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Monoamine oxidase (MAO) inhibitors reduce inflammation in a number of in vitro and in vivo models. This finding led to the development of a novel MAO-B selective inhibitor (RG0216) designed to reduce blood-brain barrier penetration. To elucidate RG0216's regulatory role in inflammation-relevant signaling pathways, we employed a transcriptome analytic approach to identify genes that are differentially regulated by RG0216 and then globally identified which inflammation-relevant biological signaling pathways were altered by this drug. Primary human gingival keratinocyte (HGK) cells were treated with RG0216, and RNA was extracted (4 h). RNAseq transcriptome analysis was utilized to identify differentially expressed genes (DEGs), while Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify significantly enriched biological pathways. Relevant genes associated with these pathways and RG0216 regulation of Porphyromonnas gingivalis lipopolysaccharide (PgLPS)-induced cytokine/chemokine expression were evaluated using the real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) approach. RG0216 significantly altered the expression of 50 DEGs in HGK cells. Using GO and KEGG analytic approaches, these genes were associated with the biological pathways relevant to mitogen-activated protein kinase (MAPK) and MAPK phosphatases. These phosphatases are part of the 10-member catalytically active dual-specificity phosphatase (DUSP) family. RG0216 induced the expression of DUSP10, reduced the expression of DUSP4 and DUSP6, and decreased IL-6 and IL-8 expression in control and PgLPS-stimulated cultures. In HGK cells, a novel MAO-B inhibitor (RG0216) significantly altered DUSP4, DUSP6, and DUSP10 expression. DUSPs play a regulatory role in MAPK activity and, therefore, can alter cellular inflammatory responses. We found that RG0216 inhibited IL-6 and IL-8 expression. Further studies are planned to examine RG0216's regulatory role in DUSP expression and its impact on the regulation of cytokine/chemokine expression. Show less

The present study examines the role of morphemic units in the initial word recognition stage among beginning readers. We assess whether and to what extent sublexical units, such as morphemes, are used in processing French words and how their use varies with reading proficiency. Two experiments were conducted to investigate the perceptual and morphological effects on the recognition of words presented in central vision, using a variable-viewing-position technique. To explore changes during elementary school years, we tested children from the second and fourth grades, as well as adult readers. The percentage of correct word identification was highest near the center of the word, indicating an optimal viewing position for all three participant groups. Viewing position effects were modulated by age and the properties of the stimuli (length and morphological structure). Experiment 1 demonstrated that lexical decisions are influenced by morphological structure to a decreasing extent as reading skill develops. Experiment 2 revealed that morphological processing in children primarily relies on the orthographic information provided by morphemes (surface morphology), whereas proficient readers process morphological information at a more abstract level, exhibiting a genuine morphological-facilitation effect. Overall, our study strongly indicates that morphemic units play a crucial role in the initial stage of word identification in early reading development. This conclusion aligns with the "word and affix" model, which posits that morphological representations become increasingly independent of orthography as reading ability and word exposure improve. Show less

The prevalence of obesity is increasing worldwide, affecting both children and adults. This obesity epidemic is mostly driven by an increase in energy intake (abundance of highly palatable energy-dense food and drinks) and to a lesser degree a decrease in energy expenditure (sedentary lifestyle). A small proportion of individuals with obesity are affected by genetic forms of obesity, which often relate to mutations in the leptin-melanocortin pathway or are part of syndromes such as the Bardet-Biedl syndrome. These rare forms of obesity have provided valuable insights into the genetic architecture of obesity. Recent advances in understanding the molecular mechanisms that control appetite, hunger, and satiety have led to the development of drugs that can override genetic defects, enabling precision treatment. Leptin deficiency is uniquely treated with recombinant human metreleptin, while those with LEPR, PCSK1, or POMC deficiency can now be treated with the MC4R agonist setmelanotide. This review highlights the most frequent monogenic and syndromic forms of obesity, and the future outlook of precision treatment for these conditions. Show less

Familial hypercholesterolemia (FH) is a genetic disease, usually with onset during childhood, characterized by elevated blood LDL cholesterol levels and potentially associated with severe cardiovascular complications. Concerning mutated genes in FH, such as Show less

Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances. Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA) Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGA This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed. Identification of recurrent gene abnormalities (RGA) Show less

Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs detected through routine clinical testing. We also identified crSVs, such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, missed by routine clinical approaches, resulting in the classification of leukemia genetic subtypes for four additional patients. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs. Show less

Neonatal sepsis is a significant cause of mortality in children under 5 years of age globally, with the highest incidence reported in India. The challenges in diagnosing neonatal sepsis often result in the irrational use of antibiotics. The aim of the study was to determine the diagnostic efficacy of interleukin 27 (IL-27) as a novel biomarker for the early diagnosis of neonatal sepsis. This prospective cohort study was conducted at a tertiary care hospital in North India from May 2019 to April 2020. Eighty neonates suspected of sepsis were enrolled based on the sepsis screen criteria approved by the National Neonatal Forum of India. Blood samples were collected for culture and biomarker analysis, with C-reactive protein (CRP), procalcitonin (PCT), and IL-27 levels measured. The diagnostic performance of IL-27 was compared to that of CRP and PCT. Out of 80 neonates, 56% were male and 44% were female. Blood cultures were positive in 51.2% of cases. The most common pathogens isolated were Gram-negative bacteria (41%), fungi (34%), and Gram-positive bacteria (25%). IL-27 demonstrated a sensitivity of 78.05%, specificity of 61.54%, positive predictive value of 68.09%, and negative predictive value (NPV) of 72.73%. In comparison, PCT showed the highest sensitivity (82.93%), and CRP had the highest specificity (79.49%). IL-27 levels were notably higher in blood culture-positive cases. IL-27 is a promising biomarker for the early diagnosis of neonatal sepsis, showing comparable sensitivity and NPV to PCT, but with lower specificity than CRP. Show less

More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS. Show less

Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coagulation changes after SCI in humans are not comprehensive. Therefore, this study aims to identify blood coagulation diagnostic biomarkers and immune changes related to SCI and its severity levels. Human blood sequencing datasets were obtained from public databases. Differentially expressed coagulation-related genes were analyzed (DECRGs). Enrichment analysis and assessment of immune changes were conducted. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator logistic regression were used to identify biomarkers. Validation for these biomarkers was performed. The correlation between biomarkers and immune cells was evaluated. Transcription factors, miRNA, lncRNA, and drugs that can regulate biomarkers were analyzed. DECRGs associated with SCI and its different grades were identified, showing enrichment in altered coagulation and immune-related signaling pathways. ADAM9, CD55, and STAT4 were identified as coagulation diagnostic biomarkers for SCI. IRF4 and PABPC4 were identified as coagulation diagnostic biomarkers for American Spinal Injury Association Impairment Scale (AIS) A grade of SCI. GP9 was designated as a diagnostic biomarker for AIS D grade of SCI. Immune changes in blood of SCI and its different grades were observed. Correlation between diagnostic biomarkers and immune cells were identified. Transcription factors, miRNA, lncRNA, and drugs that can regulate diagnostic biomarker expression were discovered. Therefore, detecting the expression of these putative diagnostic biomarkers and related immune changes may be helpful for predicting the severity of SCI. Uncovering potential regulatory mechanisms for biomarkers may be beneficial for further research. Show less

Human papillomaviruses (HPVs) infect cutaneous and mucosal epithelia to cause benign (warts) and malignant lesions (e.g. cervical cancer). Bovine papillomaviruses (BPVs) infect fibroblasts to cause fibropapillomas but can also infect cutaneous epithelial cells. For HPV-1, -16, -31 and BPV-1, Show less

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression. Show less

In glucose-starved cells, macroautophagy (hereafter referred to as autophagy) is considered to serve as an energy-generating process contributing to cell survival. AMPK (adenosine monophosphate-activated protein kinase) is the primary cellular energy sensor that is activated during glucose starvation. According to the current paradigm in the field, AMPK promotes autophagy in response to energy deprivation by binding and phosphorylating ULK1 (UNC-51 like kinase 1), the protein kinase responsible for autophagy initiation. However, conflicting findings have been reported casting doubts about the current established model. In our recent study, we have thoroughly reevaluated the role of AMPK in autophagy. Contrary to the current paradigm, our study revealed that AMPK functions as a negative regulator of ULK1 activity. The study has elucidated the underlying mechanism and demonstrated the significance of the negative role in controlling autophagy and maintaining cellular resilience during energy depletion. Show less

ENDOG, a mitochondrial intermembrane space located endonuclease, participates in DNA fragmentation and apoptosis by translocating to the nucleus. ENDOG can also relocate to the mitochondrial matrix, where it regulates mitochondrial genome cleavage. However, the biological function of cytoplasm-translocated ENDOG remains unclear. Our previous study reported that starvation induces the release of ENDOG from mitochondria to the cytoplasm, promoting macroautophagy/autophagy in a process conserved across species. We demonstrate that ENDOG can be phosphorylated by GSK3B, which enhances ENDOG binding to YWHAG/14-3-3γ, and leads to the release of TSC2 and PIK3C3/VPS34 from YWHAG/14-3-3γ, followed by MTORC1 pathway suppression and autophagy initiation. Additionally, we recently reported that ENDOG can also activate the MTORC2-AKT-ACLY signaling axis by promoting the release of RICTOR and TSC2 from YWHAG/14-3-3γ, resulting in acetyl-CoA production. Furthermore, cytoplasmic ENDOG can translocate to the endoplasmic reticulum, where it binds with HSPA5/BIP to release ERN1/IRE1a-EIF2AK3/PERK to activate the endoplasmic reticulum stress response, eventually promoting lipid synthesis. Collectively, ENDOG will be released from the mitochondrial intermembrane space, and translocated to the mitochondrial matrix, cytoplasm, and nucleus during different stress stimulation, where it digests DNA or interacts with crucial proteins to regulate different biological functions, including apoptosis, autophagy, mitophagy, and lipid synthesis. Show less

Actin is a protein of central importance to many cellular functions. Its localization and activity are regulated by interactions with a high number of actin-binding proteins. In a yeast two-hybrid (Y2H) screening system, snail family transcriptional repressor 2 (SNAI2 or slug) was identified as a yet unknown potential actin-binding protein. We validated this interaction using immunoprecipitation and analyzed the functional relation between slug and actin. Since both proteins have been reported to be involved in DNA double-strand break (DSB) repair, we focused on their interaction during this process after treatment with doxorubicin or UV irradiation. Confocal microscopy elicits that the overexpression of actin fused to an NLS stabilizes complexes of slug and γH2AX, an early marker of DNA damage repair. Show less

Familial chylomicronemia syndrome (FCS) comprises a group of ultrarare disorders caused by biallelic variants in LPL or, less frequently, by GPIHBP1, APOC2, APOA5, or LMF1. To evaluate the phenotypes and management of eight non-lipoprotein lipase (LPL)-FCS patients. Seven pediatric and one adult patients with non-LPL-FCS were enrolled. Clinical features, treatment outcomes, and genetic profiles were assessed. Among the 33 patients with FCS, 25 (76%) had LPL-FCS and eight (24%) had non-LPL-FCS; five had variants in GPIHBP1, one each in the LMF1, APOC2, and one with composite heterozygous variants in APOA5 and LPL. Twelve non-LPL variants were identified, five of which were novel variants in GPIHBP1 and two in LMF1. In silico predictions indicated that all novel variants might impact protein function. Elevated baseline triglyceride (TG) levels [22.9 (17.4-30.8) mmol/L, 2026.7 (1540.0-2728.5) mg/dL] were observed in all patients. Among the pediatric patients (7/7), chylomicronemia was the most common onset symptom. Acute pancreatitis was observed in only one patient with LMF1-FCS during pregnancy. The frequency of symptoms and lipid levels in the non-LPL-FCS group were slightly lower than those in the LPL-FCS group (P > 0.05). Dietary fat restriction reduced TG levels by 84.0% to 4.21 mmol/L (372.6 mg/dL, P < 0.01). Compared with other non-LPL-FCS patients, GPIHBP1-FCS patients experienced greater challenges in managing TG levels (P < 0.05). This study unveiled the genetic profile of the Chinese FCS cohort and enriched the mutation spectrum of non-LPL-FCS. The clinical characteristics and treatment outcomes of patients with non-LPL-FCS were delineated. Show less

Vision-Language Models (VLMs), such as CLIP, excel in zero-shot image-level visual understanding but struggle with object-based tasks requiring precise localization and recognition. Visual prompts, like colorful boxes or circles, are suggested to enhance local perception. However, these methods often include irrelevant and noisy pixels, leading to suboptimal performance. The design of better visual prompts and their collaboration with text prompting remains underexplored. This paper introduces Fine-Grained Visual Text Prompting (FGVTP), a new zero-shot framework for object-based tasks using precise semantic masks and reinforced image-text alignment. FGVTP comprises Fine-Grained Visual Prompting (FGVP) and Consistency-Enhanced Text Prompting (CETP). Specifically, we carefully study visual prompting designs by exploring more visual markings that vary in shape and form. FGVP uses semantic masks from a segmenter like the Segment Anything Model (SAM) and employs background blurring (Blur Reverse Mask) to highlight targets while maintaining spatial coherence. Further, CETP enhances image-text alignment by prompting captions based on FGVP-processed images. As a result, FGVTP achieves superior zero-shot referring expression comprehension on RefCOCO/+/g benchmarks, outperforming previous SOTA methods by 5.8% on average. Part detection experiments conducted on the PACO dataset further validate the preponderance of FGVTP over existing works. Code is available at https://github.com/ylingfeng/FGVP. Show less

The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care. Show less

GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα Show less

To explore the influencing factors of osteoporosis (OP) in elderly patients with rheumatoid arthritis (RA). A total of 145 elderly patients with RA were divided into comorbidity group (with OP) of 79 patients and RA group (without OP) of 66 patients. Demographic data and laboratory parameters were collected from patients. Demographic characteristics and laboratory parameters were compared between the two groups. Multiple influencing factors of OP in RA patients were analysed. There were significant differences in age, BMI, primary disease duration, history of glucocorticoids (GC) administration, disease activity score in 28 joints (DAS-28), and Sharp score data between the two groups. There were significant differences in rheumatoid factor (RF), interleukin-27 (IL-27), procollagen I N-Terminal Propeptide (PINP), nuclear receptor of activator factor-κB ligand (RANKL), and 25-hydroxyvitamin D [25-hydroxyvitamin D, 25 (OH) D] data between the two groups (P < 0.05). Logistic analysis showed that age, primary disease duration, GC history, DAS-28, Sharp score, RANKL and 25 (OH) D were independent factors for OP in RA patients. The risk of OP in elderly RA patients is mainly related to age, primary disease duration, GC history, DAS-28, Sharp score, RANKL, and 25 (OH) D levels, and risk factors should be actively prevented. Show less

Cyanidin has a protective effect on the nervous system and has been reported to treat tumor effectively. However, its impact on glioma stem cells (GSC) is unknown. Using seven GSC lines, the anti-tumor effect of cyanidin is tested. The effect of cyanidin on the cell viability in each cell line is evaluated. Wnt signaling pathway-related genes are checked after treatment of cyanidin. Cytoplasmic/nuclear β-catenin protein levels post cyanidin treatment is detected. Protein levels of c-Myc after cyanidin treatment are determined. Twist1 and Snail1 protein levels after cyanidin treatment are checked as well. Cyanidin significantly reduces the cell viability of all GSCs, and exhibited the most substantial effect in GBM2 but no apparent effect in 293T cells. It can regulate the Wnt signaling pathway of all GSC lines. In the GBM2, GBM7, G166, and G179 cell lines, there is upregulation of Cyanidin exerts an anti-tumor effect in glioma stem cell lines, probably through the Wnt signaling pathway. Show less

The Coastal Creole pigs in Argentina are predominantly found in the wild and can trace their lineage directly back to the Iberian breeds introduced by Spanish colonizers. They currently stand as the sole Creole breed in the country recognized by the FAO. However, there exists a dearth of studies assessing their genetic potential within the swine industry. Therefore, this study aimed to genetically characterize the meat quality of Coastal Creole pigs based on seven single nucleotide polymorphisms (SNPs) within the Ryr1, PRKAG3, MC4R, H-FABP, and CAST genes. A total of N = 158 samples were collected from specimens distributed along the coastal region. Our findings revealed all loci to exhibit polymorphism, underscoring the population's remarkable genetic diversity. Furthermore, a higher frequency of alleles favorable for the PRKAG3 Show less

Sudden cardiac death due to ventricular fibrillation (VF) during ST-elevation acute myocardial infarction (STEAMI) significantly contributes to cardiovascular-related deaths. Although VF has been linked to genetic factors, variations in copy number variation (CNV), a significant source of genetic variation, have remained largely unexplored in this context. To address this knowledge gap, this study performed whole exome sequencing analysis on a cohort of 39 patients with STEAMI who experienced VF, aiming to elucidate the role of CNVs in this pathology. The analysis revealed CNVs in the form of duplications in the Show less

CXCR3B has been positively involved in the inhibition of cancer and angiogenesis. The present study investigated the role of CXCR3B in a cell model of hepatocellular carcinoma, SK-Hep1. The blockade of CXCR3B expression in SK-Hep1 was investigated in terms of cell viability, cell cycle, and cell apoptosis using MTT assay and flow cytometry. In addition, the effect of blocking CXCR3B expression on cell migration and invasion was examined using scratch motility, transwell migration, and invasion assays. Furthermore, the cytotoxic effect of NK-92 cells against CXCR3B blocked SK-Hep1 was analyzed using the CytoTox96 assay, and the expression of NKp30 Blocking CXCR3B expression had no effect on the viability, cell cycle or apoptosis of SK-Hep1 cells. However, blockade of CXCR3B expression significantly increased the migratory and invasive ability of SK-Hep1 along with increased protein expression of slug, vimentin, and N-cadherin. CXCR3B blockade reduced the cytotoxicity of NK-92 against SK-Hep1 and inhibited the expression of activating receptors, NKp30 CXCR3B may play a positive role in suppressing HCC by attenuating natural killer cell cytotoxicity against HCC. Show less

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. The ICR mice intracerebroventricularly injected with Aβ Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis. Show less

Thymic epithelial tumors (TETs) are infrequent malignancies that arise from the anterior mediastinum. Therapeutic options for TETs, especially thymic carcinoma (TC), remain relatively constrained. This study aims to investigate the oncogenic hub gene and its underlying mechanisms in TETs, as well as to identify potential therapeutic targets. Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were utilized to identify significant oncogenes using The Cancer Genome Atlas (TCGA) database. LASSO logistic regression analysis was performed to assess the association between hub genes and clinical parameters. The influence of the hub gene on promoting epithelial-mesenchymal transition (EMT), tumor progression, and regulating cancer stem cell-like properties was assessed both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the alterations in the tumor and its microenvironment following the administration of the hub gene's inhibitor. Multiplex immunohistochemistry (mIHC) was employed to validate the results. The potential mechanism was further elucidated through the utilization of Cleavage Under Targets and Tagmentation (CUT&Tag), RNA-sequencing, chromatin immunoprecipitation (ChIP), CUT&RUN, luciferase reporter assay, co-immunoprecipitation (Co-IP), mass spectrometry (MS) and phosphoproteomic assays. SNAI1 was identified as a hub transcription factor for TETs, and its positive correlation with the invasiveness of the disease was confirmed. Subsequent experiments revealed that the upregulation of SNAI1 augmented the migration, invasion, and EMT of TET cell lines. Furthermore, we observed that the overexpression of SNAI1 sustained cancer stem cell-like properties. ScRNA-seq demonstrated that the use of a SNAI1 inhibitor inhibited the transition of macrophages from M1 to M2 phenotype, a finding further validated by multiplex immunohistochemistry (mIHC). Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) was identified as one of the downstream targets of SNAI1 through CUT&Tag and RNA-sequencing, a finding validated by ChIP-qPCR, CUT&RUN-qPCR, luciferase reporter and immunofluorescence assays. Co-IP, MS and phosphoproteomic assays further confirmed that PIK3R2 directly interacted with phosphorylated EphA2 (p-EphA2), facilitating downstream GSK3β/β-catenin signaling pathway. The tumorigenic role of SNAI1 through the PIK3R2/p-EphA2 axis was preliminarily validated in TETs. A potential therapeutic strategy for TETs may involve the inhibition of SNAI1. Show less

Circular RNA (circRNA) has been found to mediate ulcerative colitis (UC) progression by regulating intestinal mucosal barrier function. However, the role of circSOD2 in UC process and its underlying molecular mechanism still need to be further elucidated. Lipopolysaccharide (LPS)-induced Caco2 cells were used to mimic UC cell models. CircSOD2, miR-378g, and Snail1 levels were determined by quantitative real-time PCR. Cell viability was detected using MTT assay, and inflammatory cytokine levels were measured using ELISA. The intestinal mucosal barrier function was evaluated by testing transepithelial electrical resistance and fluorescein isothiocyanate (FITC)-dextran permeability. Snail1 and tight junction-related markers (Zo-1 and Claudin2) protein levels were examined using western blot. The interaction between miR-378g and circSOD2 or Snail1 was confirmed by dual-luciferase reporter assay. Dextran sulfate sodium (DSS) was used to induce UC rat models in vivo. CircSOD2 was overexpressed in UC patients, and its knockdown significantly increased cell viability, transepithelial electrical resistance, and tight junction-related protein expression, while reduced inflammation cytokine levels and the permeability of FITC-dextran in LPS-induced Caco2 cells. In terms of mechanism, circSOD2 sponged miR-378g to positively regulate Snail1 expression. MiR-378g inhibitor reversed the effect of circSOD2 knockdown on intestinal mucosal barrier injury and Snail1 expression in LPS-induced Caco2 cells. In DSS-induced UC rat models, circSOD2 knockdown also could repair the intestinal mucosal barrier injury through regulating miR-378g/Snail1 axis. CircSOD2 could destroy intestinal mucosal barrier function in LPS-induced Caco2 cells and DSS-induced UC rats by miR-378g/Snail1 axis. Show less

To isolate cancer stem cells (CSC) from a metastatic oral squamous cell carcinoma (OSCC) cell line and investigate their in vitro and in vivo phenotypic characteristics. Subpopulations with individual staining intensities for CD44 and CD326 were isolated from the OSCC cell line LN-1A by FACS: CD44 E-cadherin levels were higher in CSC-E cells while vimentin and Slug more produced by CSC-M The CSC subpopulations here described show increased cancer capabilities in vitro, tumorigenic and metastatic potential in vivo, and may be exploited in the search for novel therapeutic targets for OSCC. Show less

The release of CCL5 and CXCL10 is essential for recruiting cytotoxic immune cells into the tumor microenvironment and enhancing the efficacy of cancer immunotherapy. Type I IFNs, particularly IFNβ, activate signaling pathways that induce the expression of these chemokines. In our recent study, we explored the impact and underlying mechanisms of inhibiting the kinase activity of VPS34, a key lipid kinase in the autophagy/endosomal trafficking system, on the expression of CCL5 and CXCL10 in preclinical cancer mouse models. Using NanoString gene expression technology, we analyzed tumors from mice treated with the VPS34 inhibitor SB02024 and demonstrated that the expression of CCL5 and CXCL10 is increased through a cGAS-STING-dependent mechanism within cancer cells. CCL5 (C-C motif chemokine 5); CXCL10 (C-X-C motif chemokine 10); IFN (interferon); VPS34 (vacuolar protein sorting 34); cGAS (cyclic GMP-AMP Synthase); STING (stimulator of interferon genes protein); cGAMP (2'3'-cyclic guanosine monophosphate-adenosine monophosphate). Show less