture and Moxibustion. Both of the textbooks are in the category of the "14th Five-Year Plan". The differences in acupoint location have brought some confusion for students, full-time teachers and researchers in the field of traditional Chinese medicine. In the paper, based on GB/T 12346-2021： Nomenclature and Location of Meridian Points, published in2021, and in reference with GB/T 12346-2006： Nomenclature and Location of Acupuncture Points, published in 2006, the discrepancy in the acupoint location was systematically collated in the aspects of the expression style and layout, text expression and potential difference of location between these two textbooks, published by China Press of Traditional Chinese Medicine, People's Medical Publishing House and China Science Publishing. Based on the historical evolution and the academic controversy of acupoint positioning, the reasons of the differences in acupoint location were analyzed, the potential influences on the teaching, examination, competition and research of Chinese medicine acupuncture were explored, and the suggestions for solution were proposed.

Atopic Dermatitis Associated Retinal Detachment and Retinal Vasculitis: A Case Report.

Atopic dermatitis is usually associated with various ocular complications. We report a 21-year-old Chinese male who presented to our ophthalmology clinic with bilateral retinal detachment and cataracts. The patient had a clear medical history of atopic dermatitis, which had been diagnosed eight years earlier and had been treated with loratadine and pimecrolimus. Cataract surgery was performed for both eyes, combined with scleral buckling for the right eye and pars plana vitrectomy for the left eye. During postoperative follow-up, fundus fluorescein angiography showed retinal vasculitis in both eyes and macular edema in the left eye, which coincided with an exacerbation of atopic dermatitis. Macular edema improved after four months of regular dupilumab treatment in the dermatology department. The ocular condition remained stable three years postoperatively.

RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma.

Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.

Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.

PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury. METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC). RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy. CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.

Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors.

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.