Pathway Activity Research Articles

Palmitoylation-related gene expression and its prognostic value in ovarian cancer: insights into immune infiltration and therapeutic potential

BackgroundPalmitoylation, a key post-translational modification, plays a significant role in ovarian cancer (OV) progression. However, the impact of palmitoylation-related genes on genomic instability, immune infiltration, and therapeutic response in OV remains poorly understood. This study aimed to investigate these factors to facilitate risk stratification and therapeutic intervention, providing insights into personalized treatment strategies.MethodsData from TCGA and GEO were utilized to develop a prognostic model based on palmitoylation-related genes. Differential expression, functional enrichment, and immune infiltration analyses were performed. Immune cell composition and pathway activities in different risk groups were assessed using CIBERSORT and ssGSEA algorithms. Immunotherapy response was predicted using TIDE and SubMap, while drug sensitivity differences were evaluated using the GDSC database.ResultsUnivariate, LASSO, and multivariate Cox regression analyses identified palmitoylation-related genes with significant prognostic value. The prognostic model effectively stratified patients into high- and low-risk groups, demonstrating significant survival differences. Immune infiltration analysis revealed distinct immune cell compositions and functions between risk groups. Low-risk patients exhibited higher immune scores and increased expression of immune checkpoints (PD-1, CD274, CTLA4), suggesting greater response to immunotherapy. Drug sensitivity analysis identified compounds with differential efficacy between risk groups, highlighting potential targeted treatment options.ConclusionPalmitoylation-related genomic features significantly influence OV progression and the immune landscape, offering potential for improved risk stratification and informing immunotherapy strategies to enhance patient outcomes.

Sparstolonin B potentiates the antitumor activity of nanovesicle-loaded drugs by suppressing the phagocytosis of macrophages in vivo

BackgroundExtracellular vesicles (EVs) and extruded nanovesicles (ENVs) are promising nanovesicles (NVs) for drug delivery. However, the application of these NVs is strongly hindered by their short half-life in the circulation. Macrophages (Mφs) in the liver and spleen contribute to the rapid depletion of NVs, but the underlying mechanism is unclear.MethodsBy collecting the supernatant of PANC-1 cells and squeezing PANC-1 cells, EVs and ENVs derived from PANC-1 cells were prepared via ultracentrifugation. NVs were subsequently identified via western blot, particle size measurement, and electron microscopy. The distribution of NVs in mouse bodies was observed with a live animal imaging system. Liver Mφs were extracted and isolated after NVs were administered, and transcriptome profiling was applied to determine differentially expressed genes (DEGs). siRNAs targeting interested genes were designed and synthesized. In vitro experiments, Mφs were transfected with siRNA or treated with the corresponding inhibitor, after which NV uptake was recorded. Doxorubicin (DOX) was encapsulated in ENVs using an ultrasound method. PANC-1 cell-derived tumors were established in nude mice in vivo, inhibitor pretreatment or no treatment was administered before intravenous injection of ENVs-DOX, and the therapeutic efficacy of ENVs-DOX was evaluated.ResultsNVs derived from PANC-1 cells were first prepared and identified. After intravenous injection, most NVs were engulfed by Mφs in the liver and spleen. Seven genes of interest were selected via transcriptome sequencing and validated via RT‒PCR. These results confirmed that the TLR2 signaling pathway is responsible for phagocytosis. siTLR2 and its inhibitor sparstolonin B (SpB) significantly inhibited the internalization of NVs by Mφs and downregulated the activity of the TLR2 pathway. The accumulation of ENVs-DOX in the liver was inhibited in vivo by pretreatment with SpB 40 min before intravenous injection, ultimately delaying tumor progression.ConclusionThe TLR2 pathway plays a crucial role in the sequestration of NVs by Mφs. A novel antiphagocytic strategy in which pretreatment of mice with SpB inhibits the clearance of NVs and prolongs their half-life in vivo, thereby improving delivery efficiency, was identified.Graphical

Updates on Inflammatory Molecular Pathways Mediated by ADAM17 in Autoimmunity

ADAM17 is a member of the disintegrin and metalloproteinase (ADAM) family of transmembrane proteases with immunoregulatory activity in multiple signaling pathways. The functional ADAM17 is involved in the shedding of the ectodomain characterizing many substrates belonging to growth factors, cytokines, receptors, and adhesion molecules. The ADAM17-dependent pathways are known to be crucial in tumor development and progression and in the modulation of many pathological and physiological processes. In the last decade, ADAM17 was considered the driver of several autoimmune pathologies, and numerous substrate-mediated signal transduction pathways were identified. However, the discoveries made to date have led researchers to try to clarify the multiple mechanisms in which ADAM17 is involved and to identify any molecular gaps between the different transductional cascades. In this review, we summarize the most recent updates on the multiple regulatory activities of ADAM17, focusing on reported data in the field of autoimmunity.

MiR-184, a downregulated ovary-elevated miRNA transcriptionally activated by SREBF2, exerts anti-apoptotic properties in ovarian granulosa cells through inducing SMAD3 expression

Follicular atresia is the primary threat to female fertility. miRNAs are dysregulated in granulosa cells (GCs) during follicular atresia, and have emerged as crucial regulators of the initiation and progression of follicular atresia. However, the downregulated ovary-elevated (OE) miRNAs and their biological functions in ovary remain elusive. Here, 13 downregulated OE miRNAs were systematically identified by integrating tissue expression high-throughput data and comparative transcriptome analyses, among which miR-184 was specifically highly expressed in ovary but dramatically downregulated during follicular atresia. Low miR-184 levels were also positively correlated with follicular atresia. Based on the in vitro GC and follicle culture system, we found that miR-184 suppressed GC apoptosis and follicular atresia. Mechanistically, miR-184 induced SMAD3 transcription by acting as a saRNA, and also stabilized SMAD3 mRNA by directly binding to its 5′-UTR, which promoted TGF-β pathway activity and its anti-apoptotic effect. In addition, miR-184 was transcribed independently of host gene, which was activated by SREBF2 in an H3K4me3-dependent manner. Comparative analysis revealed that SREBF2 expression and H3K4me3 enrichment on miR-184 promoter in GCs from atretic follicles were dramatically reduced, which leads to the downregulation of miR-184 during follicular atresia. Moreover, the expression pattern, function, target, and regulatory mechanism of miR-184 among mammals are highly conserved and universal. Taken together, our findings demonstrate that miR-184, transcriptionally activated by SREBF2 in an H3K4me3-dependent manner, exerts anti-atretic effects by inducing SMAD3 expression, highlighting that it is a promising regulator for improving follicular development, ovarian health and female fertility.

LAT4 drives temozolomide induced radiotherapy resistance in glioblastoma by enhancing mTOR pathway activation

BackgroundGlioblastoma multiforme (GBM) represents the most prevalent form of primary malignant tumor within the central nervous system. The emergence of resistance to radiotherapy and chemotherapy represents a significant impediment to advancements in glioma treatment.MethodsWe established temozolomide (TMZ)-resistant GBM cell lines by chronically exposing U87MG cell lines to TMZ, and dimethyl sulfoxide (DMSO) was used as placebo control. In vivo and in vitro experiments verified the resistance of resistant cells to chemotherapy and radiotherapy. LAT4 was identified by transcriptomics to be associated with GBM treatment resistance and relapse. The relationship between LAT4 and mTOR pathway activity was also analyzed. Finally, the effect of BCH (LAT inhibitor) combined with radiotherapy on GBM prognosis was verified in vivo.ResultsWe have first confirmed that TMZ not only induces resistance to chemotherapy in GBM cells but also enhances their resistance to radiotherapy, which is a significant finding in the process of building TMZ-resistant U87MG GBM cell lines. We then performed comprehensive transcriptomic analysis and identified amino acid metabolism as a potential key factor in radiotherapy resistance. Specifically, we confirmed that the upregulation of LAT4 following chemotherapy enhances leucine metabolism within tumors in vitro and in vivo, thereby modulating the mechanistic target of mTOR pathway and leading to radiotherapy resistance. Of note, the application of inhibitors targeting leucine metabolism was shown to restore the sensitivity of these cells to radiotherapy, highlighting a potential therapeutic strategy for overcoming resistance in GBM.ConclusionsOur study links tumor sensitivity to chemotherapy and radiotherapy and highlights the critical role of LAT4 in activating the mTOR pathway and GBM radiotherapy resistance. It suggests ways to improve radiotherapy sensitivity to GBM.

SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation

The transcription factor GLI1 is the main and final effector of the Hedgehog signaling pathway, which is involved in embryonic development, cell proliferation and stemness. Whether activated through canonical or non-canonical mechanisms, GLI1 aberrant activity is associated with Hedgehog-dependent cancers, including medulloblastoma, as well as other tumoral contexts. Notwithstanding a growing body of evidence, which have highlighted the potential role of post translational modifications of GLI1, the complex mechanisms modulating GLI1 stability and activity have not been fully elucidated. Here, we present a novel role played by SMURF1 and SMURF2 in the suppression of the Hedgehog/GLI signaling pathway through a direct targeting of GLI1. Indeed, the two SMURFs can interact with GLI1, exploiting the proline rich regions present on GLI1 protein, and trigger its polyubiquitination and proteasomal degradation, leading to a suppression of the Hedgehog pathway activity and a reduction of Hh-dependent tumor cell proliferation. Overall, this study adds new relevance to a tumor suppressive role of SMURFs on the Hedgehog pathway and confers upon them the status of potential therapeutic tools, either in canonical or non-canonical Hedgehog pathway aberrant activation.

Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer.

As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.

Deep profiling of gene expression across 18 human cancers.

Clinical and biological information in large datasets of gene expression across cancers could be tapped with unsupervised deep learning. However, difficulties associated with biological interpretability and methodological robustness have made this impractical. Here we describe an unsupervised deep-learning framework for the generation of low-dimensional latent spaces for gene-expression data from 50,211 transcriptomes across 18 human cancers. The framework, which we named DeepProfile, outperformed dimensionality-reduction methods with respect to biological interpretability and allowed us to unveil that genes that are universally important in defining latent spaces across cancer types control immune cell activation, whereas cancer-type-specific genes and pathways define molecular disease subtypes. By linking latent variables in DeepProfile to secondary characteristics of tumours, we discovered that mutation burden is closely associated with the expression of cell-cycle-related genes, and that the activity of biological pathways for DNA-mismatch repair and MHC class II antigen presentation are consistently associated with patient survival. We also found that tumour-associated macrophages are a source of survival-correlated MHC class II transcripts. Unsupervised learning can facilitate the discovery of biological insight from gene-expression data.

Dexmedetomidine Improves Learning Functions in Male Rats Modeling Cognitive Impairment by Modulating the BDNF/TrkB/CREB Signaling Pathway

Dexmedetomidine (DEX) is a selective alpha-2 adrenergic receptor agonist with sedative and anxiolytic properties. Increasing evidence reports that DEX has a neuroprotective effect. In this study, we investigated the potential effects of DEX on learning and memory functions in rats with experimental cognitive impairment. In the study, 21 adult male rats were used. The rats were divided into three groups, namely control, Scopolamine (SCOP) and SCOP + DEX. Cognitive impairment was induced with 1 mg/kg SCOP daily for 21 days. DEX was administered at a dose of 10 µg/kg between days 14 and 21 of the experiment. Following the injections, a spatial memory test was performed with a Morris Water Maze (MWM). At the end of the experiment, the hippocampus was dissected. The brain-derived neurotrophic factor (BDNF), acetylcholine (ACh) and acetylcholinesterase (AChE) levels were determined by ELISA. The tropomyosin receptor kinase B (TrkB) and Cyclic AMP-Response Element-Binding Protein (CREB) levels were measured by immunohistochemistry. DEX treatment improved the learning performance of rats compared to SCOP for 5 days. However, it did not significantly change memory performance. DEX increased the BDNF and ACh levels in the hippocampus while decreasing the AChE levels. Similarly, DEX treatment significantly increased CREB phosphorylation. No significant difference was observed between the TrkB receptor levels of the groups. This study demonstrated that the role of DEX in reducing SCOP-induced cognitive impairment is partially mediated by the increase in BDNF/TrkB/CREB signaling pathway activity.

Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease.

The SORL1 locus exhibits protective effects against Alzheimer's disease (AD) across ancestries, yet systematic studies in diverse populations are sparse. Logistic regression identified AD-associated SORL1 haplotypes in East Asian (N=5249) and European (N=8588) populations. Association analysis between SORL1 haplotypes and AD-associated traits or plasma biomarkers was conducted. The effects of non-synonymous mutations were assessed in cell-based systems. Protective SORL1 variants/haplotypes were identified in the East Asian and European populations. Haplotype Hap_A showed a strong protective effect against AD in East Asians, linked to less severe AD phenotypes, higher SORL1 transcript levels, and plasma proteomic changes. A missense variant within Hap_A, rs2282647-C allele, was linked to a lower risk of AD and decreased expression of a truncated SORL1 protein isoform. Our transethnic analysis revealed key SORL1 haplotypes that exert protective effects against AD, suggesting mechanisms of the protective role of SORL1 in AD. We examined the AD-protective mechanisms of SORL1 in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort. Comparative analysis unveiled key ethnic-specific SORL1 genetic variants and haplotypes. Among these, the SORL1 minor haplotype, Hap_A, emerged as the primary AD-protective factor in East Asians. Hap_A exerts significant AD-protective effects in both APOE ε4 carriers and non-carriers. SORL1 haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune-related pathways closely connected to AD risk. Protective variants within Hap_A are linked to increased SORL1 expression in human tissues. We identified an isoform-specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.

Response of soybean root exudates and related metabolic pathways to low phosphorus stress.

Phosphorus (P) is an essential elemental nutrient required in high abundance for robust soybean growth and development. Low P stress negatively impacts plant physiological and biochemical processes, such as photosynthesis, respiration, and energy transfer. Soybean roots play key roles in plant adaptive responses to P stress and other soil-related environmental stressors. Study the changes in soybean root exudates and differences in related metabolic pathways under low phosphorus stress, analyzing the response mechanism of soybean roots to phosphorus stress from the perspective of root exudates, which provide a theoretical basis for further analyzing the physiological mechanism of phosphorus stress on soybean. In this study, soybean roots were exposed to three phosphate levels: 1 mg/L (P stress), 11 mg/L (P stress) and 31 mg/L (Normal P) for 10 days and 20 days, then root exudates were analyzed via ultra-high-performance liquid chromatography-mass spectrometry to identify effects of P stress on root metabolite profiles and associated metabolic pathways. Our results revealed that with increasing P stress severity and/or duration, soybean roots produced altered types, quantities, and increased numbers of exudate metabolites (DMs in the P1 group were primarily upregulated, whereas those in the P11 group were predominately downregulated) caused by changes in regulation of activities of numerous metabolic pathways. These pathways had functions related to environmental adaptation, energy metabolism, and scavenging of reactive oxygen species and primarily included amino acid, flavonoid, and nicotinate and nicotinamide metabolic pathways and pathways related to isoquinoline alkaloid biosynthesis, sugar catabolism, and phospholipid metabolism. These metabolites and metabolic pathways lay a foundation to support further investigations of physiological mechanisms underlying the soybean root response to P deficiency.

DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity

53BP1 plays an important role in DNA double-strand break (DSB) repair and this activity is negatively regulated by its interaction with Tudor interacting repair regulator (TIRR). However, how the TIRR-53BP1 repair axis is regulated in response to DNA damage remains elusive. Here, we demonstrate that TIRR is translocated to the cytoplasm and degraded upon DNA damage. Ubiquitination of TIRR at lysine 187 by DTX3L is a critical process that regulates NHEJ pathway activity and PARP inhibitor sensitivity by facilitating XPO1-mediated TIRR nuclear export and degradation after DNA damage. We show that DTX3L is overexpressed in prostate cancers in patients and that decreased expression of TIRR due to DTX3L overexpression impairs the negative regulatory effect of TIRR on 53BP1, which consequently induces HR deficiency and chromosomal instability and sensitizes prostate cancer cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work reveals a dual action of DTX3L on TIRR degradation and nuclear exportation and identifies DTX3L as an upstream regulator of the TIRR-53BP1 axis that governs DNA repair pathway choice and PARP inhibitor sensitivity. These findings suggest that TIRR ubiquitination and DTX3L overexpression could be viable biomarkers predicting PARP inhibitor sensitivity in cancers.

Unraveling molecular signatures and prognostic biomarkers in glioblastoma: a comprehensive study on treatment resistance and personalized strategies

BackgroundGlioblastoma (GBM) is a highly aggressive primary brain tumor with limited treatment success and poor prognosis. Despite surgical resection and adjuvant therapies, GBM often recurs, and resistance to radiotherapy and temozolomide presents significant challenges. This study aimed to elucidate molecular signatures associated with treatment responses, identify potential biomarkers, and enhance personalized treatment strategies for GBM.MethodsWe conducted a comprehensive analysis using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The GEO dataset (GSE206225) was used to identify differentially expressed genes (DEGs) between radiation-sensitive/resistant and temozolomide-sensitive/resistant GBM samples. TCGA data were utilized for subsequent analyses, including Lasso-Cox regression, risk score model construction, Kaplan–Meier survival analysis, and gene set enrichment analysis (GSEA). Hub genes were identified through survival analysis, and a gene prognostic nomogram was developed. Additionally, validation of the three-gene risk signature through multiple external cohorts and validation of protein expression levels were performed.ResultsDEG analysis identified 111 genes associated with chemoradiotherapy resistance, providing insights into the complex landscape of GBM treatment response. The risk score model effectively stratified patients, showing significant differences in overall survival and progression-free survival. GSEA offered a deeper understanding of pathway activities, emphasizing the intricate molecular mechanisms involved. NNAT, IGFBP6, and CYGB were identified as hub genes, and a gene prognostic nomogram demonstrated predictive accuracy.ConclusionThis study sheds light on the molecular intricacies governing GBM treatment response. The identified hub genes and the gene prognostic nomogram offer valuable tools for predicting patient outcomes and guiding personalized treatment strategies. These findings contribute to advancing our understanding of GBM biology and may pave the way for improved clinical management.

In Vivo Cardiovascular Molecular Imaging: Contributions to Precision Medicine and Drug Development.

Conventional forms of noninvasive cardiovascular imaging that evaluate morphology, function, flow, and metabolism play a vital role in individual treatment decisions, often based on guidelines. Innovations in molecular imaging have enhanced our ability to spatially quantify the expression of a wider array of disease-related proteins, genes, or cell types, or the activity of specific pathogenic pathways. These techniques, which usually rely on design of targeted imaging probes, have already been used extensively in cancer medicine and have now become part of cardiovascular care in conditions such as amyloidosis and sarcoidosis. The recognition that common cardiovascular conditions are caused by a substantial diversity of pathobiologic pathways and the diversity of therapies available for use have rekindled interest in expanding the role of molecular imaging of tissue phenotype to improve precision in diagnosis and therapeutic decision-making. The intent of this article is to raise awareness and understanding of approaches to molecular or cellular imaging of phenotype with targeted probes, and their potential to promote the principles of precision medicine. Also addressed are the diverse roles of molecular imaging to improve precision and efficiency of new drug development at the stages of candidate identification, preclinical testing, and clinical trials.

Exogenous H2S targeting PI3K/AKT/mTOR pathway alleviates chronic intermittent hypoxia-induced myocardial damage through inhibiting oxidative stress and enhancing autophagy.

Hydrogen sulfide (H2S) is a novel gas signaling molecule that has been researched in several physiological and pathological conditions, indicating that strategies targeting H2S may provide clinical benefits in diseases such as chronic cardiomyopathy. Here, we reveal the effect of H2S on chronic intermittent hypoxia (CIH)-related myocardial damage and its mechanistic relevance to phosphoinositol-3 kinase (PI3K). Mice were subjected to a 4-week CIH process to induce myocardial damage, which was accompanied by daily administration of NaHS (a H2S donor) and LY294002 (an inhibitor of PI3K). Changes in heart function were evaluated via echocardiography. Histological examination was applied to assess heart tissue lesions. Myocardial apoptosis was detected by TUNEL staining and apoptosis-associated protein expression. Furthermore, the effects of NaHS on autophagy and the PI3K/AKT/mTOR pathway were investigated. Finally, the level of inflammation is also affected by related proteins. The CIH group presented increased myocardial dysfunction and heart tissue lesions. Echocardiography and histological analysis revealed that, compared with control mice, CIH-treated mice presented significantly more severe left ventricular remodeling and decreased myocardial contractile function. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group compared with those in the control group. The autophagy marker Beclin-1 was decreased, while p62 was elevated by CIH treatment. H2S supplementation with NaHS significantly improved cardiac function and alleviated fibrosis, oxidative stress, and apoptosis but upregulated autophagy in CIH mice, and these effects were also observed in animals that underwent only PI3K blockade. Furthermore, PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway, the Nrf2/HO-1 pathway and proinflammatory NF-κB activity were shown to play a role in the therapeutic effect of NaHS after CIH stimulation.

FDA-approved kinase inhibitors: a promising therapeutic avenue for traumatic brain injury

Traumatic brain injury (TBI) is a complex disease that leads to significant mortality and disability worldwide each year. TBI disrupts the normal activity of kinases and molecular signaling pathways, but the effective therapeutic methods for patients remain limited. Nowadays, kinase inhibitors approved by the Food and Drug Administration (FDA) mainly for cancer treatment have shown potential effects in TBI. Preclinical studies suggest their potential in promoting recovery. There are fewer randomized clinical studies that evaluate efficacy. We search the kinase inhibitors approved by the FDA and traumatic brain injury as keywords on websites and analyze associated research. This review explores the therapeutic efficacy of kinase inhibitors, identifies limitations that must be addressed in future research to advance the application of FDA-approved kinase inhibitors, and emphasizes their promising potential.

Study on the role and mechanism of TMED2 in oral squamous cell carcinoma.

This study investigated TMED2 expression in oral squamous cell carcinoma (OSCC) and its effects on SCC9 cell behaviors, including proliferation, migration, invasion, and autophagy, to support OSCC diagnosis and treatment. TMED2 expression was analyzed in TCGA and GEO databases, and protein levels in OSCC tissues were examined via HE staining and tissue microarrays. SCC9 cells, with high TMED2 expression, were used to assess TMED2's effects on cell proliferation, invasion, and cell cycle. TMED2 knockdown was performed with lentiviral vectors, and RT-PCR and Western blotting explored the autophagy and AKT/mTOR pathways. Tumor growth was tested in TMED2 knockdown and control cells in nude mice. TMED2 was highly expressed in OSCC, correlating with poor prognosis. Knockdown of TMED2 significantly reduced SCC9 cell proliferation, migration, and invasion, induced G0/G1 cell cycle arrest, reduced AKT/mTOR pathway activity, and increased autophagy, prolonging survival in tumor-bearing mice. TMED2 is upregulated in OSCC, correlates with poor prognosis, and regulates cell proliferation, invasion, and autophagy, indicating it as a potential therapeutic target.

Interaction between human dental microbiome and the host gingival model

Objective: Interactions between the dental biofilm and host are important to study infectious oral diseases such as dental caries and periodontitis. Previous studies have reported the reaction of a host gingival model co-cultured with bacteria or biofilms. However, these studies only report results of a gingival model, and a biofilm co-cultured with a gingival model has never been investigated although the microbiome of dental biofilms is associated with maintenance of health and onset of infectious oral diseases. Therefore, we aimed to investigate the reaction of a gingival model and experimental biofilm. An in situ dental biofilm model, which enables biofilm formation in the oral cavity, was used to prepare experimental biofilms. Methods: The in situ biofilm was co-cultured with a reconstructed gingival model (RHG). We performed 16S rRNA sequence analysis, metagenomic function prediction analysis, total bacterial cell counts using quantitative polymerase chain reaction, and confocal laser microscopic observation in addition to gene expression and histological investigation of RHG. Results: We found a change in Veillonella abundance in the in situ biofilms co-cultured with RHG. Metagenomic function prediction analysis revealed that the activity of certain pathways associated with amino acid production, lactic acid fermentation, and glycolysis system significantly increased in biofilms co-cultured with RHG. Conclusion: The microbiome and functions of dental biofilms can be affected by host gingival tissues. Our findings will contribute to the establishment of a host–biofilm interaction model to understand the pathophysiology of oral infectious diseases.

Purification, characterization, and hypoglycemic activity of exopolysaccharides from Lactiplantibacillus plantarum MY04

As natural polymers, Lactiplantibacillus plantarum exopolysaccharides (EPS) possess a wide range of bioactivities but suffer from low yields and unclear relationships between functional activity and structure. To this end, the chemical structure and bioactive properties of EPS from Lactiplantibacillus plantarum MY04 were investigated. As a result, three polysaccharide fractions (EPS-1, EPS-2, EPS-3) were separated and purified, of which EPS-2 had better antioxidant activity and α-glucosidase inhibitory ability. More importantly, EPS-2 can significantly enhance insulin sensitivity in HepG2 cells by upregulating enzyme activities in the glycolytic pathway and mitigating oxidative stress-induced damage. In addition, the structural characterization of EPS-2 was also comprehensively elucidated. It was found that EPS-2 was mainly composed of mannose with a molecular weight of 2.3 × 106 Da, and its main chain structure is →3)-Manp-(1 → 2)-Manp-(1 → 2,6)-Manp-(1 → 2,6)-Manp-(1→, providing a theoretical basis for understanding the relationship between structure and function of polysaccharides.

Altered purine and pentose phosphate pathway metabolism in uteroplacental insufficiency-induced intrauterine growth restriction offspring rats impairs intestinal function

BackgroundThis study aimed to identify metabolic alterations in the small intestine of newborn rats with intrauterine growth restriction (IUGR), a condition linked to intestinal dysfunction. MethodsPregnant Sprague Dawley rats underwent bilateral uterine artery ligation on gestational day 17 to induce intrauterine growth restriction or sham surgery. Rat pups were delivered spontaneously on gestational day 22. Small intestine tissues were collected on postnatal days 0 and 7 from offspring. Liquid chromatography-mass spectrometry analysis was performed to investigate untargeted metabolomic profiles. Western blot analysis assessed protein expression of key regulators. ResultsNewborn rats with intrauterine growth restriction exhibited distinct small intestine metabolic profiles compared to controls on postnatal day 0. Notably, significant alterations were observed in purine metabolism, the pentose phosphate pathway, and related pathways. Western blot analysis revealed a decrease expression in transketolase, a key enzyme of the pentose phosphate pathway, suggesting impaired activity of the pentose phosphate pathway. Additionally, decreased expression of tight junction proteins ZO-1 and occludin indicated compromised intestinal barrier function in rats with intrauterine growth restriction. Similar metabolic disruptions persisted on postnatal day 7, with further reductions in tricarboxylic acid cycle intermediates and folate biosynthesis precursors. Interestingly, lysyl-glycine, a protein synthesis marker, was elevated in rats with intrauterine growth restriction. ConclusionsOur findings reveal a distinct metabolic signature in the small intestine of neonatal rats with intrauterine growth restriction, characterized by disruptions in the pentose phosphate pathway, purine metabolism, and energy production pathways. These novel insights suggest potential mechanisms underlying IUGR-associated intestinal dysfunction and impaired growth.