Unravelling oncosis: morphological and molecular insights into a unique cell death pathway.

Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance.

Comprehensive Analysis of Immune Responses to Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer.

BACKGROUND: Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of early stage non-small cell lung cancer (NSCLC). However, little is known about which patients are likely to benefit most from neoadjuvant immunotherapy. In this study, we performed a multiplatform analysis on samples from resectable NSCLC treated with neoadjuvant immunotherapy to explore molecular characteristics related to immune responses. PATIENTS AND METHODS: A total of 17 patients with resectable stage IB-IIIA NSCLC treated with neoadjuvant immunotherapy were included. A multiplex cytokine assay, bulk TCR sequencing in peripheral blood, and multiplexed immunohistochemistry were performed. RESULTS: Low levels of stromal cell-derived factor (SDF)-1alpha at baseline were associated with unfavorable disease-free survival (DFS). Patients with major pathologic response (MPR) showed a decrease in HGF after one cycle of neoadjuvant immunotherapy. An increase in IDO and IP-10 was observed in patients who developed immune-related adverse events (irAEs) after neoadjuvant immunotherapy. There were no correlations between irAEs and MPR or DFS. The MPR group presented a significant decrease in white blood cells and neutrophil count after neoadjuvant immunotherapy. The high peripheral baseline TCR convergence was correlated with MPR and favorable DFS in lung squamous cell carcinoma (LUSC) receiving neoadjuvant immunotherapy. Neoadjuvant immunotherapy led to a significant increase in CD4+, CD8+, and CD8+CD39+ T-cell infiltration in tumor areas. CONCLUSIONS: This study suggests the potential roles of cytokines and TCR convergence for predicting ICIs response in resectable NSCLC and LUSC. CD8+CD39+T cells and CD4+ T cells could be involved in the action of neoadjuvant immunotherapy.

SIRT1-driven mechanism: sevoflurane's interference with mESC neural differentiation via PRRX1/DRD2 cascade.

Investigating the sevoflurane-induced perturbation in the differentiation of mouse embryonic stem cells (mESCs) into neural stem cells (mNSCs), our study delineates a novel SIRT1/PRRX1/DRD2/PKM2/NRF2 axis as a key player in this intricate process. Sevoflurane treatment hindered mESC differentiation, evidenced by altered expression patterns of pluripotency and neural lineage markers. Mechanistically, sevoflurane downregulated Sirt1, setting in motion a signaling cascade. Sevoflurane may inhibit PKM2 dimerization and NRF2 signaling pathway activation by inhibiting the expression of SIRT1 and its downstream genes Prrx1 and DRD2, ultimately inhibiting mESCs differentiation into mNSCs. These findings contribute to our understanding of the molecular basis of sevoflurane-induced neural toxicity, presenting a potential avenue for therapeutic intervention in sevoflurane-induced perturbation in the differentiation of mESCs into mNSCs by modulating the SIRT1/PRRX1/DRD2/PKM2/NRF2 axis.

CCTA-Derived Fat Attenuation Index Predict Future Percutaneous Coronary Intervention.

OBJECTIVES: This study aims to investigate the differences in plaque characteristics and fat attenuation index (FAI) between in patients who received revascularization versus those who did not receive revascularization and examine whether the machine-learning (ML) based model constructed by plaque characteristics and FAI can predict revascularization. MATERIALS & METHODS: This study was a post hoc analysis of a prospective single-center registry of sequential patients undergoing CCTA, referred from inpatient and emergency department settings (n = 261, 63 years ± 8; 188 men). The primary outcome was revascularization by percutaneous coronary revascularization. The CTA images were analyzed by experienced radiologists using a dedicated workstation in a blinded fashion. The ML-based model was automatically computed. RESULTS: The study cohort consisted of 261 subjects. Revascularization was performed in 105 subjects. Patients receiving revascularization had higher FAI value (67.35±5.49 Hu vs -80.10±7.75 Hu, p < 0.001) as well as higher plaque length, calcified, lipid and fibrous plaque burden and volume. When FAI was incorporated into a ML risk model based on plaque characteristics to predict revascularization, the area under the curve increased from 0.84 (95% CI: 0.68-0.99) to 0.95 (95% CI: 0.88-1.00). CONCLUSION: ML-algorithms based on FAI and characteristics could help improve the prediction of future revascularization and identify patients likely to receive revascularization. ADVANCES IN KNOWLEDGE: Pre-procedural FAI could help guide revascularization in symptomatic CAD patients.

CCL3 Promotes Cutaneous Wound Healing Through Recruiting Macrophages in Mice.

Wound healing is a complex process, which involves three stages: inflammation, proliferation, and remodeling. Inflammation is the first step; thus, immune factors play an important regulatory role in wound healing. In this study, we focused on a chemokine, C-C motif chemokine ligand 3 (CCL3), which is often upregulated for expression during wound healing. We compared cutaneous wound healing at the histological, morphological, and molecular levels in the presence and absence of CCL3. The results showed that the wound healing rate in the wild-type and CCL3-/- + CCL3 mice was faster than that of CCL3-/- mice (P < 0.01), and application of CCL3 to wounds increased the healing rate. In the process of wound healing, the degree of reepithelialization and the rate of collagen deposition in the wound of CCL3-/- mice were significantly lower than those of wild-type mice (P < 0.01). The number of macrophages and the expression levels of tumor necrosis factor(TNF)-α and transforming growth factor (TGF)-ß1 in the wounds of wild-type mice were much higher than those of the CCL3-/- mice. Removal of macrophages and CCL3-/- mice share similar phenotypes. Therefore, we infer that the wound healing requires the participation of macrophages, and CCL3 may play an important regulatory role through recruiting macrophages to the wound sites.

A CNN model for early detection of pepper Phytophthora blight using multispectral imaging, integrating spectral and textural information.

BACKGROUND: Pepper Phytophthora blight is a devastating disease during the growth process of peppers, significantly affecting their yield and quality. Accurate, rapid, and non-destructive early detection of pepper Phytophthora blight is of great importance for pepper production management. This study investigated the possibility of using multispectral imaging combined with machine learning to detect Phytophthora blight in peppers. Peppers were divided into two groups: one group was inoculated with Phytophthora blight, and the other was left untreated as a control. Multispectral images were collected at 0-h samples before inoculation and at 48, 60, 72, and 84 h after inoculation. The supporting software of the multispectral imaging system was used to extract spectral features from 19 wavelengths, and textural features were extracted using a gray-level co-occurrence matrix (GLCM) and a local binary pattern (LBP). The principal component analysis (PCA), successive projection algorithm (SPA), and genetic algorithm (GA) were used for feature selection from the extracted spectral and textural features. Two classification models were established based on effective single spectral features and significant spectral textural fusion features: a partial least squares discriminant analysis (PLS_DA) and one-dimensional convolutional neural network (1D-CNN). A two-dimensional convolutional neural network (2D-CNN) was constructed based on five principal component (PC) coefficients extracted from the spectral data using PCA, weighted, and summed with 19-channel multispectral images to create new PC images. RESULTS: The results indicated that the models using PCA for feature selection exhibit relatively stable classification performance. The accuracy of PLS-DA and 1D-CNN based on single spectral features is 82.6% and 83.3%, respectively, at the 48h mark. In contrast, the accuracy of PLS-DA and 1D-CNN based on spectral texture fusion reached 85.9% and 91.3%, respectively, at the same 48h mark. The accuracy of the 2D-CNN based on 5 PC images is 82%. CONCLUSIONS: The research indicates that Phytophthora blight infection can be detected 48 h after inoculation (36 h before visible symptoms). This study provides an effective method for the early detection of Phytophthora blight in peppers.

Neuron-level Prediction and Noise can Implement Flexible Reward-Seeking Behavior.

We show that neural networks can implement reward-seeking behavior using only local predictive updates and internal noise. These networks are capable of autonomous interaction with an environment and can switch between explore and exploit behavior, which we show is governed by attractor dynamics. Networks can adapt to changes in their architectures, environments, or motor interfaces without any external control signals. When networks have a choice between different tasks, they can form preferences that depend on patterns of noise and initialization, and we show that these preferences can be biased by network architectures or by changing learning rates. Our algorithm presents a flexible, biologically plausible way of interacting with environments without requiring an explicit environmental reward function, allowing for behavior that is both highly adaptable and autonomous. Code is available at https://github.com/ccli3896/PaN.

Clinical association between plan complexity and the local-recurrence-free-survival of non-small-cell lung cancer patients receiving stereotactic body radiation therapy.

PURPOSE: To investigate the clinical impact of plan complexity on the local recurrence-free survival (LRFS) of non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Data from 123 treatment plans for 113 NSCLC patients were analyzed. Plan-averaged beam modulation (PM), plan beam irregularity (PI), monitor unit/Gy (MU/Gy) and spherical disproportion (SD) were calculated. The γ passing rates (GPR) were measured using ArcCHECK 3D phantom with 2 %/2mm criteria. High complexity (HC) and low complexity (LC) groups were statistically stratified based on the aforementioned metrics, using cutoffs determined by their significance in correlation with survival time, as calculated using the R-3.6.1 packages. Kaplan-Meier analysis, Cox regression, and Random Survival Forest (RSF) models were employed for the analysis of local recurrence-free survival (LRFS). Propensity-score-matched pairs were generated to minimize bias in the analysis. RESULTS: The median follow-up time for all patients was 25.5 months (interquartile range 13.4-41.2). The prognostic capacity of PM was suggested using RSF, based on Variable Importance and Minimal Depth methods. The 1-, 2-, and 3-year LRFS rates in the HC group were significantly lower than those in the LC group (p = 0.023), when plan complexity was defined by PM. However, no significant difference was observed between the HC and LC groups when defined by other metrics (p > 0.05). All γ passing rates exceeded 90.5 %. CONCLUSIONS: This study revealed a significant association between higher PM and worse LRFS in NSCLC patients treated with SBRT. This finding offers additional clinical evidence supporting the potential optimization of pre-treatment quality assurance protocols.

Low-Temperature Cross-Linked Hole Transport Layer for High-Performance Blue Quantum-Dot Light-Emitting Diodes.

Quantum-dot light-emitting diodes (QLEDs), a kind of promising optoelectronic device, demonstrate potential superiority in next-generation display technology. Thermal cross-linked hole transport materials (HTMs) have been employed in solution-processed QLEDs due to their excellent thermal stability and solvent resistance, whereas the unbalanced charge injection and high cross-linking temperature of cross-linked HTMs can inhibit the efficiency of QLEDs and limit their application. Herein, a low-temperature cross-linked HTM of 4,4'-bis(3-(((4-vinylbenzyl)oxy)methyl)-9H-carbazol-9-yl)-1,1'-biphenyl (DV-CBP) with a flexible styrene side chain is introduced, which reduces the cross-linking temperature to 150 °C and enhances the hole mobility up to 1.01 × 10-3 cm2 V-1 s-1. More importantly, the maximum external quantum efficiency of 21.35% is successfully obtained on the basis of the DV-CBP as a cross-linked hole transport layer (HTL) for blue QLEDs. The low-temperature cross-linked high-mobility HTL using flexible side chains could be an excellent alternative for future HTL development.

Coronary slow flow and angiography-derived index of microcirculatory resistance as prognostic predictors in patients with angina and normal coronary arteries: a retrospective cohort study.

BACKGROUND: This study aims to investigate prognostic implications of coronary slow flow (CSF) and angiography-derived index of microcirculatory resistance (caIMR) in patients with angina and normal coronary arteries. METHODS: A total of 582 patients were enrolled with angiographically normal coronary arteries. caIMR was calculated using a commercial software. Patients were followed up for a median of 45 months. The primary endpoint was defined as major adverse cardiovascular events (MACEs) comprising death, myocardial infarction and readmission for angina or heart failure. RESULTS: CSF was diagnosed when TIMI grade 2 flow presented in at least one coronary artery. Multivariate analysis indicated TIMI-flow-based determination of CSF was not significantly associated with MACEs [hazard ratio (HR): 2.14; 95% confidence interval (CI): 0.87-5.31; p = 0.099), while caIMR >42 (HR: 2.53; 95% CI: 1.02-6.32; p = 0.047) were independent predictors of MACEs. Incorporation of caIMR improved the area under the curve from 0.587 to 0.642. CONCLUSIONS: caIMR was an independent prognostic factor of long-term cardiovascular events in patients with CSF. Evaluation of caIMR improved the risk stratification of patients with angiographically-normal coronary arteries.

Photothermal Synergic Cross-Linking Hole Transport Layer for Highly Efficient RGB QLEDs.

Developing an insoluble cross-linkable hole transport layer (HTL) plays an important role for solution-processed quantum dots light-emitting diodes (QLEDs) to fabricate a multilayer device with separated quantum dots layers and HTLs. In this work, a facile photothermal synergic cross-linking strategy is simultaneous annealing and UV irradiation to form the high-quality cross-linked film as the HTL without any photoinitiator, which efficiently reduces the cross-linking temperature to the low temperature of 130 °C and enhances the hole mobility of the 3-vinyl-9-{4-[4-(3-vinylcarbazol-9-yl)phenyl]phenyl}carbazole (CBP-V) thin films. The obtained high-quality cross-linked CBP-V films exhibited smooth morphology, excellent solvent resistance, and high mobility. Moreover, the high-performance red, green, and blue (RGB) QLEDs are successfully fabricated by using the photothermal synergic cross-linked HTLs, which achieved the maximum external quantum efficiency of 25.69, 24.42, and 16.51%, respectively. This work presents a strategy of using the photothermal synergic cross-linked HTLs for fabrication of high-performance QLEDs and advancing their related device applications.

Real-world performance of indobufen versus aspirin after percutaneous coronary intervention: insights from the ASPIRATION registry.

BACKGROUND: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. METHODS: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. RESULTS: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. CONCLUSIONS: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. TRIAL REGISTRATION: Chinese Clinical Trial Register ( https://www.chictr.org.cn ); Number: ChiCTR2300067274.

Charge Carrier Regulation for Efficient Blue Quantum-Dot Light-Emitting Diodes Via a High-Mobility Coplanar Cyclopentane[b]thiopyran Derivative.

The performance of blue quantum dot light-emitting diodes (QLEDs) is limited by unbalanced charge injection, resulting from insufficient holes caused by low mobility or significant energy barriers. Here, we introduce an angular-shaped heteroarene based on cyclopentane[b]thiopyran (C8-SS) to modify the hole transport layer poly-N-vinylcarbazole (PVK), in blue QLEDs. C8-SS exhibits high hole mobility and conductivity due to the π···π and S···π interactions. Introducing C8-SS to PVK significantly enhanced hole mobility, increasing it by 2 orders of magnitude from 2.44 × 10-6 to 1.73 × 10-4 cm2 V-1 s-1. Benefiting from high mobility and conductivity, PVK:C8-SS-based QLEDs exhibit a low turn-on voltage (Von) of 3.2 V. More importantly, the optimized QLEDs achieve a high peak power efficiency (PE) of 7.13 lm/W, which is 2.65 times that of the control QLEDs. The as-proposed interface engineering provides a novel and effective strategy for achieving high-performance blue QLEDs in low-energy consumption lighting applications.

Chemosensory detection of polyamine metabolites guides C. elegans to nutritive microbes.

Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm Caenorhabditis elegans is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by C. elegans to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive Escherichia coli and pathogenic Enterococcus faecalis, and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by E. coli activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.

Validation of a new non-hyperemic physiological index: the constant-resistance ratio (cRR).

OBJECTIVES: The instantaneous wave-free ratio (iwFR) has limited availability. A new resting index called the constant-resistance ratio (cRR), which dynamically identifies cardiac intervals with constant and minimum resistance, has been developed; however, its diagnostic performance is unknown. The aim of this study was to validate the cRR by retrospectively calculating the cRR values from raw pressure waveforms of 2 publicly available datasets and compare them with those of the iwFR. METHODS: Waveform data from the CONTRAST and VERIFY 2 studies were used. The primary endpoint was Bland-Altman bias between cRR and iwFR. Secondary endpoints included diagnostic agreement, correlation, receiver operating characteristic (ROC) analysis, and success rates of cRR and iwFR. RESULTS: Among the 1036 waveforms, 871 were successful in determining paired cRR and iwFR values, while cRR was 6% more successful than iwFR (P less than .0001). The mean bias between cRR and iwFR was 0.003, with 95% limits of agreement [-0.021,0.028]. These 2 indices were highly correlated (r = 0.991; P less than .0001). Using an iwFR of 0.89 or less as the reference standard, the optimal cRR cutoff was 0.89, with an area under the ROC curve of 0.991 (P less than .001) and a diagnostic accuracy of 96.9% (95% CI [96%, 98%]). CONCLUSIONS: The cRR, a new resting index for identifying dynamic cardiac intervals with constant and minimum resistance, demonstrated high numerical agreement, diagnostic consistency, and a higher success rate than the iwFR based on the 2 publicly available datasets.

Chinese consumer preference for beef with geographical indications and other attributes.

As the demand for beef products grows in the Chinese market, understanding consumer preferences for beef, especially those related to quality labelling, is essential. The recent agreement between China and the European Union to promote Geographical Indications (GIs) provides a new insight into preferences for beef with quality labelling. This paper assesses consumer preferences for beef products with GIs and other attributes. A nationwide survey is conducted including 1210 respondents in China by a choice experiment attributing GI label, 'green', 'hazard-free', and 'organic' labels, feeding regimes (grain-fed, grass-fed), country of origin (China, Ireland, Australia, Brazil), and price (30, 40, 80, 100 ¥/500 g). The random parameter logit model with error component reveals that Chinese consumers have a significant preference for grain-fed beef and domestic beef, and they are willing to pay a premium price for GI-labelled beef compared with other attributes. The interaction between GIs and country of origin is included to indicate the positive price impact of GIs on imported beef products. Demographic factors such as place of residence and occupation are found to affect consumer preferences for GIs.

A novel intracoronary hypothermia device reduces myocardial reperfusion injury in pigs.

BACKGROUND: Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury. METHODS: This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (5 and 42 days post-MI) and a series of biomarkers/histological studies were performed. RESULTS: The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH. CONCLUSIONS: The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.

Hierarchical architecture of ZIF-8@ZIF-67-Derived N-doped carbon nanotube hollow polyhedron supported on 2D Ti3C2Tx nanosheets targeting enhanced lithium-ion capacitors.

The matching of long cycle life, high power density, and high energy density has been an inevitable requirement for the development of efficient anode materials for lithium-ion capacitors (LICs). Here, we introduce an N-doped carbon nanotube hollow polyhedron structure (Co3O4-CNT-800) with high specific surface area and active sites, which is anchored with two-dimensional (2D) Ti3C2Tx nanosheets with metallic conductivity and abundant surface functional groups by electrostatic adsorption to form a hierarchical multilevel hollow semi-covered framework structure. Benefiting from the synergistic effect between Co3O4-CNT-800 and Ti3C2Tx, the composites exhibit superior energy storage efficiency and long cycling stability. The Co3O4-CNT-800/Ti3C2Tx electrodes exhibit a high specific capacity of 817C/g at a current density of 0.5 A/g under the three-electrode system, and the capacity retention rate is 91 % after 5000 cycles at a current density of 2 A/g. Additionally, we assembled Co3O4-CNT-800/Ti3C2Tx as the anode and Activated carbon (AC) cathode to form LIC devices, which showed an electrochemical test result of 90.01 % capacitance retention after 8000 cycles at 2 A/g, and the maximum power density of the LIC was 3000 W/kg and the maximum energy density was 121 Wh/kg. This work pioneered the combination of N-doped carbon nanotube hollow polyhedron structure with two-dimensional Ti3C2Tx, which provides an effective strategy for preparing LIC negative electrode materials with high specific capacitance and long cycling stability.

Activation of STING signaling aggravates chronic alcohol exposure-induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis.

AIMS: Chronic alcohol exposure leads to persistent neurological disorders, which are mainly attributed to neuroinflammation and apoptosis. Stimulator of IFN genes (STING) is essential in the cytosolic DNA sensing pathway and is involved in inflammation and cellular death processes. This study was to examine the expression pattern and biological functions of STING signaling in alcohol use disorder (AUD). METHODS: Cell-free DNA was extracted from human and mouse plasma. C57BL/6J mice were given alcohol by gavage for 28 days, and behavior tests were used to determine their mood and cognition. Cultured cells were treated with ethanol for 24 hours. The STING agonist DMXAA, STING inhibitor C-176, and STING-siRNA were used to intervene the STING. qPCR, western blot, and immunofluorescence staining were used to assess STING signaling, inflammation, and apoptosis. RESULTS: Circulating cell-free mitochondrial DNA (mtDNA) was increased in individuals with AUD and mice chronically exposed to alcohol. Upregulation of STING signaling under alcohol exposure led to inflammatory responses in BV2 cells and mitochondrial apoptosis in PC12 cells. DMXAA exacerbated alcohol-induced cognitive impairment and increased the activation of microglia, neuroinflammation, and apoptosis in the medial prefrontal cortex (mPFC), while C-176 exerted neuroprotection. CONCLUSION: Activation of STING signaling played an essential role in alcohol-induced inflammation and mitochondrial apoptosis in the mPFC. This study identifies STING as a promising therapeutic target for AUD.