The immune factors have complex causal regulation effects on kidney stone disease: a mendelian randomization study.

PURPOSE: Previous studies have reported the potential impact of immune cells on kidney stone disease (KSD), but definitive causal relationships have yet to be established. The purpose of this paper is to elucidate the potential causal association between immune cells and KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between immune cell traits and kidney stone disease. We included a total of four immune traits (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)), which are publicly available data. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: After FDR correction, the CD8 on HLA DR + CD8br (OR = 0.95, 95% CI = 0.93-0.98, p-value = 7.20 × 10- 4, q-value = 0.088) was determined to be distinctly associated with KSD, and we also found other 25 suggestive associations between immune cells and KSD, of which 13 associations were suggested as protective factors and 12 associations were suggested as risk factors. There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our Cochrane Q-test, MR Egger's intercept test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study has explored the potential causal connection between immune cells and KSD by Mendelian randomization analysis, thus providing some insights for future clinical studies.

Effects of postweaning cadmium exposure on socioemotional behaviors in adolescent male mice.

Exposure to cadmium (Cd), a toxic heavy metal classified as an environmental endocrine disruptor, can exert significant toxicity in both animals and humans. However, the potential effects of Cd exposure on socioemotional behaviors are still poorly understood, as are the underlying mechanisms. In the present study, employing a series of behavioral tests as well as 16 S rRNA sequencing analysis, we investigated the long-term effects of Cd exposure on socioemotional behaviors and their associated mechanisms in mice based on the brain-gut interaction theory. The results showed that postweaning exposure to Cd reduced the ability to resist depression, decreased social interaction, subtly altered sexual preference, and changed the composition of the gut microbiota in male mice during adolescence. These findings provided direct evidence for the deleterious effects of exposure to Cd in the postweaning period on socioemotional behaviors later in adolescence, and suggested that these effects of Cd exposure may be linked to changes in the gut microbiota.

NIMO: A Natural Product-Inspired Molecular Generative Model Based on Conditional Transformer.

Natural products (NPs) have diverse biological activity and significant medicinal value. The structural diversity of NPs is the mainstay of drug discovery. Expanding the chemical space of NPs is an urgent need. Inspired by the concept of fragment-assembled pseudo-natural products, we developed a computational tool called NIMO, which is based on the transformer neural network model. NIMO employs two tailor-made motif extraction methods to map a molecular graph into a semantic motif sequence. All these generated motif sequences are used to train our molecular generative models. Various NIMO models were trained under different task scenarios by recognizing syntactic patterns and structure-property relationships. We further explored the performance of NIMO in structure-guided, activity-oriented, and pocket-based molecule generation tasks. Our results show that NIMO had excellent performance for molecule generation from scratch and structure optimization from a scaffold.

TCAF2 drives glioma cellular migratory/invasion properties through STAT3 signaling.

Glioma is an intracranial tumor characterized by high mortality and recurrence rates. In the present study, the association of TRPM8 channel-associated factor 2 (TCAF2) in glioma was investigated using bioinformatics, showing significant relationships with age, WHO grade, IDH, and 1p/19q status, as well as being an independent predictor of prognosis. Immunohistochemistry of a glioma sample microarray showed markedly increased TCAF2 expression in glioblastoma relative to lower-grade glioma, with elevated expression predominating in the tumor center. Raised TCAF2 levels promote glioma cell migratory/invasion properties through the epithelial-to-mesenchymal transition-like (EMT-like) process, shown by Transwell and scratch assays and western blotting. It was further found that the effects of TCAF2 were mediated by the activation of STAT3. These results suggest that TCAF2 promotes glioma cell migration and invasion, rendering it a potential drug target in glioma therapy.

RAB1A regulates glioma cellular proliferation and invasion via the mTOR signaling pathway and epithelial-mesenchymal transition.

Aim: We aimed at investigating the mechanism of RAB1A proliferation and invasion in gliomas. Materials & methods: Genome-wide expression profile data and immunohistochemistry were analyzed to assess RAB1A expression in gliomas. The Transwell assay, wound healing assay, brain slice coculture model, cellular fluorescence and intracranial xenograft model of nude mice were used to determine the proliferation and invasion of glioma cells. Results & conclusion: RAB1A was highly expressed in gliomas compared with normal brain tissue. The overall survival time of glioma patients with high RAB1A expression was significantly shortened. RAB1A regulated the activity of RAC1 by inhibiting the mTOR signaling pathway, affecting actin polymerization, cell morphology and cell polarity. RAB1A downregulation inhibited the epithelial-mesenchymal transition, proliferation and invasion of glioma cells.

Molecular and clinical characterization of Galectin-9 in glioma through 1,027 samples.

In recent years, research on glioma immunotherapy have grown rapidly. However, the autoimmune-like side effects that are caused by blocking immunological checkpoints hinder their clinical application in gliomas currently. Galectin-9, a ligand for T-cell immunoglobulin mucin 3, has shed a new light on the treatment of malignant glioma. However, the potential mechanism of Galectin-9 is still under discussion. In this study, first, we methodically gathered 1,027 glioma patients with RNA-seq and 986 patients with survival data to explore the role and mechanism of Galectin-9 in gliomas. Second, we analyzed glioma samples from 50 patients in the Department of Neurosurgery, Tianjin Medical University General Hospital. Finally, we found that Galectin-9 was strongly upregulated in glioblastoma multiforme compared with normal brain tissues and lower-grade glioma. Patients with Galectin-9 overexpression had a significantly shorter overall survival. Moreover, the tissue microarray data displayed that the expression of Galectin-9 in the core of tumor is higher than that in the border and was correlated with the shorter survival in glioma patients. Galectin-9 is more highly expressed in the mesenchymal subtype of glioblastoma multiforme than in the other subtypes. Simultaneously, Galectin-9 was closely associated with the immune response and lymphocyte activation, especially T-cell activation. To further determine the underlying role of Galectin-9 in the immune response, we selected seven immune metagenes. Through cluster analysis and correlation analysis, we discovered that Galectin-9 was highly correlated with immune checkpoint molecules and M2 tumor-associated macrophages. In summary, Galectin-9 serves as a potential therapeutic target to treat glioblastoma multiforme.

NKCC1 promotes EMT-like process in GBM via RhoA and Rac1 signaling pathways.

Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium-potassium-chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition-like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial-mesenchymal transition (EMT)-like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N-cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E-cadherin. These findings indicate that NKCC1 promotes an EMT-like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT-like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT-like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.

Features of chicken egg yolk immunoglobulin (IgY) against the infection of red-spotted grouper nervous necrosis virus.

Red-spotted grouper nervous necrosis virus (RGNNV) is one of the most important viruses which mainly infects the larva of marine and freshwater fish with high mortality and affects the fishery industry worldwide. Currently, there are no effective vaccines available for the fish larva infected with NNV. Immunoglobulin yolk (IgY) origin of oviparous animals is passed from the blood serum and concentrated in the egg yolk. With the advantages of high yield, cost-effectiveness, and high stability, IgY can be widely used in passive immunization, especially in young animals in which adaptive immunity is not fully developed. In this study, we have cloned and expressed the recombinant capsid protein of RGNNV in Escherichia coli and used as an immunogen for generating specific anti-RGNNV IgY antibody in laying hens. Water-soluble fractions (WSF) of the specific IgY were isolated from egg yolk and purified by two-step precipitation with saturated ammonium sulfate salting. By Enzyme linked immunosorbent assay (ELISA), the titer of the IgY reached a peak at the 6th week post of immunization and had a strong stability at a wide range of temperature, pH, and pepsin enzyme digestion. The purified IgY was competent to neutralize and completely inhibited the RGNNV replication in the grouper fin cell line (GF-1), indicating that it was highly specific and effectively recognized RGNNV. The results will pave a new way for the prevention of RGNNV infection.

Nutrient sensing signaling integrates nutrient metabolism and intestinal immunity in grass carp, Ctenopharyngodon idellus after prolonged starvation.

Starvation has been shown to affect growth and nutrient metabolism in fish; however, little information about the nutrient sensing signaling and mucosal adaptive immunity in fish was known. In the present study, grass carp was starved for 8weeks to simulate the natural aquaculture practice in Hubei during winter. The histology of liver was significantly affected with decreased expression of tight junction proteins including claudin-3, claudin-b and ZO-1. Muscle gene expression was also affected, with decreased expression of muscle growth promoting factors such as Myogenin, MyoD, Myf5, and increased expression of muscle degradation factors, such as CathepsinD. In addition, mucosal adaptive immunity was also significantly affected, with decreased expression of antibodies including IgZ and IgM in gut. Along with these changes was the inhibition of several nutrient sensing signaling including MAPK and TOR signaling, which leads to the inhibition of the synthesis of protein including immunoglobulin. The increased phosphorylation of eIF2α not only inhibited the translation, but also resulted in the decreased expression of IkB and increased expression of NF-B, with the activation of pro-inflammatory genes including IL8 and TNF.

gWEGA: GPU-accelerated WEGA for molecular superposition and shape comparison.

Virtual screening of a large chemical library for drug lead identification requires searching/superimposing a large number of three-dimensional (3D) chemical structures. This article reports a graphic processing unit (GPU)-accelerated weighted Gaussian algorithm (gWEGA) that expedites shape or shape-feature similarity score-based virtual screening. With 86 GPU nodes (each node has one GPU card), gWEGA can screen 110 million conformations derived from an entire ZINC drug-like database with diverse antidiabetic agents as query structures within 2 s (i.e., screening more than 55 million conformations per second). The rapid screening speed was accomplished through the massive parallelization on multiple GPU nodes and rapid prescreening of 3D structures (based on their shape descriptors and pharmacophore feature compositions).

ChemStable: a web server for rule-embedded naïve Bayesian learning approach to predict compound stability.

Predicting compound chemical stability is important because unstable compounds can lead to either false positive or to false negative conclusions in bioassays. Experimental data (COMDECOM) measured from DMSO/H2O solutions stored at 50 °C for 105 days were used to predicted stability by applying rule-embedded naïve Bayesian learning, based upon atom center fragment (ACF) features. To build the naïve Bayesian classifier, we derived ACF features from 9,746 compounds in the COMDECOM dataset. By recursively applying naïve Bayesian learning from the data set, each ACF is assigned with an expected stable probability (p(s)) and an unstable probability (p(uns)). 13,340 ACFs, together with their p(s) and p(uns) data, were stored in a knowledge base for use by the Bayesian classifier. For a given compound, its ACFs were derived from its structure connection table with the same protocol used to drive ACFs from the training data. Then, the Bayesian classifier assigned p(s) and p(uns) values to the compound ACFs by a structural pattern recognition algorithm, which was implemented in-house. Compound instability is calculated, with Bayes' theorem, based upon the p(s) and p(uns) values of the compound ACFs. We were able to achieve performance with an AUC value of 84% and a tenfold cross validation accuracy of 76.5%. To reduce false negatives, a rule-based approach has been embedded in the classifier. The rule-based module allows the program to improve its predictivity by expanding its compound instability knowledge base, thus further reducing the possibility of false negatives. To our knowledge, this is the first in silico prediction service for the prediction of the stabilities of organic compounds.

Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets.

Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the posttherapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by posttranslational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multiomics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of posttreatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.

Antibacterial Activity and Action Mechanism of Bacteriocin Paracin wx7 as a Selective Biopreservative against Vancomycin-Resistant Enterococcus faecalis in Fresh-Cut Lettuce.

Fresh-cut vegetables are widely consumed, but there is no food preservative available to selectively inhibit vancomycin-resistant E. faecalis, which is a serious health menace in fresh-cut vegetables. To develop a promising food biopreservative, a bacteriocin, paracin wx7, was synthesized, showing selective inhibition against E. faecalis with MIC values of 4-8 µM. It showed instant bactericidal mode within 1 h at high concentrations with concomitant cell lysis against vancomycin-resistant E. faecalis. Its lethal effect was visualized in a dose-dependent manner by PI/SYTO9 staining observation. The results of an in vivo control experiment carried out on E. faecalis in fresh-cut lettuce showed that 99.97% of vancomycin-resistant E. faecalis were dead after 64 µM paracin wx7 treatment for 7 days without influencing total bacteria. Further, the action mechanism of paracin wx7 was investigated. Confocal microscopy showed that paracin wx7 was located both on the cell envelope and in cytoplasm. For the cell envelope, the studies of membrane permeability using SYTOX Green dyeing and DNA leakage revealed that paracin wx7 damaged the membrane integrity of E. faecalis. Simultaneously, it exhibited membrane depolarization after analysis using DiSC3(5). Damage to the cell envelope resulted in cell deformation observed by scanning electron microscopy. On entering the cytoplasm, the paracin wx7 induced the production of endogenous reactive oxygen species.

N-carbamylglutamate supplementation induces functional egg production in layers by modulating liver transcriptome profiles.

Eggs rich in polyunsaturated fatty acids (PUFA), known as functional eggs, are animal products deemed beneficial to human health and possess high economic value. The production of functional eggs involves supplementing exogenous additives with the ability to regulate lipid metabolism. As N-Carbamylglutamate (NCG) serves as an endogenous arginine synthesizer, and arginine acts as the substrate for the formation of nitric oxide (NO), the biological function of NCG is partially mediated by NO. NO is a key regulatory molecule in lipid metabolism, suggesting that NCG may also have the ability to modulate lipid metabolism. In order to assess the capacity of NCG in regulating liver lipid metabolism and its potential application in producing functional eggs, we conducted a study to investigate the effects of dietary supplementation of NCG on production performance, serum, and liver NO levels, yolk fatty acid composition, and the liver transcriptome of layers. In this study, we utilized 30 layers of the Jinghong No.1 breed, all aged 45 wk. All the birds were randomly divided into 2 groups. Each group had 5 replicates, and each replicate had 3 birds. We provided them with different diets: one group received the basic diet, and the other group's diet was supplemented with 0.08% NCG. The experiment lasted for 14 wk. The results did not reveal any positive impact of NCG on production performance. However, NCG supplementation elevated NO levels in serum and liver, along with an increase in yolk PUFA, ω-3, and ω-6 fatty acids. Liver transcriptome analysis identified 124 upregulated differentially expressed genes (DEGs) and 43 downregulated DEGs due to NCG supplementation. Functional annotation using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted 3 upregulated DEGs (CPT1A, MOGAT1, and CHKA) and 2 downregulated DEGs (FASN and ETNPPL) associated with lipid metabolism. Pathway enrichment analysis revealed that CPT1A was enriched in the AMPK signaling pathway and the PPAR signaling pathway, while FASN was enriched in the AMPK signaling pathway. Thus, CPT1A and FASN are potential functional genes related to lipid metabolism facilitated by NCG supplementation. In summary, our study suggests that NCG supplementation modulates liver lipid metabolism, leading to the production of functional eggs in layers.

Role of ferroptosis in Porphyromonas gingivalis-induced impairment of epithelial junction.

Objectives: This study aims to clarify the effect of ferroptosis by P. gingivalis on periodontal epithelium impairment and potential mechanisms. Materials and methods: The expression of epithelial junction proteins (CDH1, OCLN, ZO-1), FTL and GPX4 in healthy and periodontitis tissues was analyzed using bioinformatics analysis and validated in vivo. An in vitro model was constructed to evaluate ferroptosis by mitochondria morphology, content of iron and GSH, and level of lipid peroxidation, FTL, GPX4 and SLC7A11. The iron concentration was changed with iron chelator DFO and iron supplementation FAC. The epithelial impairment was assessed by protein expression. To investigate the mechanism, si-MYB (a negative transcription factor of SLC7A11) and GPX4 inhibitor RSL3 were employed. Results: CDH1, OCLN, ZO-1 and GPX4 expression was decreased, while FTL expression was elevated in periodontitis tissues. Infected cells showed ferroptosis change of the mitochondria with higher level of lipid peroxidation, iron, FTL and lower level of GPX4, GSH, SLC7A11. FAC augmented ferroptosis and weakened epithelial junction, while DFO exhibited a counteractive effect. Silencing MYB rescued SLC7A11, GPX4 and epithelial junction proteins, which was hindered by RSL3. Conclusions: Our study demonstrated that P. gingivalis weakened the oral epithelial barrier by causing ferroptosis via inhibiting SLC7A11/GSH/GPX4 axis.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

PURPOSE: Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

Identification of Protein-Protein Interaction Associated Functions Based on Gene Ontology.

Protein-protein interactions (PPIs) involve the physical or functional contact between two or more proteins. Generally, proteins that can interact with each other always have special relationships. Some previous studies have reported that gene ontology (GO) terms are related to the determination of PPIs, suggesting the special patterns on the GO terms of proteins in PPIs. In this study, we explored the special GO term patterns on human PPIs, trying to uncover the underlying functional mechanism of PPIs. The experimental validated human PPIs were retrieved from STRING database, which were termed as positive samples. Additionally, we randomly paired proteins occurring in positive samples, yielding lots of negative samples. A simple calculation was conducted to count the number of positive samples for each GO term pair, where proteins in samples were annotated by GO terms in the pair individually. The similar number for negative samples was also counted and further adjusted due to the great gap between the numbers of positive and negative samples. The difference of the above two numbers and the relative ratio compared with the number on positive samples were calculated. This ratio provided a precise evaluation of the occurrence of GO term pairs for positive samples and negative samples, indicating the latent GO term patterns for PPIs. Our analysis unveiled several nuclear biological processes, including gene transcription, cell proliferation, and nutrient metabolism, as key biological functions. Interactions between major proliferative or metabolic GO terms consistently correspond with significantly reported PPIs in recent literature.

Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury.

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201-259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCµ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB.

IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.