Interaction between resveratrol and SIRT1: role in neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, pose significant health challenges and economic burdens worldwide. Recent studies have emphasized the potential therapeutic value of activating silent information regulator-1 (SIRT1) in treating these conditions. Resveratrol, a compound known for its ability to potently activate SIRT1, has demonstrated promising neuroprotective effects by targeting the underlying mechanisms of neurodegeneration. In this review, we delve into the crucial role of resveratrol-mediated SIRT1 upregulation in improving neurodegenerative diseases. The role of the activation of SIRT1 by resveratrol was reviewed. Moreover, network pharmacology was used to elucidate the possible mechanisms of resveratrol in these diseases. Activation of SIRT1 by resveratrol had positive effects on neuronal function and survival and alleviated the hallmark features of these diseases, such as protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In terms of network pharmacology, the signaling pathways by which resveratrol protects against different neurodegenerative diseases were slightly different. Although the precise mechanisms underlying the neuroprotective effects of resveratrol and SIRT1 activation remain under investigation, these findings offer valuable insights into potential therapeutic strategies for neurodegenerative diseases.

Design and Verification of Piano Playing Assisted Hand Exoskeleton Robot.

Finger technique is a crucial aspect of piano learning, and hand exoskeleton mechanisms effectively assist novice piano players in maintaining correct finger technique consistently. Addressing current issues with exoskeleton robots, such as the inability to provide continuous correction of finger technique and their considerable weight, a novel hand exoskeleton robot has been developed to enhance finger technique through continuous correction and reduced weight. Initial data are gathered using finger joint angle sensors to analyze movements during piano playing, focusing on the trajectory and angular velocity of key strikes. This analysis informs the design of a 6-bar double-closed-loop mechanism with an end equivalent sliding pair, using analytical methods to establish the relationship between motor extension and input rod rotation. Simulation studies assess the exoskeleton's motion space and dynamics, confirming its capability to meet structural and functional demands for accurate key striking. Prototype testing validates the exoskeleton's ability to maintain correct finger positioning and mimic natural strike speeds, thus improving playing technique while ensuring comfort and safety.

Flow and performance: a quantitative study of elicitation modeling in a piano performance perspective.

Introduction: Flow, defined as a heightened state of consciousness characterized by intense concentration during an activity, is influenced primarily by the perceived challenge and the dynamic equilibrium of skills. This investigation focuses on the patterns of flow state attainment and its elicitation mechanisms within the context of piano performance among Chinese music college students. Methods: Our study establishes a framework for accessing flow, utilizing quantitative data from music ontology to gauge the level of challenge and the level of music acquisition to assess skills. Additionally, we integrate external factors such as music culture heterogeneity and demographic variables to elucidate the causes and moderating effects of flow on piano performance. Results: The findings reveal a positive correlation between flow and performance, with the model of challenge and skill induction partially explaining these results. Notably, melodic Shannon Entropy emerges as a potential indicator of challenge, suggesting its relevance in future studies on flow. Discussion: This research provides multidimensional insights into the interplay between performance and flow in piano performance, guiding future investigations to explore the musical quantitative perspective more deeply.

Aerobic exercise-induced HIF-1α upregulation in heart failure: exploring potential impacts on MCT1 and MPC1 regulation.

BACKGROUND: The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia. METHODS: The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid transfection. RESULTS: Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level. CONCLUSION: The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.

The deubiquitinating protein OTUD6B promotes lung adenocarcinoma progression by stabilizing RIPK1.

BACKGROUND: There is growing evidence indicating that deubiquitinating enzymes may contribute to tumor progression and can serve as promising therapeutic targets. METHODS: The overexpression of deubiquitinase OTUD6B in lung adenocarcinoma (LUAD) and its adjacent tissues was analyzed by immunohistochemistry and TCGA/GO database. Survival analysis further supported OTUD6B as a potential target for LUAD treatment. We assessed the effect of OTUD6B on LUAD cell growth using cell viability assays and conducted TUNEL staining, migration, and invasion experiments to investigate the impact of OTUD6B on the apoptosis and metastasis of LUAD cells. Additionally, we established a transplanted tumor model in nude mice to validate our findings in vivo. Finally, using IP mass spectrometry and co-IP experiments, we screened and confirmed the influence of RIPK1 as a substrate of OTUD6B in LUAD. RESULTS: OTUD6B is highly overexpressed in human LUAD and predicts poor prognosis in LUAD patients. OTUD6B knockdown inhibited the proliferation of LUAD cells and enhanced apoptosis and inhibited metastasis in LUAD cells suppressed. A549 xenografts revealed that OTUD6B deletion can slow down tumour growth. Additionally, OTUD6B can bind to RIPK1, reduce its ubiquitination level and increase its protein stability. CONCLUSIONS: Our results suggest that OTUD6B is a promising clinical target for LUAD treatment and that targeting OTUD6B may constitute an effective anti-LUAD strategy.

Amino-Acid-Encoded Supramolecular Nanostructures for Persistent Bioluminescence Imaging of Tumor.

Bioluminescence imaging (BLI) is a powerful technique for noninvasive monitoring of biological processes and cell transplantation. Nonetheless, the application of D-luciferin, which is widely employed as a bioluminescent probe, is restricted in long-term in vivo tracking due to its short half-life. This study presents a novel approach using amino acid-encoded building blocks to accumulate and preserve luciferin within tumor cells, through a supramolecular self-assembly strategy. The building block platform called Cys(SEt)-X-CBT (CXCBT, with X representing any amino acid) utilizes a covalent-noncovalent hybrid self-assembly mechanism to generate diverse luciferin-containing nanostructures in tumor cells after glutathione reduction. These nanostructures exhibit efficient tumor-targeted delivery as well as sequence-dependent well-designed morphologies and prolonged bioluminescence performance. Among the selected amino acids (X = Glu, Lys, Leu, Phe), Cys(SEt)-Lys-CBT (CKCBT) exhibits the superior long-lasting bioluminescence signal (up to 72 h) and good biocompatibility. This study demonstrates the potential of amino-acid-encoded supramolecular self-assembly as a convenient and effective method for developing BLI probes for long-term biological tracking and disease imaging.

Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation.

We previously reported that loss of function of TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether TYW1 loss affects neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe and therefore affected the translation efficiency of UUU codon. Using the brain organoid model, we showed impaired neuron differentiation when TYW1 was depleted. Interestingly, retrotransposons were differentially regulated in TYW1-/- hESCs (human embryonic stem cells). In particular, one kind of human-specific endogenous retrovirus-K (HERVK/HML2), whose reactivation impaired human neurodevelopment, was significantly up-regulated in TYW1-/- hESCs. Consistently, a UUU codon-enriched protein, SMARCAD1, which was a key factor in controlling endogenous retroviruses, was reduced. Taken together, TYW1 loss leads to up-regulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.

The safety of maxillary sinus floor elevation and the accuracy of implant placement using dynamic navigation.

OBJECTIVE: To date, it remains a challenge to conduct maxillary sinus floor elevation (MSFE) owing to heterogeneity of anatomical structures and limited operative visibility of the maxillary sinus. The aim of this study is to investigate the safety of MSFE and the accuracy of implant placement using dynamic navigation. METHODS: Forty-two implants were placed in thirty-five patients requiring implantation in posterior maxilla with dynamic navigation. They were assigned to either lateral window sinus floor elevation (LWSFE) group (n = 22) or transcrestal sinus floor elevation (TSFE) group (n = 20) according to the residual alveolar bone height (RBH). Platform deviation, apex deviation and angular deviation between actual and planned implant placement were measured in precision evaluation software. Three deviations of two groups were compared via SPSS 22.0 software. RESULTS: Neither accidental bleeding nor perforation of Schneiderian membrane occurred in any patients. The actual window position of LWSFE was consistent with the preoperative design. There were no significant differences in platform, apex and angular deviations between the two groups (P > 0.05). CONCLUSION: In this study the dynamic navigation harvested clinically acceptable safety of MSFE and accuracy for implant placement in posterior maxillary region. The dynamic navigation would provide the clinician with assistance in achieving precise preoperative planning and reducing complications in surgical procedures. The granular bone grafts used in the LWSFE did not significantly affection on the accuracy of the simultaneous implant placement under the guidance of dynamic navigation.

The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers.

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists.

Constructing an Asymmetric Covalent Triazine Framework to Boost the Efficiency and Selectivity of Visible-Light-Driven CO2 Photoreduction.

The photocatalytic reduction of CO2 represents an environmentally friendly and sustainable approach for generating valuable chemicals. In this study, a thiophene-modified highly conjugated asymmetric covalent triazine framework (As-CTF-S) is developed for this purpose. Significantly, single-component intramolecular energy transfer can enhance the photogenerated charge separation, leading to the efficient conversion of CO2 to CO during photocatalysis. As a result, without the need for additional photosensitizers or organic sacrificial agents, As-CTF-S demonstrates the highest photocatalytic ability of 353.2 µmol g-1 and achieves a selectivity of ≈99.95% within a 4 h period under visible light irradiation. This study provides molecular insights into the rational control of charge transfer pathways for high-efficiency CO2 photoreduction using single-component organic semiconductor catalysts.

Inactivation of Myostatin Delays Senescence via TREX1-SASP in Bovine Skeletal Muscle Cells.

The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and age-associated muscle loss in other animals are related. In this study, we utilized MSTN gene-edited bovine skeletal muscle cells to investigate the mechanisms relating to MSTN and muscle cell senescence. The expression of MSTN was higher in older individuals than in younger individuals. We obtained consecutively passaged senescent cells and performed senescence index assays and transcriptome sequencing. We found that senescence hallmarks and the senescence-associated secretory phenotype (SASP) were decreased in long-term-cultured myostatin inactivated (MT-KO) bovine skeletal muscle cells (bSMCs). Using cell signaling profiling, MSTN was shown to regulate the SASP, predominantly through the cycle GMP-AMP synthase-stimulator of antiviral genes (cGAS-STING) pathway. An in-depth investigation by chromatin immunoprecipitation (ChIP) analysis revealed that MSTN influenced three prime repair exonuclease 1 (TREX1) expression through the SMAD2/3 complex. The downregulation of MSTN contributed to the activation of the MSTN-SMAD2/3-TREX1 signaling axis, influencing the secretion of SASP, and consequently delaying the senescence of bSMCs. This study provided valuable new insight into the role of MSTN in cell senescence in large animals.

Epidemiological features of 1,332 cases of hip fracture in Shanghai, China (2015-2020).

PURPOSE: This study aimed to analyze the epidemiological characteristics of hip fracture in all age groups in Shanghai, and to evaluate the hospitalization cost of patients with hip fracture. METHODS: A total of 1,332 hip fracture patients admitted to a tertiary general hospital between January 2015 and May 2020 in Shanghai were included. Age, sex, diagnosis, cause of injury and site, fracture type, comorbidities, length of stay, treatment, outcomes (at discharge) and hospitalization expenses were recorded. The epidemiological characteristics of hip fracture were analyzed by using SPSS 26.0 software. RESULTS: The average age of hip fracture was 77.24 ± 12.66 years, and 69.0% of the patients were female. Overall, 886 patients had femoral neck fracture, and 446 patients suffered from intertrochanteric fracture. Most of the fractures caused by falls at the same level and falls from a height occurred in those aged 81-90 years; and traffic accident injuries mostly took place in patients aged 50-60. Among the 1,302 hip fracture patients who underwent surgical treatment, hip replacement was the major choice for femoral neck fracture, accounting for 49.2%. Internal fixation was the main treatment choice for intertrochanteric fracture, making up 97.8%. The median length of hospital stay lasted 8 days and at cost of hospitalization was ¥49,138.18 RMB. CONCLUSION: This epidemiological study found that patients with hip fracture had certain distribution characteristics in age, sex, type of fracture, injury season, cause of injury, mode of operation, length of stay, cost, and so on. Proper medical management, social preventive measures, and prevention of falls are needed to reduce the risk of hip fracture and the socioeconomic burden.

Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Incidence of thromboembolic events in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

ABSTRACT: The incidence of thromboembolic events (TEs) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) has rarely been reported. The MEDLINE, EMBASE, and the Cochrane Library databases were searched. The primary outcome was the incidence of TEs, and the secondary outcome was the relationship between TEs and overall survival (OS) following ICI therapy. A subgroup analysis of TE incidents was performed according to the TE type and combination regimens. The I2 statistic was used to determine the heterogeneity, and funnel plots and Egger's test were used to assess publication bias. A total of 16,602 patients with NSCLC in 63 experimental arms were included in the analysis. The rate of TEs ranged from 0.1% to 13.8%, and the pooled overall incidence of all-grade TEs was 3% (95% confidence interval [CI], 2%-4%). The pooled rate of high-grade TEs was 1% (95% CI, 1%-2%). The venous and arterial TE rates were 3% (95% CI, 2%-4%) and 1% (95% CI, 1%-2%), respectively. Patients who received immunotherapy + chemoradiotherapy had the highest incidence of TEs (7%). The TE pooled rate was higher in patients treated with combined ICIs than in those treated with mono ICIs (4% vs. 2%). The OS was lower in patients with TEs than in those without TEs (hazard ratio, 1.4; 95% CI, 1.02%-1.92%). The incidence of TEs in NSCLC patients treated with ICIs was reasonable. Nonetheless, clinicians must be aware of potential thrombotic complications and treat them promptly.

Assessment of supply-demand relationships considering the interregional flow of ecosystem services.

Accurate assessment of ecosystem service (ES) supply, demand, and flow is essential for identifying and enhancing the ES supply-demand relationship and promoting regional sustainable development. Based on the InVEST model, supply-demand ratio, coupling coordination analysis, breakpoint and field strength model, and GIS spatial analysis method, we evaluated the supply and demand of water yield, food supply, carbon storage, and soil conservation service in the Loess Plateau in 2000 and 2020 and analyzed the supply-demand relationship before and after considering the interregional ecosystem service flow (ESF). The results showed that (1) from 2000 to 2020, the supply and demand of the four types of ESs in the Loess Plateau increased. Before considering ESF, the surplus degree in water yield, food supply, and soil conservation increased, and carbon storage decreased. In most counties, the coupling coordination between the supply and demand of the soil conservation is mostly extreme incoordination and moderate incoordination, and other types of ESs are mostly reluctant coordination and moderate incoordination. The degree of incoordination in water yield and soil conservation have eased, while food supply and carbon storage have strengthened. For the comprehensive supply-demand relationship of ES, the degree of surplus and coordination increased, with most counties were in a state of surplus and coordination. (2) Water yield and soil conservation services flow primarily to the western and northwestern portions of the Loess Plateau, with a decrease in the number of flow paths but an increase in the total flow rate for the former and a decrease in flow paths and total flow rate for the latter. The food supply and carbon storage flow in all directions and the total flow rate increases, with a significant increase in the number of flow paths for carbon storage. (3) After considering ESF, the supply-demand relationship of each type of ES and the comprehensive ES supply-demand relationship are changed, in which the degree of surplus and coordination of deficit counties are significantly improved, and some counties even become surplus or improve the level of coordination. After considering ESF, the supply-demand ratio changes even more relative to the degree of coupling coordination. This study is of great significance for identifying the cross-regional transfer pattern of ES, understanding in-depth the dynamic supply-demand relationship of ES, and mitigating the mismatch between supply and demand of ES. It provides a scientific and objective theoretical basis for promoting regional sustainable development.

Synergism of non-thermal plasma and low concentration RSL3 triggers ferroptosis via promoting xCT lysosomal degradation through ROS/AMPK/mTOR axis in lung cancer cells.

BACKGROUND: Though (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3. METHODS: CCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3. RESULTS: We found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment. CONCLUSION: Our research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.

Genetic association of lipid-lowering drugs with aortic aneurysms: a Mendelian randomization study.

AIMS: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. METHODS AND RESULTS: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. CONCLUSION: This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

KEY FINDINGS: High expression of HMGCR, PCSK9, and CETP was positively correlated with the risk of aortic aneurysms, highlighting that the corresponding lipid-lowering drugs may be preferred for preventing arterial aneurysms in high-risk individuals with dyslipidemia. We found that genetically predicted HMGCR inhibitors were positively associated with smaller aortic lumen size, which is the first time to support the causal association of gene HMGCR on the lumen size of aortic aneurysms.

This Mendelian randomization study used publicly available data involving over 1 million individuals to demonstrate the causal relationship between five target genes of LDL-C-lowering medicines and the risk of aortic aneurysms, and implied one lipid-lowering drug may link with the lumen size of aortic aneurysms.

Exogenous carbon monoxide promotes GPX4-dependent ferroptosis through ROS/GSK3ß axis in non-small cell lung cancer.

The gas therapy is drawing increasing attention in the treatment of many diseases including cancer. As one of gas signaling molecules, carbon monoxide (CO) has been proved to exert anti-cancer effects via triggering multiple cell death types, such as autophagy, apoptosis and necrosis. Here, we showed that low concentration CO delivered from CO-releasing molecule 3 (CORM-3) effectively induced ferroptosis, known as a novel proinflammatory programmed cell death, in vitro and in vivo. Mechanistically, we found that CO triggered ferroptosis by modulating the ROS/GSK3ß/GPX4 signaling pathway, resulting in the accumulation of lipid hydroperoxides and the occurrence of ferroptosis. We think our findings provide novel insights into the anti-cancer mechanisms of CO, and suggest that CO could potentially be exploited as a novel ferroptosis inducer for cancer treatment in the future.