AIM2 regulates autophagy to mitigate oxidative stress in aged mice with acute liver injury.

The cytoplasmic pattern recognition receptor, absent in melanoma 2 (AIM2), detects cytosolic DNA, activating the inflammasome and resulting in pro-inflammatory cytokine production and pyroptotic cell death. Recent research has illuminated AIM2's contributions to PANoptosis and host defense. However, the role of AIM2 in acetaminophen (APAP)-induced hepatoxicity remains enigmatic. In this study, we unveil AIM2's novel function as a negative regulator in the pathogenesis of APAP-induced liver damage in aged mice, independently of inflammasome activation. AIM2-deficient aged mice exhibited heightened lipid accumulation and hepatic triglycerides in comparison to their wild-type counterparts. Strikingly, AIM2 knockout mice subjected to APAP overdose demonstrated intensified liver injury, compromised mitochondrial stability, exacerbated glutathione depletion, diminished autophagy, and elevated levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, our investigation revealed AIM2's mitochondrial localization; its overexpression in mouse hepatocytes amplified autophagy while dampening JNK phosphorylation. Notably, induction of autophagy through rapamycin administration mitigated serum alanine aminotransferase levels and reduced the necrotic liver area in AIM2-deficient aged mice following APAP overdose. Mechanistically, AIM2 deficiency exacerbated APAP-induced acute liver damage and inflammation in aged mice by intensifying oxidative stress and augmenting the phosphorylation of JNK and ERK. Given its regulatory role in autophagy and lipid peroxidation, AIM2 emerges as a promising therapeutic target for age-related acute liver damage treatment.

Identification of molecular subtypes and diagnostic model in clear cell renal cell carcinoma based on collagen-related genes may predict the response of immunotherapy.

Background: Collagen represents a prominent constituent of the tumor's extracellular matrix (ECM). Nonetheless, its correlation with the molecular subtype attributes of clear cell renal cell carcinoma (ccRCC) remains elusive. Our objective is to delineate collagen-associated molecular subtypes and further construct diagnostic model, offering insights conducive to the precise selection of ccRCC patients for immunotherapeutic interventions. Methods: We performed unsupervised non-negative matrix factorization (NMF) analysis on TCGA-KIRC samples, utilizing a set of 33 collagen-related differentially expressed genes (33CRDs) for clustering. Our analysis encompassed evaluations of subtype-associated differences in pathways, immune profiles, and somatic mutations. Through weighted gene co-expression network analysis (WGCNA) and four machine learning algorithms, two core genes were found and a diagnostic model was constructed. This was subsequently validated in a clinical immunotherapy cohort. Single cell sequencing analysis and experiments demonstrated the role of core genes in ccRCC. Finally, we also analyzed the roles of MMP9 and SCGN in pan-cancer. Results: We described two novel collagen related molecular subtypes in ccRCC, designated subtype 1 and subtype 2. Compared with subtype 1, subtype 2 showed more infiltration of immune components, but had a higher TIDE (tumor immunedysfunctionandexclusion) score and increased levels of immune checkpoint molecules. Furthermore, reduced prognosis for subtype 2 was a consistent finding in both high and low mutation load subgroups. MMP9 and SCGN were identified as key genes for distinguishing subtype 1 and subtype 2. The diagnostic model based on them could better distinguish the subtype of patients, and the differentiated patients had different progression free survival (PFS) in the clinical immunotherapy cohort. MMP9 was predominantly expressed in macrophages and has been extensively documented in the literature. Meanwhile, SCGN, which was overexpressed in tumor cells, underwent experimental validation, emphasizing its role in ccRCC. In various cancers, MMP9 and SCGN were associated with immune-related molecules and immune cells. Conclusion: Our study identifies two collagen-related molecular subtypes of ccRCC and constructs a diagnostic model to help select appropriate patients for immunotherapy.

Gross Hematuria Does not Affect the Selection of Nephrectomy Types for Clinical Stage 1 Clear Cell Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: This study aimed to discuss the correlation between gross hematuria and postoperative upstaging (from T1 to T3a) in patients with cT1 clear cell renal cell carcinoma (ccRCC) and to compare oncologic outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) in patients with gross hematuria. METHODS: A total of 2145 patients who met the criteria were enrolled in the study (including 363 patients with gross hematuria). The least absolute selection and shrinkage operator logistic regression was used to evaluate the risk factor of postoperative pathological upstaging. The propensity score matching (PSM) and stable inverse probability of treatment weighting (IPTW) analysis were used to balance the confounding factors. The Kaplan-Meier analysis and multivariate Cox proportional risk regression model were used to assess the prognosis. RESULTS: Gross hematuria was a risk factor of postoperative pathological upstaging (odds ratio [OR] = 3.96; 95% confidence interval [CI] 2.44-6.42; P < 0.001). After PSM and stable IPTW adjustment, the characteristics were similar in corresponding patients in the PN and RN groups. In the PSM cohort, PN did not have a statistically significant impact on recurrence-free survival (hazard ratio [HR] = 1.48; 95% CI 0.25-8.88; P = 0.67), metastasis-free survival (HR = 1.24; 95% CI 0.33-4.66; P = 0.75), and overall survival (HR = 1.46; 95% CI 0.31-6.73; P = 0.63) compared with RN. The results were confirmed in sensitivity analyses. CONCLUSIONS: Although gross hematuria was associated with postoperative pathological upstaging in patients with cT1 ccRCC, PN should still be the preferred treatment for such patients.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score.

BACKGROUND: Partial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes. METHODS: A retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW). RESULTS: A total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046-0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021-0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011-0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016-0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified. CONCLUSIONS: Our findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-ß1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance.

Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor-ß1 (TGF-ß1) and membrane-localized programmed death ligand-1 (PD-L1). Meanwhile, cytoplasm-distributed PD-L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD-L1 antibodies in inhibiting cytoplasm-distributed PD-L1 limits their effectiveness. Therefore, a nanoadjuvant is developed to sensitize cancer to radiotherapy via multi-level immunity activation through depressing PD-L1 and TGF-ß1 by triphenylphosphine-derived metformin, and activating the cGAS-STING pathway by generating Mn2+ from MnO2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp-Met@MnO2@Alb effectively enhances the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long-term memory of antitumor immunity without discernible side effects. Overall, Tpp-Met@MnO2@Alb has the potential to be clinically applied for overcoming radio-immunotherapy resistance.

Margin-Maximized Norm-Mixed Representation Learning for Autism Spectrum Disorder Diagnosis With Multi-Level Flux Features.

Early diagnosis and timely intervention are significantly beneficial to patients with autism spectrum disorder (ASD). Although structural magnetic resonance imaging (sMRI) has become an essential tool to facilitate the diagnosis of ASD, these sMRI-based approaches still have the following issues. The heterogeneity and subtle anatomical changes place higher demands for effective feature descriptors. Additionally, the original features are usually high-dimensional, while most existing methods prefer to select feature subsets in the original space, in which noises and outliers may hinder the discriminative ability of selected features. In this article, we propose a margin-maximized norm-mixed representation learning framework for ASD diagnosis with multi-level flux features extracted from sMRI. Specifically, a flux feature descriptor is devised to quantify comprehensive gradient information of brain structures on both local and global levels. For the multi-level flux features, we learn latent representations in an assumed low-dimensional space, in which a self-representation term is incorporated to characterize the relationships among features. We also introduce mixed norms to finely select original flux features for the construction of latent representations while preserving the low-rankness of latent representations. Furthermore, a margin maximization strategy is applied to enlarge the inter-class distance of samples, thereby increasing the discriminative ability of latent representations. The extensive experiments on several datasets show that our proposed method can achieve promising classification performance (the average area under curve, accuracy, specificity, and sensitivity on the studied ASD datasets are 0.907, 0.896, 0.892, and 0.908, respectively) and also find potential biomarkers for ASD diagnosis.

Cyanobacterial VOCs ß-ionone and ß-cyclocitral poisoning Lemna turionifera by triggering programmed cell death.

ß-Ionone and ß-cyclocitral are two typical components in cyanobacterial volatiles, which can poison aquatic plants and even cause death. To reveal the toxic mechanisms of the two compounds on aquatic plants through programmed cell death (PCD), the photosynthetic capacities, caspase-3-like activity, DNA fragmentation and ladders, as well as expression of the genes associated with PCD in Lemna turionifera were investigated in exposure to ß-ionone (0.2 mM) and ß-cyclocitral (0.4 mM) at lethal concentration. With prolonging the treatment time, L. turionifera fronds gradually died, and photosynthetic capacities gradually reduced and even disappeared at the 96th h. This demonstrated that the death process might be a PCD rather than a necrosis, due to the gradual loss of physiological activities. When L. turionifera underwent the death, caspase-3-like was activated after 3 h, and reached to the strongest activity at the 24th h. TUNEL-positive nuclei were detected after 12 h, and appeared in large numbers at the 48th h. The DNA was cleaved by Ca2+-dependent endonucleases and showed obviously ladders. In addition, the expression of 5 genes (TSPO, ERN1, CTSB, CYC, and ATR) positively related with PCD initiation was up-regulated, while the expression of 2 genes (RRM2 and TUBA) negatively related with PCD initiation was down-regulated. Therefore, ß-ionone and ß-cyclocitral can poison L. turionifera by adjusting related gene expression to trigger PCD.

Identification of algicidal monoterpenoids from four chemotypes of Cinnamomum camphora and their algicidal mechanisms on Microcystis aeruginosa.

Cyanobacterial blooms cause serious environmental issues, and plant secondary metabolites are considered as new algaecide for controlling them. Cinnamomum camphora produces a wide spectrum of terpenoids and has 4 main chemotypes, including linalool, camphor, eucalyptol and borneol chemotype. To develop the new cyanobacterial algaecide by using suitable chemotype of Cinnamomum camphora and the main terpenoids, we analyzed the terpenoid composition in the 4 chemotype extracts, evaluated the algicidal effects of the extracts and their typical monoterpenoids on Microcystis aeruginosa, and investigated the algicidal mechanism of the stronger algicidal agents. Among the 4 chemotypes, eucalyptol and borneol chemotype extracts exhibited stronger algicidal effects. In the 4 chemotype extracts, monoterpenoids were the main compounds, of which linalool, camphor, eucalyptol and borneol were the typical components. Among the 4 typical monoterpenoids, eucalyptol and borneol showed stronger algicidal effects, which killed 78.8% and 100% M. aeruginosa cells, respectively, at 1.2 mM after 48 h. In 1.2 mM eucalyptol and borneol treatments, the reactive oxygen species levels markedly increased, and the caspase-3-like activity also raised. With prolonging the treatment time, M. aeruginosa cells gradually shrank and wrinkled, and the cell TUNEL fluorescence intensity and DNA degradation gradually enhanced, indicating that the lethal mechanism is causing apoptosis-like programmed cell death (PCD). Therefore, eucalyptol and borneol chemotype extracts and their typical monoterpenoids have the potential for developing as algaecides to control cyanobacteria through triggering apoptosis-like PCD.

Adjusting function of camphor on primary metabolism in Cinnamomum camphora stressed by high temperature.

Cinnamomum camphora has great economic value for its wide utilization in traditional medicine and furniture material, and releases lots of monoterpenes to tolerate high temperature. To uncover the adjusting function of monoterpenes on primary metabolism and promoting their utilization as anti-high temperature agents, the photosynthetic capacities, primary metabolite levels, cell ultrastructure and associated gene expression were surveyed in C. camphora when it was blocked monoterpene biosynthesis with fosmidomycin (Fos) and fumigated with camphor (a typical monoterpene in the plant) under high temperature (Fos+38 °C+camphor). Compared with the control (28 °C), high temperature at 38 °C decreased the starch content and starch grain size, and increased the fructose, glucose, sucrose and soluble sugar content. Meanwhile, high temperature also raised the lipid content, with the increase of lipid droplet size and numbers. These variations were further intensified in Fos+ 38 °C treatment. Compared with Fos+ 38 °C treatment, Fos+ 38 °C+camphor treatment improved the starch accumulation by promoting 4 gene expression in starch biosynthesis, and lowered the sugar content by suppressing 3 gene expression in pentose phosphate pathway and promoting 15 gene expression in glycolysis and tricarboxylic acid cycle. Meanwhile, Fos+ 38 °C+camphor treatment also lowered the lipid content, which may be caused by the down-regulation of 2 genes in fatty acid formation and up-regulation of 4 genes in fatty acid decomposition. Although Fos+ 38 °C+camphor treatment improved the photosynthetic capacities in contrast to Fos+ 38 °C treatment, it cannot explain the variations of these primary metabolite levels. Therefore, camphor should adjust related gene expression to maintain the primary metabolism in C. camphora tolerating high temperature.

Visualization of Charge Dynamics when Water Droplets Bounce on a Hydrophobic Surface.

Visualizing the motion of water droplets and understanding their electrification behavior holds significance for applications related to droplet transport, self-cleaning, and anti-icing/deicing and for providing a comprehensive explanation of the solid-liquid triboelectrification mechanism. Here, by constructing microcolumnar structures on the polytetrafluoroethylene surface, a water droplet-based single electrode triboelectric nanogenerator was fabricated for visualizing charge dynamics when a water droplet bounces on a hydrophobic surface. The motion state of the water droplet is closely linked to its electrification behavior through the integration of a high-speed camera and an ammeter. The electrification behavior stemming from the bounce of the water droplet is dynamically captured in real-time. The results show that the magnitude and polarity of the electrical signal have strong dependence on the motion state of the water droplet. For instance, when a water droplet approaches or moves away from the substrate in a single direction, a unipolar electrical signal is generated. However, when the water droplet reaches its limit in the initial motion direction, it signifies a static equilibrium state, resulting in the electrical signal being at zero. Furthermore, we examine the impact of factors such as impact speed, drop contact area, contact line spreading/retraction speed, and impact angle on electrification. Finally, based on the close relationship between poly(ethylene oxide) (PEO) droplet bounce dynamics and electrical signals, the bouncing details of PEO droplets with different concentrations are tracked by electrical signals. This study digitally presents the whole process of droplet bounce in situ and provides a means for monitoring and tracking droplet movement.

Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity.

Hepatoblastoma is the most frequent liver malignancy in children. HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture. Intriguingly, we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells. The calcium signal is in connection with a series of processes critical in the tumorigenesis. Here, we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells. Mechanistically, calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase (FAK), protein kinase B, and p38 mitogen-activated protein kinase. The inhibitor of FAK or Ca 2+/calmodulin-dependent kinase Ⅱ (CaMKⅡ) reversed the Ca 2+-induced effects on HepG2 cells, including cell proliferation and migration, epithelial-mesenchymal transition protein expression levels, and phosphorylation levels of FAK and protein kinase B. Moreover, calcium ions decreased HepG2 cells' sensitivity to cisplatin. Furthermore, we found that the expression levels of FAK and CaMKⅡ were increased in hepatoblastoma. The group with high expression levels of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8 + T and NK cells. The expression of CaMKⅡ was positively correlated with that of PDCD1 and LAG3. Correspondingly, the expression of FAK was negatively correlated with that of TNFSF9, TNFRSF4, and TNFRSF18. Collectively, extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡ and enhances cisplatin resistance. FAK and CaMKⅡ shape immune cell infiltration and responses in tumor microenvironments, thereby serving as potential targets for hepatoblastoma.

FOXM1-regulated ZIC2 promotes the malignant phenotype of renal clear cell carcinoma by activating UBE2C/mTOR signaling pathway.

Background: As a transcription factor, Zic family member 2 (ZIC2) has been involved in more and more studies of tumorigenesis, which has been proved by our research team to be an effective prognostic marker for Pan-cancer. However, the prognosis, tumor promoting effect and regulatory mechanism of ZIC2 in clear cell renal cell carcinoma (ccRCC) are still unknown. Methods: The potential clinical significance of ZIC2 was evaluated by bioinformatics analysis using data from TCGA, GEO, and ArrayExpress data sets. WB and IHC were used to detect ZIC2 expression in tumors and adjacent tissues. CCK-8, EdU, colony formation, cell cycle, wound healing, transwell, subcutaneous xenograft, and lung metastasis models were used to detect the biological function of ZIC2. The regulatory mechanism of ZIC2 was confirmed by data of RNA-seq, ATAC-seq, MS-PCR, Chip-PCR, and luciferase reporter experiments. Results: ZIC2 was markedly upregulated and correlated with poor clinicopathological features in ccRCC. Knockdown of ZIC2 resulted in reduced cell proliferation, invasion, migration, induction of G2/M phase arrest, and reduced tumor formation and lung metastasis in nude mice. The opposite was observed after overexpression. Mechanistically, the high expression of ZIC2 is regulated by hypomethylation and high H3K4Me3 in the promoter region, as well as positive transcriptional regulation by FOXM1. And then, ZIC2 transcriptase-positively regulates UBE2C and activates AKT/mTOR signaling pathway to promote tumor malignant progression. Conclusion: This study reveals that FOXM1-ZIC2-UBE2C-mTOR signaling axis promotes the progression of ccRCC, which can be used as a prognostic indicator and potential therapeutic target.

Multi-level fusion network for mild cognitive impairment identification using multi-modal neuroimages.

Objective. Mild cognitive impairment (MCI) is a precursor to Alzheimer's disease (AD) which is an irreversible progressive neurodegenerative disease and its early diagnosis and intervention are of great significance. Recently, many deep learning methods have demonstrated the advantages of multi-modal neuroimages in MCI identification task. However, previous studies frequently simply concatenate patch-level features for prediction without modeling the dependencies among local features. Also, many methods only focus on modality-sharable information or modality-specific features and ignore their incorporation. This work aims to address above-mentioned issues and construct a model for accurate MCI identification.Approach. In this paper, we propose a multi-level fusion network for MCI identification using multi-modal neuroimages, which consists of local representation learning and dependency-aware global representation learning stages. Specifically, for each patient, we first extract multi-pair of patches from multiple same position in multi-modal neuroimages. After that, in the local representation learning stage, multiple dual-channel sub-networks, each of which consists of two modality-specific feature extraction branches and three sine-cosine fusion modules, are constructed to learn local features that preserve modality-sharable and modality specific representations simultaneously. In the dependency-aware global representation learning stage, we further capture long-range dependencies among local representations and integrate them into global ones for MCI identification.Main results. Experiments on ADNI-1/ADNI-2 datasets demonstrate the superior performance of the proposed method in MCI identification tasks (Accuracy: 0.802, sensitivity: 0.821, specificity: 0.767 in MCI diagnosis task; accuracy: 0.849, sensitivity: 0.841, specificity: 0.856 in MCI conversion task) when compared with state-of-the-art methods. The proposed classification model has demonstrated a promising potential to predict MCI conversion and identify the disease-related regions in the brain.Significance. We propose a multi-level fusion network for MCI identification using multi-modal neuroimage. The results on ADNI datasets have demonstrated its feasibility and superiority.

Inhibitor of nuclear factor kappa B kinase subunit epsilon regulates murine acetaminophen toxicity via RIPK1/JNK.

Drug-induced liver injury (DILI) still poses a major clinical challenge and is a leading cause of acute liver failure. Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) is essential for inflammation and metabolic disorders. However, it is unclear how IKBKE regulates cellular damage in acetaminophen (APAP)-induced acute liver injury. Here, we found that the deficiency of IKBKE markedly aggravated APAP-induced acute liver injury by targeting RIPK1. We showed that APAP-treated IKBKE-deficient mice exhibited severer liver injury, worse mitochondrial integrity, and enhanced glutathione depletion than wild-type mice. IKBKE deficiency may directly upregulate the expression of total RIPK1 and the cleaved RIPK1, resulting in sustained JNK activation and increased translocation of RIPK1/JNK to mitochondria. Moreover, deficiency of IKBKE enhanced the expression of pro-inflammatory factors and inflammatory cell infiltration in the liver, especially neutrophils and monocytes. Inhibition of RIPK1 activity by necrostatin-1 significantly reduced APAP-induced liver damage. Thus, we have revealed a negative regulatory function of IKBKE, which acts as an RIPK1/JNK regulator to mediate APAP-induced hepatotoxicity. Targeting IKBKE/RIPK1 may serve as a potential therapeutic strategy for acute or chronic liver injury.

Correlation between stem cell molecular phenotype and atherosclerotic plaque neointima formation and analysis of stem cell signal pathways.

Vascular stem cells exist in the three-layer structure of blood vessel walls and play an indispensable role in angiogenesis under physiological conditions and vascular remodeling under pathological conditions. Vascular stem cells are mostly quiescent, but can be activated in response to injury and participate in endothelial repair and neointima formation. Extensive studies have demonstrated the differentiation potential of stem/progenitor cells to repair endothelium and participate in neointima formation during vascular remodeling. The stem cell population has markers on the surface of the cells that can be used to identify this cell population. The main positive markers include Stem cell antigen-1 (Sca1), Sry-box transcription factor 10 (SOX10). Stromal cell antigen 1 (Stro-1) and Stem cell growth factor receptor kit (c-kit) are still controversial. Different parts of the vessel have different stem cell populations and multiple markers. In this review, we trace the role of vascular stem/progenitor cells in the progression of atherosclerosis and neointima formation, focusing on the expression of stem cell molecular markers that occur during neointima formation and vascular repair, as well as the molecular phenotypic changes that occur during differentiation of different stem cell types. To explore the correlation between stem cell molecular markers and atherosclerotic diseases and neointima formation, summarize the differential changes of molecular phenotype during the differentiation of stem cells into smooth muscle cells and endothelial cells, and further analyze the signaling pathways and molecular mechanisms of stem cells expressing different positive markers participating in intima formation and vascular repair. Summarizing the limitations of stem cells in the prevention and treatment of atherosclerotic diseases and the pressing issues that need to be addressed, we provide a feasible scheme for studying the signaling pathways of vascular stem cells involved in vascular diseases.

Epigenetic Regulation in Urothelial Carcinoma

Urothelial carcinoma (UC) is a common malignancy that remains a clinical challenge: Non-muscle-invasive urothelial carcinoma (NMIUC) has a high rate of recurrence and risk of progression, while muscle-invasive urothelial carcinoma (MIUC) has a high mortality. Although some new treatments, such as immunotherapies, have shown potential effects on some patients, most cases of advanced UC remain incurable. While treatments based on epigenetic mechanisms, whether combined with traditional platinum-based chemotherapy or emerging immunotherapy, show therapeutic advantages. With the advancement of sequencing and bioinformatics, the study of epigenomics, containing DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, is increasingly linked with the occurrence and progression of UC. Since the epigenetics of UC is a constantly developing field of medicine, this review aims to summarize the latest research on epigenetic regulation of UC, generalize the mechanism of epigenetics in UC, and reveal the potential epigenetic therapies in the clinical setting, in order to provide some new clues on the discovery of new drugs based on the epigenetics.

Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming.

Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.

Toxic mechanism of two cyanobacterial volatiles ß-cyclocitral and ß-ionone on the photosynthesis in duckweed by altering gene expression.

Volatile organic compounds (VOCs) promote cyanobacteria dominating eutrophicated waters, with aquatic plant decrease and even disappearance. To uncover the toxic mechanism of cyanobacterial VOCs on aquatic plants, we investigated the growth, photosynthetic pigment levels, photosynthetic abilities and related gene expression in duckweed treated with ß-cyclocitral and ß-ionone, 2 main components in the VOCs. The levels of chlorophylls and carotenoids gradually declined with raising the concentration of the 2 compounds and prolonging the treatment time. Their decline should result from the down-regulation of 8 genes associated with photosynthetic pigment biosynthesis and up-regulation of 2 genes involved in carotenoid degradation. The reduction was also found in the photosystem II (PSII) efficiency and O2 evolution rate, which should result from the lowered photosynthetic pigment levels and down-regulation of 38 genes related with photosynthetic process. The frond numbers, total frond area and fresh weight gradually decreased with raising the 2 compound concentration, which may result from the lowered photosynthetic abilities as well as down-regulated expression of 7 genes associated with growth-promoting hormone biosynthesis and signal transduction. It can be speculated that cyanobacterial VOCs may poison aquatic plants by lowering the photosynthesis and growth through altering related gene expression.

Identifying a Ferroptosis-Related Gene Signature for Predicting Biochemical Recurrence of Prostate Cancer.

Ferroptosis induced by lipid peroxidation is closely related to cancer biology. Prostate cancer (PCa) is not only a malignant tumor but also a lipid metabolic disease. Previous studies have identified ferroptosis as an important pathophysiological pathway in PCa development and treatment, but its role in the prognosis of PCa is less well known. In this study, we constructed a nine-ferroptosis-related gene risk model that demonstrated strong prognostic and therapeutic predictive power. The higher risk score calculated by the model was significantly associated with a higher ferroptosis potential index, higher Ki67 expression, higher immune infiltration, higher probability of biochemical recurrence, worse clinicopathological characteristics, and worse response to chemotherapy and antiandrogen therapy in PCa. The mechanisms identified by the gene set enrichment analysis suggested that this signature can accurately distinguish high- and low-risk populations, which is possibly closely related to variations in steroid hormone secretion, regulation of endocrine processes, positive regulation of humoral immune response, and androgen response. Results of this study were confirmed in two independent PCa cohorts, namely, The Cancer Genome Atlas cohort and the MSK-IMPACT Clinical Sequencing Cohort, which contributed to the body of scientific evidence for the prediction of biochemical recurrence in patients with PCa. In addition, as the main components of this signature, the effects of the AIFM2 and NFS1 genes on ferroptosis were evaluated and verified by in vivo and in vitro experiments, respectively. The above findings provided new insights and presented potential clinical applications of ferroptosis in PCa.

Decreased interferon regulatory factor 6 expression due to DNA hypermethylation predicts an unfavorable prognosis in clear cell renal cell carcinoma.

Background: Emerging evidences have indicated that IRF6, as a member of the Interferon regulatory factors (IRFs) family, plays important roles in a variety of tumors. However, the expression status of IRF6 and its prognostic value in clear cell renal cell carcinoma (ccRCC) remain unclear. Methods: In this study, we used TCGA-KIRC, GEO and TIP databases and immunohistochemistry staining to determine the expression profile, clinico-pathological features and prognostic value of IRF6 in ccRCC. MSP and demethylation analysis were utilized to verify the regulatory effect of DNA methylation on IRF6 expression. Results: Our results found that IRF6 expression was downregulated in ccRCC tissues and cell lines, and decreased IRF6 expression was associated with worse clinicopathological features and poorer prognosis. Besides, the results of multivariate Cox regression analysis also confirmed that decreased IRF6 expression was an independently risk factor predictor of shorter Overall Survival (OS) (HR: 0.8524, 95%CI: 0.7614-0.9543, P=0.0056) and Disease Free Survival (DFS) (HR: 0.7024, 95%CI: 0.6087-0.8104, P<0.0001) in ccRCC patients. Moreover, the results of MSP and demethylation analysis validated that decreased IRF6 expression was caused by DNA hypermethylation. Furthermore, our results showed that IRF6 expression was associated with the infiltration levels of multiple immune cells in ccRCC. Conclusions: These findings demonstrated that IRF6 expression was significantly reduced in ccRCC and DNA hypermethylation played an important role in decreased IRF6 expression. In addition, the decrease of IRF6 was related to the unfavorable prognosis of ccRCC patients and the alterations of tumor immune cells infiltration.