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PubMed2003

Expressed sequence tag profiling identifies developmental and anatomic partitioning of gene expression in the mouse prostate.

BACKGROUND: The prostate gland is an organ with highly specialized functional attributes that serves to enhance the fertility of mammalian species. Much of the information pertaining to normal and pathological conditions affecting the prostate has been obtained through extensive developmental, biochemical and genetic analyses of rodent species. Although important insights can be obtained through detailed anatomical and histological assessments of mouse and rat models, further mechanistic explanations are greatly aided through studies of gene and protein expression. RESULTS: In this article we characterize the repertoire of genes expressed in the normal developing mouse prostate through the analysis of 50,562 expressed sequence tags derived from 14 mouse prostate cDNA libraries. Sequence assemblies and annotations identified 15,009 unique transcriptional units of which more than 600 represent high quality assemblies without corresponding annotations in public gene expression databases. Quantitative analyses demonstrate distinct anatomical and developmental partitioning of prostate gene expression. This finding may assist in the interpretation of comparative studies between human and mouse and guide the development of new transgenic murine disease models. The identification of several novel genes is reported, including a new member of the beta-defensin gene family with prostate-restricted expression. CONCLUSIONS: These findings suggest a potential role for the prostate as a defensive barrier for entry of pathogens into the genitourinary tract and, further, serve to emphasize the utility of the continued evaluation of transcriptomes from a diverse repertoire of tissues and cell types.

Amino Acid Sequence↗

PubMed2006

Transcriptional regulators of stamen development in Arabidopsis identified by transcriptional profiling.

In Arabidopsis, jasmonate is required for stamen and pollen maturation. Mutants deficient in jasmonate synthesis, such as opr3, are male-sterile but become fertile when jasmonate is applied to developing flower buds. We have used ATH1 oligonucleotide arrays to follow gene expression in opr3 stamens for 22 h following jasmonate treatment. In these experiments, a total of 821 genes were specifically induced by jasmonate and 480 genes were repressed. Comparisons with data from previous studies indicate that these genes constitute a stamen-specific jasmonate transcriptome, with a large proportion (70%) of the genes expressed in the sporophytic tissue but not in the pollen. Bioinformatics tools allowed us to associate many of the induced genes with metabolic pathways that are probably upregulated during jasmonate-induced maturation. Our pathway analysis led to the identification of specific genes within larger families of homologues that apparently encode stamen-specific isozymes. Extensive additional analysis of our dataset identified 13 transcription factors that may be key regulators of the stamen maturation processes triggered by jasmonate. Two of these transcription factors, MYB21 and MYB24, are the only members of subgroup 19 of the R2R3 family of MYB proteins. A myb21 mutant obtained by reverse genetics exhibited shorter anther filaments, delayed anther dehiscence and greatly reduced male fertility. A myb24 mutant was phenotypically wild-type, but production of a myb21myb24 double mutant indicated that introduction of the myb24 mutation exacerbated all three aspects of the myb21 phenotype. Exogenous jasmonate could not restore fertility to myb21 or myb21myb24 mutant plants. Together with the data from transcriptional profiling, these results indicate that MYB21 and MYB24 are induced by jasmonate and mediate important aspects of the jasmonate response during stamen development.

Arabidopsis↗

PubMed2004

Global transcriptome analysis of the heat shock response of Shewanella oneidensis.

Shewanella oneidensis is an important model organism for bioremediation studies because of its diverse respiratory capabilities. However, the genetic basis and regulatory mechanisms underlying the ability of S. oneidensis to survive and adapt to various environmentally relevant stresses is poorly understood. To define this organism's molecular response to elevated growth temperatures, temporal gene expression profiles were examined in cells subjected to heat stress by using whole-genome DNA microarrays for S. oneidensis. Approximately 15% (n = 711) of the total predicted S. oneidensis genes (n = 4,648) represented on the microarray were significantly up- or downregulated (P < 0.05) over a 25-min period after shift to the heat shock temperature. As expected, the majority of the genes that showed homology to known chaperones and heat shock proteins in other organisms were highly induced. In addition, a number of predicted genes, including those encoding enzymes in glycolysis and the pentose cycle, serine proteases, transcriptional regulators (MerR, LysR, and TetR families), histidine kinases, and hypothetical proteins were induced. Genes encoding membrane proteins were differentially expressed, suggesting that cells possibly alter their membrane composition or structure in response to variations in growth temperature. A substantial number of the genes encoding ribosomal proteins displayed downregulated coexpression patterns in response to heat stress, as did genes encoding prophage and flagellar proteins. Finally, a putative regulatory site with high conservation to the Escherichia coli sigma32-binding consensus sequence was identified upstream of a number of heat-inducible genes.

Bacterial Proteins↗

PubMed2006

Transcriptional profiling of sunflower plants growing under low temperatures reveals an extensive down-regulation of gene expression associated with chilling sensitivity.

Being able to sow early to maximize the growing season and to escape drought stress has increased the importance of low-temperature tolerance in sunflower. Yet knowledge about the molecular basis of sunflower response to low temperature is still lacking. To address this issue, nylon microarrays containing >8000 putative unigenes were developed and used. Early- and late-flowering genotypes were sown at 15 degrees C and grown until the two-leaf stage when they were subjected to 7 degrees C until the four-leaf stage. The transcriptional profiles of low temperature-grown plants (15 degrees C and 7 degrees C) were compared with those grown under standard conditions (25 degrees C). Two-step ANOVA normalization and analysis models were used to identify the differentially expressed genes. A total of 108 cDNA clones having a P-value <10(-3) were found to be differentially expressed between the low temperature-grown plants (15 degrees C and 7 degrees C) and their corresponding two-leaf- and four-leaf-stage controls across the two genotypes. About 90% of these genes were down-regulated. This includes genes potentially involved in the metabolism of carbohydrate and energy, protein synthesis, signal transduction, and transport function. Comparing gene expression profiles at 15 degrees C and 7 degrees C revealed that only four genes can be considered as differentially expressed, in both genotypes, suggesting that similar genetic programmes underlie the response of sunflower plants to these temperature regimes. The analysis also revealed that early- and late-flowering genotypes respond similarly to low-temperature tolerance as justified by the low number of genes showing a significant genotype x treatment interaction effect. It seems likely that the down-regulation and/or non-induction of genes having a critical role in low-temperature tolerance may be responsible for the sensitivity of sunflower plants to low-temperature tolerance. The results reported provide an initial characterization of the transcriptome activity of sunflower, as a chilling-sensitive plant under suboptimal temperatures, and could be of importance to reveal the potential differences between chilling-sensitive and chilling-tolerant species.

Acclimatization↗

PubMed2004

Suppression of tumorigenesis and activation of Wnt signaling by bone morphogenetic protein 4 in human cancer cells.

Aberrations in BMP signaling have recently been implicated as a cause of human cancer. Here we demonstrate and define the tumor suppressive properties of BMP4. Consistent with its potential role in a tumor suppressor pathway, BMP4 treatment eliminated the tumorigenic potential of an undifferentiated human cancer cell line. This loss of tumorigenicity was accompanied by an increase in apoptosis, alterations in cell cycle profile, and an increase in cell size. Interestingly, human colon cancer cells were resistant to the growth-suppressive properties of BMP4. To identify putative downstream mediators of BMP4-mediated tumor suppression, Affymetrix Genechips were employed to identify BMP4-regulated genes. The human BMP4 transcriptome was characterized by the modulation of many genes well known to play important roles in differentiation and development, including the induction of numerous genes involved in Wnt signaling. Modulation of Wnt gene expression by BMP4 had several functional consequences--BMP4 treatment led to activation of TCF reporters; complete activation of at least one BMP4-responsive gene required TCF sites; and treatment with a Wnt ligand was sufficient to mimic several of the phenotypic effects of BMP4 treatment. These data demonstrate the tumor suppressive properties of BMP4 signaling, show that colon cancer cells are resistant to BMP4-induced differentiation and growth suppression, further define the BMP4 transcriptome, and raise the intriguing possibility that interactions between the Wnt and BMP signaling pathways may play an important role in differentiation and tumor suppression.

Animals↗

PubMed2005

Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis.

BACKGROUND: Microarray technology is a powerful tool that can probe the molecular pathogenesis of renal injury. In this present study microarray analysis was used to monitor serial changes in the renal transcriptome of a rat model of mesangial proliferative glomerulonephritis. Administration of anti-Thy1 antibody results in phases of acute mesangial injury (day 2), cell proliferation (day 5), matrix expansion (days 5 and 7), and subsequent healing (day 14). METHODS: Using Affymetrix (RAE230A) microarrays coupled with sequential primary biologic function-focused and secondary "baited" global cluster analysis, a cohort of established and putative novel modulators of mesangial cell turnover was identified. RESULTS: Cluster analysis of proliferative genes identified a number of gene expression profiles. The most striking pattern was increased gene expression at day 5, a cluster that included platelet-derived growth factor (PDGF), cyclins and transforming growth factor-beta (TGF-beta). The gene expression patterns identified by primary focused cluster analysis were used as bioinformatic bait and resulted in the identification of novel families of genes such as the S100 family. The expression of established and novel genes was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). Next, in vivo gene expression was compared to PDGF-stimulated mesangial cells in vitro revealing similar patterns of dysregulation. CONCLUSION: Transcriptomic analysis defined both known and novel molecules involved in mesangial cell proliferation in vitro and in vivo and defined a panel of molecules that are potential contributors to mesangial cell dysfunction in glomerular disease.

Animals↗

PubMed2006

Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL) are derived from different cell types, namely T cells and B cells, respectively. However, both lymphomas share a similar cytological and immunohistochemical tumor cell phenotype with little resemblance to their cells of origin. DESIGN AND METHODS: In this study, the transcriptional profiles of ALCL cell lines, primary ALCL tumor cells from peripheral blood and HL cell lines were compared to each other and to normal B-cell subsets, B non-Hodgkin's lymphomas (NHL) and B NHL- and Epstein-Barr virus (EBV)-transformed B-cell lines in order to establish their relationship at the transcriptional level and to identify genes with possible pathobiological impact. Expression of some of the genes identified was confirmed in microdissected primary tumor cells by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: HL samples clustered separately from ALCL samples, but HL and ALCL were found to be more closely related to each other than to any normal or malignant B-cell sample in the dataset. Their relationship was determined to a large extent, but not exclusively, by lack of expression of B-cell antigens and by the over-expression of mRNA encoding activation markers and structural proteins. Apart from established differences between HL and ALCL, further genes of interest could be identified that distinguish both entities from each other and from the other samples. The differential expression of PRAME, DDR2, SOCS3 and CEBPD in HL and ALCL was confirmed in primary tumor tissue by immunohistochemistry and/or RT-PCR. INTERPRETATION AND CONCLUSIONS: At a transcriptional level HL is more closely related to Alk+ ALCL than to the B-NHL or B-cell samples investigated, although it is a B-cell derived lymphoma. The newly identified genes discriminating HL and ALCL may be pathobiologically important and may serve as possible therapeutic targets.

Adult↗

PubMedDate not supplied

Gene expression profiling of ductal carcinomas in situ and invasive breast tumors.

UNLABELLED: Comparative and functional genomics are powerful tools to advance the understanding of the molecular basis of cancer. It is believed that genes are epigenetically regulated and, thus, each tumor type and stage will be characterized by a gene expression fingerprint. In this study we identified genes that are differentially expressed in ductal carcinoma in situ and invasive ductal carcinoma of the breast. To isolate genes that are associated with progression of breast cancer we performed differential display and subtractive cloning procedures using matched RNA from normal and tumor tissue. cDNA microarray analysis generated gene expression profiles typical of the transition from in situ to invasive breast cancer when we used mRNA extracted from a case of low- to intermediate-grade DCIS and a case of high-grade DCIS/IDC. cDNAs from these samples were the probes in a cDNA microarray hybridization to 9183 unique cDNAs representing 8507 genes. Signals from both transcriptomes were obtained for 8083 genes, and the balanced differential expression values between pure DCIS and DCIS/invasive tumors revealed 303 distinct cDNAs with a ratio of > 2. Interferon inducible genes were found to be expressed at the highest level in the pure DCIS sample. Genes most abundantly expressed in the invasive tumor were immunoglobulin heavy constant gamma 3 and calgranulin B. Further analysis of RNA and protein expression in breast tumor cell lines and patient tissue samples revealed that: IGFBP-rP1 is down-regulated in invasive tumors whereas cyclin I protein is regulated by ubiquitination and is associated with ER-negative breast cancers. CONCLUSION: The known and novel genes discussed here represent targets for molecular characterization during breast cancer development as well as for designing novel strategies for diagnosis and treatment.

Biomarkers, Tumor↗

PubMed2005

Phosphoproteome and transcriptome analysis of the neuronal response to a CDK5 inhibitor.

In Alzheimer's disease and amyotrophic lateral sclerosis deregulation of cyclin-dependent kinase 5 (CDK5) causes hyperphosphorylation of tau and neurofilament proteins, respectively, leading to neuronal cell death. We have demonstrated recently that pharmacological inhibition of CDK5 protects neurons under various stressful conditions (Weishaupt J. H., et al., Molec. Cell. Neurosci. 2003, 24, 489-502). To get an overview on the cellular mechanisms of action we analyzed global changes in protein phosphorylation in cultured cerebellar granule neurons by [(32)P]orthophosphate labeling after administration of a CDK5 inhibitor. Since CDK5 has recently been shown to phosphorylate and inactivate transcription factor MEF2, we included gene expression profiling using cDNA microarrays. By two-dimensional gel electrophoresis and matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry we identified several phosphoproteins that were modulated by compound administration. Among them syndapin I which is involved in vesicle recycling, and dynein light intermediate chain 2 which represents a regulatory subunit of the dynein protein complex. These findings are consistent with the known physiological function of CDK5 in synaptic signaling and axonal transport. Moreover, we detected phosphoproteins acting in neuronal surival and/or neurite outgrowth, such as cofilin and collapsin response mediator protein. Subsequent testing in cell cultures revealed that the CDK5 inhibitor blocked mitochondrial translocation of pro-apoptotic cofilin in cerebellar granule neurons and enhanced neurite outgrowth in dorsal root ganglia. Numerous genes exhibiting MEF2 consensus binding sequences were modulated by CDK5 inhibitor treatment. Among them some that may contribute to neurite elongation or neuronal survival, but also several genes functioning in synaptic transmission. Taken together, phosphoproteome and transcriptome analysis indicate that the compound promotes both neuronal survival and neurite outgrowth, but also may affect synaptic function in cultured neurons.

Animals↗

PubMed2005

Differential gene expression profiling of Staphylococcus aureus cultivated under biofilm and planktonic conditions.

It is well known that biofilm formation by pathogenic staphylococci on implanted medical devices leads to "chronic polymer-associated infections." Bacteria in these biofilms are more resistant to antibiotics and the immune defense system than their planktonic counterparts, which suggests that the cells in a biofilm have altered metabolic activity. To determine which genes are up-regulated in Staphylococcus aureus biofilm cells, we carried out a comparative transcriptome analysis. Biofilm growth was simulated on dialysis membranes laid on agar plates. Staphylococci were cultivated planktonically in Erlenmeyer flasks with shaking. mRNA was isolated at five time points from cells grown under both conditions and used for hybridization with DNA microarrays. The gene expression patterns of several gene groups differed under the two growth conditions. In biofilm cells, the cell envelope appeared to be a very active compartment since genes encoding binding proteins, proteins involved in the synthesis of murein and glucosaminoglycan polysaccharide intercellular adhesin, and other enzymes involved in cell envelope synthesis and function were significantly up-regulated. In addition, evidence was obtained that formate fermentation, urease activity, the response to oxidative stress, and, as a consequence thereof, acid and ammonium production are up-regulated in a biofilm. These factors might contribute to survival, persistence, and growth in a biofilm environment. Interestingly, toxins and proteases were up-regulated under planktonic growth conditions. Physiological and biochemical tests for the up-regulation of urease, formate dehydrogenase, proteases, and the synthesis of staphyloxanthin confirmed the microarray data.

Ammonia↗

PubMed2000

Transcriptome analysis of fibroblast cells immediate-early after human cytomegalovirus infection.

Human cytomegalovirus (HCMV) has been shown to have the potential to alter cellular gene expression early after infection. However, one-gene approaches and the use of closed system gene expression technologies have identified only few cellular genes whose activity changed immediate-early. We therefore used serial analysis of gene expression (SAGE) to investigate the transcriptional program of human fibroblasts in response to HCMV in the immediate-early phase of infection. Differential expression of various cellular genes was monitored. Transcriptional expression changes of genes coding for ribosomal proteins reflected a general cellular response to starvation and stress. But differential regulation of genes coding for transcription factors and proteins associated with cellular metabolism, homeostasis and cell structure may represent transcriptional alterations in response to HCMV infection. Expression kinetics by 5' nuclease fluorigenic real-time PCR of selected genes revealed partial protection of infected cells against initial stress-associated alterations of gene expression and indicated fluctuations of transcriptional levels over time. Additionally, agreement with the quantitative results obtained by SAGE was observed only for genes up-regulated in HCMV-infected cells. This finding pointed to various technical and statistical parameters that all may be critical for quantitative transcriptome studies using global approaches, especially when exploring biological systems in a critical phase of cellular physiology.

Cell Cycle↗

PubMed2004

yMGV: a cross-species expression data mining tool.

The yeast Microarray Global Viewer (yMGV @ http://transcriptome.ens.fr/ymgv) was created 3 years ago as a database that houses a collection of Saccharomyces cerevisiae and Schizosaccharo myces pombe microarray data sets published in 82 different articles. yMGV couples data mining tools with a user-friendly web interface so that, with a few mouse clicks, one can identify the conditions that affect the expression of a gene or list of genes regulated in a set of experiments. One of the major new features we present here is a set of tools that allows for inter-organism comparisons. This should enable the fission yeast community to take advantage of the large amount of available information on budding yeast transcriptome. New tools and ongoing developments are also presented here.

Computational Biology↗

PubMed2003

Comparative analysis of the Arabidopsis pollen transcriptome.

We present a genome-wide view of the male gametophytic transcriptome in Arabidopsis based on microarray analysis. In comparison with the transcriptome of the sporophyte throughout development, the pollen transcriptome showed reduced complexity and a unique composition. We identified 992 pollen-expressed mRNAs, nearly 40% of which were detected specifically in pollen. Analysis of the functional composition of the pollen transcriptome revealed the over-representation of mRNAs encoding proteins involved in cell wall metabolism, cytoskeleton, and signaling and under-representation of mRNAs involved in transcription and protein synthesis. For several gene families, we observed a common pattern of mutually exclusive gene expression between pollen and sporophytic tissues for different gene family members. Our results provide a 50-fold increase in the knowledge of genes expressed in Arabidopsis pollen. Moreover, we also detail the extensive overlap (61%) of the pollen transcriptome with that of the sporophyte, which provides ample potential to influence sporophytic fitness through gametophytic selection.

Arabidopsis↗

PubMed2005

Mast cell-specific genes--new drug targets/pathogenesis.

It has become possible to see all the expressed genes present in a cell (transcriptome) at once using microarray. We have applied microarray technology in various studies involving allergic diseases. Although we and others have discovered various novel molecules crucially involved in the pathogenesis of the disease, transcriptome assay is now expected as a tool for understanding the whole molecule balancing, i.e., system biology. Here I introduce examples of our trials for understanding the whole functional roles of mast cells as has been published in the web database for transcriptomes expressed by several mast cell types and various cell types. In the near future, we will be able to construct human mast cell models in silico (in a computer) by analyzing integrative information regarding the genome, transcriptome and proteome of mast cells, and will be able to test our hypotheses without having to perform in vitro tests.

Animals↗

PubMed2003

Transcriptome analysis of Listeria monocytogenes identifies three groups of genes differently regulated by PrfA.

PrfA is the major regulator of Listeria virulence gene expression. This protein is a member of the Crp/Fnr family of transcription regulators. To gain a deeper understanding of the PrfA regulon, we constructed a whole-genome array based on the complete genome sequence of Listeria monocytogenes strain EGDe and evaluated the expression profiles of the wild-type EGDe and a prfA-deleted mutant (EGDe Delta prfA). Both strains were grown at 37 degrees C in brain-heart infusion broth (BHI) and BHI supplemented with either activated charcoal, a compound known to enhance virulence gene expression, or cellobiose, a sugar reported to downregulate virulence gene expression in spite of full expression of PrfA. We identified three groups of genes that are regulated differently. Group I comprises, in addition to the 10 already known genes, two new genes, lmo2219 and lmo0788, both positively regulated and preceded by a putative PrfA box. Group II comprises eight negatively regulated genes: lmo0278 is preceded by a putative PrfA box, and the remaining seven genes (lmo0178-lmo0184) are organized in an operon. Group III comprises 53 genes, of which only two (lmo0596 and lmo2067) are preceded by a putative PrfA box. Charcoal addition induced upregulation of group I genes but abolished regulation by PrfA of most group III genes. In the presence of cellobiose, all the group I genes were downregulated, whereas group III genes remained fully activated. Group II genes were repressed in all conditions tested. A comparison of the expression profiles between a second L. monocytogenes strain (P14), its spontaneous mutant expressing a constitutively active PrfA variant (P14prfA*) and its corresponding prfA-deleted mutant (P14 Delta prfA) and the EGDe strain revealed interesting strain-specific differences. Sequences strongly similar to a sigma B-dependent promoter were identified upstream of 22 group III genes. These results suggest that PrfA positively regulates a core set of 12 genes preceded by a PrfA box and probably expressed from a sigma A-dependent promoter. In contrast, a second set of PrfA-regulated genes lack a PrfA box and are expressed from a sigma B-dependent promoter. This study reveals that PrfA can act as an activator or a repressor and suggests that PrfA may directly or indirectly activate different sets of genes in association with different sigma factors.

Bacterial Proteins↗

PubMed2025

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for 1) extracellular matrix structure and metabolism (TM1 subtype), 2) secreted ligand signaling to support Schlemm's canal cells (TM2), and 3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2,491 TM cells). In V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), to enhance mitochondrial function and metabolic resilience, significantly protected Lmx1b mutant mice from IOP elevation.

Journal Article↗

PubMed2026

TNFα-induced endothelial extracellular vesicles regulate astrocyte function: an integrated transcriptomic and proteomic study.

Endothelial cells and astrocytes are critical structural and functional components of the blood-brain barrier. In many neuroinflammatory diseases, endothelial cells are among the first to respond to inflammatory stimuli and release extracellular vesicles (EVs). However, whether inflammatory stimulation alters EV RNA cargo and subsequently regulates astrocyte function remains unclear. In this study, we performed integrated RNA sequencing and proteomic analyses to investigate the effects of TNFα-stimulated endothelial EVs on astrocytes. RNA profiling revealed significant alterations in EV cargo after TNFα stimulation, including 867 upregulated and 577 downregulated mRNAs, 317 upregulated and 15 downregulated lncRNAs, and 88 upregulated and 62 downregulated miRNAs. The results of functional enrichment analysis suggested that altered EV RNAs may primarily promote inflammatory responses, cell migration, and RNA splicing in astrocytes while reducing their regulatory effects on neuronal projection and calcium homeostasis. Further integrative analysis of EV RNAs and astrocytic proteomics revealed key overlapping targets, including upregulated expression of ICAM1, SOD2, TFPI2, and TNFAIP8, whereas NFKBIA expression was consistently decreased. Network analysis revealed NF-κB as the central regulatory node. Reduced levels of EV-derived NFKBIA mRNA were associated with decreased IκBα protein levels in astrocytes, which promoted NF-κB activation and inflammatory cytokine release. Finally, overexpression of IκBα in astrocytes significantly attenuated TNFα EV-induced IL-1β and IL-6 secretion. Collectively, these findings demonstrate that TNFα-stimulated endothelial EVs coordinately regulate astrocyte function through mRNA, lncRNA, and miRNA cargo and that the IκBα/NF-κB axis may be a key mechanism underlying endothelial EV-mediated inflammatory disruption of the blood-brain barrier.

Astrocytes↗

PubMed2026

Exposome influences: a multi-omics perspective on the combined toxic effects of pharmaceuticals and personal care products in Alzheimer's disease.

According to WHO data, approximately 57 million people worldwide were affected by dementia in 2021, with prevalence projected to rise. Alzheimer's disease (AD), responsible for 60%-80% of dementia cases, continues to be a leading cause of mortality, with current treatments offering limited efficacy and disease-modifying therapies lacking widespread adoption or conclusive safety evidence, shifting the focus toward prevention and risk modification. Risk factors for AD include both non-modifiable elements, such as age, genetics, and gender, and modifiable factors, like environmental pollution, health status, and diet. While age remains the primary non-modifiable risk factor, early-onset dementia represents only up to 9% of cases. Addressing modifiable factors is essential, as it could prevent or delay almost half of dementia cases, with interventions-such as increased physical activity, smoking cessation, alcohol limitation, and overall health management-being significantly associated with a reduced risk. In this context, the exposome approach offers a comprehensive, integrative framework in which both modifiable and non-modifiable risk factors interact to influence individual susceptibility. Within the neural exposome, chronic low-dose exposure to xenobiotics-such as industrial chemicals, pesticides, metals, pharmaceuticals and personal care products (PPCPs), and air pollutants-may induce neurodegeneration via mechanisms including oxidative stress, neuroinflammation, proteinopathies, and epigenetic modifications, although establishing causality remains challenging. Integration of genomics, transcriptomics, proteomics, metabolomics, and lipidomics, combined with artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL), provides promising avenues for biomarker discovery, enhanced preventive strategies, early non-invasive diagnosis, and therapeutic target identification by integrating multi-layered biological data with exposure profiles. This review highlights emerging AD risk factors-including PPCPs-underscoring complex, multifactorial nature of AD and exposome, and the requirement for an interdisciplinary research approach, while also addressing several critical research gaps and methodological limitations.

Alzheimer’s disease↗