Pyroptosis of oral keratinocyte contributes to energy metabolic reprogramming of T cells in oral lichen planus via OPA1-mediated mitochondrial fusion.

Oral lichen planus (OLP) is a chronic inflammatory disease that is associated with an increased risk of carcinogenesis. The typical pathological features of OLP include submucosal T-cell banding, infiltration, and liquefactive degeneration of basal epithelial cells. However, the histological appearance of basal cell death cannot be explained by apoptosis of keratinocytes alone. The aim of this study was to explore a novel mechanism of epithelial cell death, pyroptosis, and its role in the development of OLP. The immunohistochemical results initially revealed pyroptosis in the epithelial cells of OLP. There was significant upregulation of pyroptosis-related inflammatory cytokines, specifically IL-1ß. The expression of IL-1ß is closely related to the severity of the patient's condition. In vitro, the culture supernatant from epithelial cells and exogenous IL-1ß significantly promote the proliferation and activation of T cells. This effect can be inhibited by neutralizing antibody or receptor inhibitor of IL-1ß. Stimulation with exogenous IL-1ß enhances both glycolysis and oxidative phosphorylation in T cells, with a more pronounced increase in glycolysis. This is due to the regulation of NAD+ availability and mitochondrial dynamics by IL-1ß. IL-1ß specifically stimulates the expression of optic atrophy 1 (OPA1), particularly L-OPA1, which promotes mitochondrial fusion and increases NAD+ availability. This process upregulated glycolysis in T cells. The knockdown of OPA1 reverses these changes by reducing the proliferation and activation of T cells. In this study, IL-1ß promoted OPA1 transcription by activating the NF-κB pathway. The expression of OPA1 is inhibited by the inhibitor of NF-κB pathway. These results suggest that OLP keratinocytes undergo pyroptosis, which then secrete inflammatory factors that activate the NF-κB signaling pathway of T cells. This pathway regulates OPA1-mediated mitochondrial fusion and energy metabolism reprogramming in T cells, contributing to the development of OLP. These findings provide new insights into the mechanisms and therapeutic strategies for OLP.

Investigating thermal properties of 2D non-layered material using a NEMS-based 2-DOF approach towards ultrahigh-performance bolometer.

Two-dimensional (2D) non-layered materials in many aspects differ from their layered counterparts, and the exploration of their physical properties has produced many intriguing findings. However, due to challenges in applying existing experimental techniques to such nanoscale samples, their thermal properties have remained largely uncharacterized, hindering further exploration and device application using this promising material system. Here, we demonstrate an experimental study of thermal conduction in ß-In2S3, a typical non-layered 2D material, using a resonant nanoelectromechanical systems (NEMS) platform. We devise a new two-degrees-of-freedom technique, more responsive and sensitive than Raman spectroscopy, to simultaneously determine both the thermal conductivity to be 3.7 W m-1 K-1 and its interfacial thermal conductance with SiO2 as 6.4 MW m-2 K-1. Leveraging such unique thermal properties, we further demonstrate a record-high power-to-frequency responsivity of -447 ppm/µW in ß-In2S3 NEMS sensors, the best among drumhead NEMS-based bolometers. Our findings offer an effective approach for studying thermal properties and exploring potential thermal applications of 2D non-layered materials.

A graph-learning based model for automatic diagnosis of Sjögren's syndrome on digital pathological images: a multicentre cohort study.

BACKGROUND: Sjögren's Syndrome (SS) is a rare chronic autoimmune disorder primarily affecting adult females, characterized by chronic inflammation and salivary and lacrimal gland dysfunction. It is often associated with systemic lupus erythematosus, rheumatoid arthritis and kidney disease, which can lead to increased mortality. Early diagnosis is critical, but traditional methods for diagnosing SS, mainly through histopathological evaluation of salivary gland tissue, have limitations. METHODS: The study used 100 labial gland biopsy, creating whole-slide images (WSIs) for analysis. The proposed model, named Cell-tissue-graph-based pathological image analysis model (CTG-PAM) and based on graph theory, characterizes single-cell feature, cell-cell feature, and cell-tissue feature. Building upon these features, CTG-PAM achieves cellular-level classification, enabling lymphocyte recognition. Furthermore, it leverages connected component analysis techniques in the cell graph structure to perform SS diagnosis based on lymphocyte counts. FINDINGS: CTG-PAM outperforms traditional deep learning methods in diagnosing SS. Its area under the receiver operating characteristic curve (AUC) is 1.0 for the internal validation dataset and 0.8035 for the external test dataset. This indicates high accuracy. The sensitivity of CTG-PAM for the external dataset is 98.21%, while the accuracy is 93.75%. In comparison, the sensitivity and accuracy for traditional deep learning methods (ResNet-50) are lower. The study also shows that CTG-PAM's diagnostic accuracy is closer to skilled pathologists compared to beginners. INTERPRETATION: Our findings indicate that CTG-PAM is a reliable method for diagnosing SS. Additionally, CTG-PAM shows promise in enhancing the prognosis of SS patients and holds significant potential for the differential diagnosis of both non-neoplastic and neoplastic diseases. The AI model potentially extends its application to diagnosing immune cells in tumor microenvironments.

Cross-Priming-Linked Hierarchical Isothermal Amplification Programming Progressive Activating Clustered Regularly Interspaced Short Palindromic Repeats/Cas12a in miRNA Signaling.

Cascade isothermal nucleic acid amplification, which integrates several different amplification protocols to enhance the assay performance, is widely utilized in biosensing, particularly for detecting microRNAs (miRNAs), crucial biomarkers associated with tumor initiation and progression. However, striking a balance between a high amplification efficiency and simplicity in design remains a challenge. Therefore, methods achieving high amplification efficiency without significantly increasing complexity are highly favored. In this study, we propose a novel approach for miRNA detection, employing cross-priming-linked hierarchical isothermal amplification (CP-HIA) to progressively activate the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a system. The CP-HIA method strategically combines nicking-rolling circle amplification (n-RCA) and palindrome-aided circular strand displacement amplification (p-CSDA) for miRNA detection. Remarkably, this method utilizes only two main probes. Its key innovation lies in the interactive cross-priming strategy, wherein the amplification product from n-RCA is recycled to further drive p-CSDA, and vice versa. This interactive process establishes a hierarchical amplification, significantly enriching the activation probes for progressive CRISPR/Cas12a activation and subsequent target signal amplification. Consequently, the method exhibits greatly enhanced analytical performance, including high sensitivity and specificity in detecting low concentrations of miRNA. As low as 1.06 fM miRNA can thus be quantitatively detected, and the linear response of the miRNA is from 10 fM to 10 nM. These features demonstrate its potential for early disease diagnosis and monitoring. We anticipate that the CP-HIA method will serve as a promising platform for developing advanced molecular diagnostic tools for biomedical research.

Ferroptosis-related gene signature and clinical prognostic factors as prognostic marker for colon adenocarcinoma.

Aim: To build a ferroptosis-related prognostic model for patients with colon adenocarcinoma (COAD). Methods: COAD expression profiles from The Cancer Genome Atlas were used as the training set and GSE39582 from Gene Expression Omnibus as the validation set. Differentially expressed ferroptosis-related genes between patients with COAD and normal controls were screened, followed by tumor subtype exploration based on ferroptosis-related gene expression levels. A ferroptosis score (FS) model was constructed using least absolute shrinkage and selection operator penalized Cox analysis. Based on FS, patients were subgrouped into high- and low-risk subgroups and overall survival was predicted. The potential prognostic value of the FS model and the clinical characteristics were investigated using receiver operating characteristic curves. Results: Twenty-four differentially expressed ferroptosis-related genes were identified, four of which (CYBB, PRNP, ACSL4, and ACSL6) were included in the prognostic signature. Moreover, age, pathological T stage, and tumor recurrence were independent prognostic factors for COAD. The FS model combined with three independent prognostic factors showed the best prognostic value (The Cancer Genome Atlas: area under the curve = 0.897; GSE39582: area under the curve = 0.858). Conclusion: The novel prognostic model for patients with COAD constructed by pairing the FS model with three important independent prognostic factors showed promising clinical predictive value.

A Microenvironment-Responsive, Controlled Release Hydrogel Delivering Embelin to Promote Bone Repair of Periodontitis via Anti-Infection and Osteo-Immune Modulation.

Periodontitis, a prevalent chronic inflammatory disease, poses significant challenges for effective treatment due to its complex etiology involving specific bacteria and the inflammatory immune microenvironment. Here, this study presents a novel approach for the targeted treatment of periodontitis utilizing the immunomodulatory and antibacterial properties of Embelin, a plant-derived compound, within an injectable hydrogel system. The developed Carboxymethyl Chitosan-Oxidized Dextran (CMCS-OD) hydrogel formed via dynamic chemical bonds exhibited self-healing capabilities and pH-responsive behavior, thereby facilitating the controlled release of Embelin and enhancing its efficacy in a dynamic oral periodontitis microenvironment. This study demonstrates that this hydrogel system effectively prevents bacterial invasion and mitigates excessive immune response activation. Moreover, it precisely modulates macrophage M1/M2 phenotypes and suppresses inflammatory cytokine expression, thereby fostering a conducive environment for bone regeneration and addressing periodontitis-induced bone loss. These findings highlight the potential of the approach as a promising strategy for the clinical management of periodontitis-induced bone destruction.

Extracellular vesicles meet mitochondria: Potential roles in regenerative medicine.

Extracellular vesicles (EVs), secreted by most cells, act as natural cell-derived carriers for delivering proteins, nucleic acids, and organelles between cells. Mitochondria are highly dynamic organelles responsible for energy production and cellular physiological processes. Recent evidence has highlighted the pivotal role of EVs in intercellular mitochondrial content transfer, including mitochondrial DNA (mtDNA), proteins, and intact mitochondria. Intriguingly, mitochondria are crucial mediators of EVs release, suggesting an interplay between EVs and mitochondria and their potential implications in physiology and pathology. However, in this expanding field, much remains unknown regarding the function and mechanism of crosstalk between EVs and mitochondria and the transport of mitochondrial EVs. Herein, we shed light on the physiological and pathological functions of EVs and mitochondria, potential mechanisms underlying their interactions, delivery of mitochondria-rich EVs, and their clinical applications in regenerative medicine.

Poly(p-coumaric acid) nanoparticles alleviate temporomandibular joint osteoarthritis by inhibiting chondrocyte ferroptosis.

Oxidative stress and inflammation are key drivers of osteoarthritis (OA) pathogenesis and disease progression. Herein we report the synthesis of poly(p-coumaric) nanoparticles (PCA NPs) from p-courmaic acid (p-CA), a naturally occurring phytophenolic acid, to be a multifunctional and drug-free therapeutic for temporomandibular joint osteoarthritis (TMJOA). Compared to hyaluronic acid (HA) that is clinically given as viscosupplementation, PCA NPs exhibited long-term efficacy, superior anti-oxidant and anti-inflammatory properties in alleviating TMJOA and repairing the TMJ cartilage and subchondral bone in a rat model of TMJOA. Notably, TMJ repair mediated by PCA NPs could be attributed to their anti-oxidant and anti-inflammatory properties in enhancing cell proliferation and matrix synthesis, while reducing inflammation, oxidative stress, matrix degradation, and chondrocyte ferroptosis. Overall, our study demonstrates a multifunctional nanoparticle, synthesized from natural p-coumaric acid, that is stable and possess potent antioxidant, anti-inflammatory properties and ferroptosis inhibition, beneficial for treatment of TMJOA.

Quantitative regulation of electron-phonon coupling.

Electron-phonon (e-p) coupling plays a crucial role in various physical phenomena, and regulation of e-p coupling is vital for the exploration and design of high-performance materials. However, the current research on this topic lacks accurate quantification, hindering further understanding of the underlying physical processes and its applications. In this work, we demonstrate quantitative regulation of e-p coupling, by pressure engineering andin-situspectroscopy. We successfully observe both a distinct vibrational mode and a strong Stokes shift in layered CrBr3, which are clear signatures of e-p coupling. This allows us to achieve precise quantification of the Huang-Rhys factorSat the actual sample temperature, thus accurately determining the e-p coupling strength. We further reveal that pressure efficiently regulates the e-p coupling in CrBr3, evidenced by a remarkable 40% increase inSvalue. Our results offer an approach for quantifying and modulating e-p coupling, which can be leveraged for exploring and designing functional materials with targeted e-p coupling strengths.

Dandelion-like VSe2-embellished CuSe-Co3Se4 hollow nanotube clusters as bifunctional catalysts for high-performance alkaline hydrogen evolution and solar cells.

Among the various non-precious metal catalysts that drive hydrogen evolution reactions (HERs) and dye-sensitized solar cells (DSSCs), transition metal selenides (TMSs) stand out due to their unique electronic properties and tunable morphology. Herein, the multicomponent selenide CuSe-Co3Se4@VSe2 was successfully synthesized by doping with metal element vanadium and selenization on the copper-cobalt carbonate hydroxide (CuCo-CH) template. CuSe-Co3Se4@VSe2 exhibited the dandelion-like cluster structure composed of hollow nanotubes doped with VSe2 nanoparticles. Due to the unique structure and the synergistic effect of various elements, CuSe-Co3Se4@VSe2 showed excellent alkaline HER and DSSC performances. The DSSC based on CuSe-Co3Se4@VSe2 exhibited an impressive power conversion efficiency (PCE) of 9.64 %, which was much higher than that of Pt (8.39 %). Besides, it possessed a low HER overpotential of 76 mV@10 mA cm-2 and a small Tafel slope of 88.9 mV dec-1 in 1.0 M KOH.

Susceptibility gene identification and risk evaluation model construction by transcriptome-wide association analysis for salt sensitivity of blood pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.

Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC.

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine-glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.

Multiple aortic root pseudoaneurysms with dissecting aneurysm of the interventricular septum diagnosed by multimodal imaging.

Aortic root pseudoaneurysm is a devastating complication post aortic valve replacement with a high mortality rate. And dissecting aneurysm into the interventricular septum is a rare variant of aortic root pseudoaneurysm, which is scarcely reported. Multimodal imaging is of great value in its diagnosis and differential diagnosis.

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors.

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.

A Bayesian Change Point Model for Dynamic Alternative Transcription Start Site Usage During Cellular Differentiation.

ABSTRACT An alternative transcription start site (ATSS) is a major driving force for increasing the complexity of transcripts in human tissues. As a transcriptional regulatory mechanism, ATSS has biological significance. Many studies have confirmed that ATSS plays an important role in diseases and cell development and differentiation. However, exploration of its dynamic mechanisms remains insufficient. Identifying ATSS change points during cell differentiation is critical for elucidating potential dynamic mechanisms. For relative ATSS usage as percentage data, the existing methods lack sensitivity to detect the change point for ATSS longitudinal data. In addition, some methods have strict requirements for data distribution and cannot be applied to deal with this problem. In this study, the Bayesian change point detection model was first constructed using reparameterization techniques for two parameters of a beta distribution for the percentage data type, and the posterior distributions of parameters and change points were obtained using Markov Chain Monte Carlo (MCMC) sampling. With comprehensive simulation studies, the performance of the Bayesian change point detection model is found to be consistently powerful and robust across most scenarios with different sample sizes and beta distributions. Second, differential ATSS events in the real data, whose change points were identified using our method, were clustered according to their change points. Last, for each change point, pathway and transcription factor motif analyses were performed on its differential ATSS events. The results of our analyses demonstrated the effectiveness of the Bayesian change point detection model and provided biological insights into cell differentiation.

Lactate dehydrogenase B as a metabolism-related marker for immunotherapy in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies. Lactate dehydrogenase family genes (LDHs) play a critical role in tumor metabolism, but their functions in HNSCC have not been investigated thoroughly. Thus, we aimed to explore the value of LDHs in HNSCC. METHODS: The association between LDHs expression and mutations, methylation, copy number variations (CNVs), alternative splicing (AS) and competing endogenous RNA (ceRNA) was investigated in The Cancer Genome Atlas (TCGA). The expression level of LDHs in OSCC tissues and adjacent normal tissues was verified by qPCR. Algorithms, such as ssGSEA, ESTIMATE, xCell and TIDE were utilized to analyze the characteristics of immune infiltration. Pathway alternations were enriched by GO, GSEA and KEGG analysis. The Mantel test was employed to elucidate the correlation between metabolism and the tumor microenvironment (TME). Subsequently, MTT and colony formation assays were utilized to assess the impact of LDHB knockdown on cellular proliferation. Additionally, ATP and lactate assays were performed to examine metabolic alterations. Co-culture experiments further investigated the effect of LDHB knockdown on T cell differentiation. RESULTS: LDHs were completely analyzed in multiple databases, among which LDHB was differentially expressed in HNSCC and significantly associated with prognosis. Low LDHB expression had better clinicopathological characteristics. Downregulated LDHB expression was associated with enhanced immune cell infiltration and could influence tumor metabolism. Despite having worse cytotoxic T lymphocyte dysfunction, the LDHBlow group was predicted to respond more favorably to immune checkpoint inhibitors (ICIs) therapy. Moreover, the correlation between metabolism and TME was depicted. In vitro, LDHB knockdown resulted in inhibited cell proliferation, increased lactate levels and decreased ATP levels, while promoted the Th1 differentiation of T cells. CONCLUSIONS: Our study provided a comprehensive analysis of the LDHs and illustrated low LDHB expression could inhibit tumor cell proliferation and ATP production by influencing metabolism, with improved immune cell infiltration and better response to immunotherapy.

Arterial transit artifacts and carotid Plaque-RADS may predict symptoms in patients with carotid stenosis.

AIM: To analyze the correlation of carotid stenosis severity, the Plaque Reporting and Data System (RADS) score, arterial transit artifacts (ATAs), and cerebral blood flow (CBF) with clinical cerebral ischemic symptoms in patients with carotid artery stenosis (CAS). MATERIALS AND METHODS: Sixty-one patients with unilateral internal carotid artery stenosis or occlusion (≥50% stenosis) diagnosed by ultrasound, Computed Tomography(CT) angiography, or Magnetic Resonance(MR) angiography in Yichang City Central People's Hospital from January 2022 to February 2024 were retrospectively enrolled and divided into two groups according to the presence or absence of symptoms. Both groups underwent MR plaque imaging and arterial spin labeling (ASL)-based 3.0 T MRI to compare the differences in stenosis degree, Plaque-RADS score, ATA grade, and CBF between the two groups. Binary regression analysis was used to identify the parameters with statistically significant differences between the two groups and to evaluate their diagnostic efficacy using the area under the workup curve of the subjects. RESULTS: The Plaque-RADS score, ATA grade, and CBF differences in the anterior cerebral artery(ACA)blood supply region were correlated with symptoms, and the areas under the ROC curves for the CBF differences in the ACA blood supply region, Plaque-RADS score, ATA grade and a joint model that combines all three to predict symptoms in CAS patients were 0.672, 0.796, 0.788 and 0.919, respectively. CONCLUSIONS: CBF, Plaque-RADS and ATAs were identified as independent risk factors for symptoms in patients with CAS and have a certain predictive value for symptoms, and the combined predictive value is greater, potentially providing a more effective imaging modality for clinical treatment and evaluation.

Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism.

BACKGROUND: Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence-associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor-derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation-induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear. METHODS: Beta-galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence-associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation-induced sEVs. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to explore changes in the levels of proteins in radiation-induced sEVs. Cell Counting Kit-8 and colony formation assays were performed to investigate the function of radiation-induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation-induced sEVs and V-9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence. RESULTS: We determined that the radiation-induced SASP triggered OSCC cell proliferation. Additionally, radiation-induced sEVs exacerbated OSCC cell malignancy. LC-MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation-induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation-induced sEVs in OSCC. CONCLUSION: Radiation-induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.

The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.