An interdisciplinary treatment to reshape upper anterior displaced teeth by using dynamic occlusal recording with an intraoral scanner.

OBJECTIVE: This article describes an interdisciplinary treatment that helped a patient with displaced upper anterior teeth. A gingivectomy, root canal therapies, digital smile design, digital wax-up, and guided tooth preparations were applied. CLINICAL CONSIDERATIONS: A patient with pathologically migrated teeth asked for treatment without orthodontic involvement due to a primary failed orthodontic treatment history. A smile photo was taken and superimposed with the dentition in a CAD software to accomplish a digital smile design. The jaw movements were recorded with two different methods, a mechanical articulator and an intraoral scanner with Patient-Specific-Motion function. The occlusal contacts during protrusive and lateral movements were compared and the digital wax-up was designed according to the later occlusal data. An aesthetic crown lengthening and pre-op root canal treatment were carried out in advance accordingly. After guided tooth preparation with a silicone index, the final fixed restorations were manufactured and cemented. A 2-year follow-up showed that our prosthesis functions well. CONCLUSIONS: This clinical report revealed that an intraoral scanner with Patient-Specific-Motion function can effectively record individual dynamic occlusal patterns and these data can be integrated into the CAD/CAM process to enhance the fulfillment of clinical requirements. CLINICAL SIGNIFICANCE: This clinical procedure with a 2-year follow-up demonstrated that a prosthodontic-based interdisciplinary treatment of pathologically migrated teeth using dynamic occlusal recording with an intraoral scanner could achieve satisfactory esthetics in a relatively short treatment period. The Patient Specific Motion module may be used to record a personalized functional movement and the data can be integrated into the design process of the final restorations.

Unraveling the Solvent Regulation in the Heteroatom-Doped Endohedral Gold Clusters: A Theoretical Study on the Electronic Properties and O2 Activation.

Liquid-phase synthesis of atomically precise nanoclusters has experienced rapid development recently, where polar solvents are indispensable in such a process. However, the regulation effect of solvents on the structural and electronic properties of different metal clusters and cluster assembly materials is still not well understood. Herein, a comprehensive density functional theory calculation has been performed to explore the solvation effect on heteroatom-doped endohedral gold clusters that always have remarkable stabilities and tunable electronic structures. The solvation free energy of the M@Au12 clusters (M = Cr, Mo, W, Co, Rh, Ir, Cu, Ag, and Au) was found to be related to the charge distribution of the central doped-atom M and the outer Au12 cage. Moreover, the aqueous solvent was observed to be able to increase the adsorption capacity of M@Au12 to O2 following the activation of O2 through the charge transfer from M@Au12 to O2, in which the transferred electrons occupy the π antibonding orbital of O2. In addition, the water solvent can also improve the hydrogenation reaction of O2 to form OOH over M@Au12, where the activation energy barrier for this process is very low with the participation of the solvent. Considering the importance of solvents in the liquid-phase synthesis of atomically precise clusters, these findings highlighted here could provide valuable theoretical guidance in potential applications of functional gold nanoclusters, especially in the liquid-phase cluster catalysis.

Beyond Shell-Filling: Strong Enhancement of Electron Affinity of Metal Clusters through a Noninvasive Oriented External Electric Field.

Traditional electron counting rules, like the Jellium model, have long been successfully utilized in designing superhalogens by modifying clusters to have one electron less than a filled electronic shell. However, this shell-filling approach, which involves altering the intrinsic properties of the clusters, can be complex and challenging to control, especially in experiments. In this letter, we theoretically establish that the oriented external electric field (OEEF) can substantially enhance the electron affinity (EA) of diverse aluminum-based metal clusters with varying valence electron configurations, leading to the creation of superhalogen species without altering their shell arrangements. This OEEF approach offers a noninvasive alternative to traditional superatom design strategies, as it does not disrupt the clusters' geometrical structures and superatomic states. These findings contribute a vital piece to the puzzle of constructing superalkalis and superhalogens, extending beyond conventional shell-filling strategies and potentially expanding the range of applications for functional clusters.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

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.

Global 30-day morbidity and mortality of surgery for perforated peptic ulcer: GRACE study.

BACKGROUND: There is little international data on morbidity and mortality of surgery for perforated peptic ulcer (PPU). This study aimed to understand the global 30-day morbidity and mortality of patients undergoing surgery for PPU and to identify variables associated with these. METHOD: We performed an international study of adults (≥ 18 years) who underwent surgery for PPU from 1st January 2022 to 30th June 2022. Patients who were treated conservatively or had an underlying gastric cancer were excluded. Patients were divided into subgroups according to age (≤ 50 and > 50 years) and time from onset of symptoms to hospital presentation (≤ 24 and > 24 h). Univariate and Multivariate analyses were carried out to identify factors associated with higher 30-day morbidity and mortality. RESULTS:  1874 patients from 159 centres across 52 countries were included. 78.3% (n = 1467) of the patients were males and the median (IQR) age was 49 years (25). Thirty-day morbidity and mortality were 48.5% (n = 910) and 9.3% (n = 174) respectively. Median (IQR) hospital stay was 7 (5) days. Open surgery was performed in 80% (n = 1505) of the cohort. Age > 50 years [(OR = 1.7, 95% CI 1.4-2), (OR = 4.7, 95% CI 3.1-7.6)], female gender [(OR = 1.8, 95% CI 1.4-2.3), (OR = 1.9, 95% CI 1.3-2.9)], shock on admission [(OR = 2.1, 95% CI 1.7-2.7), (OR = 4.8, 95% CI 3.2-7.1)], and acute kidney injury [(OR = 2.5, 95% CI 1.9-3.2), (OR = 3.9), 95% CI 2.7-5.6)] were associated with both 30-day morbidity and mortality. Delayed presentation was associated with 30-day morbidity [OR = 1.3, 95% CI 1.1-1.6], but not mortality. CONCLUSIONS: This study showed that surgery for PPU was associated with high 30-day morbidity and mortality rate. Age, female gender, and signs of shock at presentation were associated with both 30-day morbidity and mortality.

Association of anion gap and albumin corrected anion gap with acute kidney injury in patients with acute ischemic stroke.

BACKGROUND: Acute kidney injury (AKI) has become a common complication of acute ischemic stroke (AIS) and may have a significant impact on clinical outcomes. Anion gap (AG)/albumin corrected anion gap (ACAG) are used to assess acid-base balance status and help identify the severity of metabolic acidosis. OBJECTIVES: To explore the association of AG and ACAG with the risk of AKI in AIS patients admitted to the intensive care unit (ICU). MATERIAL AND METHODS: Data of AIS patients in this retrospective cohort study were extracted from the electronic ICU (eICU) databases (2014-2015). The outcome was the occurrence of AKI after ICU admission. The covariates included demographic data, vital signs, comorbidities, laboratory parameters, and medication use. The association of AG and ACAG levels with AKI risk in AIS patients was evaluated using univariate and multivariate logistic regression models with odds ratios (ORs) and 95% confidence intervals (95% CIs). The predictive performance of AG and ACAG for the risk of AKI in AIS patients was assessed with the area under the curve (AUC). To further explore the association of AG and ACAG levels with AKI risk, subgroup analyses were performed according to comorbidities. RESULTS: Of the 1,260 AIS patients, 546 (43%) developed AKI. Elevated AG (OR = 1.73, 95% CI: 1.32-2.29) and ACAG (OR = 1.57, 95% CI: 1.21-2.04) were associated with the risk of AKI in AIS patients. The AUC of ACAG was superior to AG for predicting the risk of AKI (0.581 vs 0.558; p = 0.024). Elevated ACAG levels were associated with the risk of AKI in AIS patients without ischemic heart disease (OR = 1.60, 95% CI: 1.19-2.15), diabetes (OR = 1.58, 95% CI: 1.19-2.10) and hypertension (OR = 1.69, 95% CI: 1.24-2.30). CONCLUSIONS: Albumin corrected anion gap was a better predictor than AG for AKI risk in AIS patients, which may help clinicians identify high-risk patients for AKI.

Dual External Field Strategy in Regulating the Superhalogen Characteristics of the Non-Noble Metal Constituted Tantalum Oxide Clusters.

The identification of the non-noble metal constituted TaO cluster as a potential analogue to the noble metal Au is significant for the development of tailored materials. It leverages the superatom concept to engineer properties with precision. However, the impact of incrementally integrating TaO units on the electronic configurations and properties within larger TaO-based clusters remains to be elucidated. By employing the density functional theory calculations, the global minima and low-lying isomers of the TanOn (n = 2-5) clusters were determined, and their structural evolution was disclosed. In the cluster series, Ta5O5 was found to possess the highest electron affinity (EA) with a value of 2.14 eV, based on which a dual external field (DEF) strategy was applied to regulate the electronic property of the cluster. Initially, the electron-withdrawing CO ligand was affixed to Ta5O5, followed by the application of an oriented external electric field (OEEF). The CO ligation was found to be able to enhance the Ta5O5 cluster's electron capture capability by adjusting its electron energy levels, with the EA of Ta5O5(CO)4 peaking at 2.58 eV. Subsequently, the introduction of OEEF further elevated the EA of the CO-ligated cluster. Notably, OEEF, when applied along the +x axis, was observed to sharply increase the EA to 3.26 eV, meeting the criteria for superhalogens. The enhancement of EA in response to OEEF intensity can be quantified as a functional relationship. This finding highlights the advantage of OEEF over conventional methods, demonstrating its capacity for precise and continuous modulation of cluster EAs. Consequently, this research has adeptly transformed tantalum oxide clusters into superhalogen structures, underscoring the effectiveness of the DEF strategy in augmenting cluster EAs and its promise as a viable tool for the creation of superhalogens.

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.

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.

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.

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.

[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.

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.

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.

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.