Peripheral Blood Transcriptome Research Articles

Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia

This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

Circulating miR-30e-3p induces disruption of neurite development in SH-SY5Y cells by targeting ABI1, a novel biomarker for schizophrenia

Schizophrenia (SCZ) represents a set of enduring mental illnesses whose underlying etiology remains elusive, posing a significant challenge to public health. Previous studies have shown that the neurodevelopmental process involving small molecules such as miRNA and mRNA is one of the etiological hypotheses of SCZ. We identified and verified that miR-30e-3p and ABI1 can be used as biomarkers in peripheral blood transcriptome sequencing data of patients with SCZ, and confirmed the regulatory relationship between them. To further explore their involvement, we employed retinoic acid (RA)-treated SH-SY5Y differentiated cells as a model system. Our findings indicate that in RA-induced SH-SY5Y cells, ABI1 expression is up-regulated, while miR-30e-3p expression is down-regulated. Functionally, both miR-30e-3p down-regulation and ABI1 up-regulation promote apoptosis and inhibit the proliferation of SH-SY5Y cells. Subsequently, the immunofluorescence assay detected the expression location and abundance of the neuron-specific protein β-tubulinIII. The expression levels of neuronal marker genes MAPT, TUBB3 and SYP were detected by RT-qPCR. We observed that these changes of miR-30e-3p and ABI1 inhibit the neurite growth of SH-SY5Y cells. Rescue experiments further support that ABI1 silencing can correct miR-30e-3p down-regulation-induced SH-SY5Y neurodevelopmental defects. Collectively, our results establish that miR-30e-3p′s regulation of neurite development in SH-SY5Y cells is mediated through ABI1, highlighting a potential mechanism in SCZ pathogenesis.

Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma

Peripheral blood transcriptomes from 383 newly-diagnosed melanoma patients were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor infiltrating lymphocytes (TILs)) and evidence of systemic inflammation (high-sensitivity C-reactive protein (hsCRP) and fibrinogen levels). Higher fibrinogen levels were associated with thicker primaries. In single gene analysis hsCRP levels were significantly associated with higher blood CD274 expression, (coding for PD-L1), but each was independently prognostic, with hsCRP associated with increased mortality, and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signalling pathways in the blood of people with thicker tumors and notable upregulation of STAT1 in people with brisk TILs. Transcriptomic data provided evidence for increased NFB signalling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274 suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer TILs, at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma suggesting that systemic inflammation contributes to that reduced immune function.

An autophagy-associated diagnostic signature based on peripheral blood for antibody-mediated rejection in renal transplantation

BackgroundAntibody-mediated rejection (ABMR) emerged as a major cause of graft loss in renal transplantation. Needle biopsy is the gold standard for diagnosis of ABMR in renal allografts. Thus, noninvasive diagnosis methods of ABMR with high accuracy are urgently needed to prevent unnecessary biopsies. MethodsWe collected peripheral blood transcriptome data from two independent renal transplantation cohorts with patients with ABMR, stable well-functioning transplants (STA), and T-cell mediated rejection (TCMR). Differentially expressed genes (DEGs) were identified by comparing the ABMR group with the STA group. In addition, functional enrichment analysis and gene set enrichment analysis were performed to seek new key underlying mechanisms in ABMR. Subsequently, we utilized a Boruta algorithm and least absolute shrinkage and selection operator logistic algorithm to establish a diagnostic model which was then evaluated and validated in an independent cohort. ResultsAccording to functional enrichment analysis, autophagy was found to be the primary upregulated biological process in ABMR. Based on algorithms, three autophagy-associated genes, ubiquitin specific peptidase 33 (USP33), Ras homolog mTORC1 binding (RHEB), and ABL proto-oncogene 2 (ABL2), were selected to establish the diagnostic model in the training cohort. This autophagy-related gene model possessed good diagnostic value in distinguishing ABMR from STA blood samples in the training cohort (AUC = 0.907) and in the validation cohort (AUC = 0.972). In addition, this model also showed good discernibility in distinguishing ABMR from TCMR in the training and validation cohorts (AUCs = 0.908 and 0.833). ConclusionWe identified and validated an autophagy-associated diagnostic model with high accuracy for renal transplant patients with ABMR. Our study provided a new potential test for the non-invasive diagnosis of ABMR in clinical practice and highlighted the importance of autophagy in ABMR.

A multi-cohort study of the hippocampal radiomics model and its associated biological changes in Alzheimer’s Disease

There have been no previous reports of hippocampal radiomics features associated with biological functions in Alzheimer’s Disease (AD). This study aims to develop and validate a hippocampal radiomics model from structural magnetic resonance imaging (MRI) data for identifying patients with AD, and to explore the mechanism underlying the developed radiomics model using peripheral blood gene expression. In this retrospective multi-study, a radiomics model was developed based on the radiomics discovery group (n = 420) and validated in other cohorts. The biological functions underlying the model were identified in the radiogenomic analysis group using paired MRI and peripheral blood transcriptome analyses (n = 266). Mediation analysis and external validation were applied to further validate the key module and hub genes. A 12 radiomics features-based prediction model was constructed and this model showed highly robust predictive power for identifying AD patients in the validation and other three cohorts. Using radiogenomics mapping, myeloid leukocyte and neutrophil activation were enriched, and six hub genes were identified from the key module, which showed the highest correlation with the radiomics model. The correlation between hub genes and cognitive ability was confirmed using the external validation set of the AddneuroMed dataset. Mediation analysis revealed that the hippocampal radiomics model mediated the association between blood gene expression and cognitive ability. The hippocampal radiomics model can accurately identify patients with AD, while the predictive radiomics model may be driven by neutrophil-related biological pathways.

COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase

Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.

Biological Signaling Network in Myocardial Infarction in Young Adults. A Study of Transcriptome Analysis

Background: Myocardial infarction (MI) is the common manifestation of coronary heart disease that develops from occlusion of coronary arteries. Several risk factors of MI were identified, but data pertaining to genetics and molecular mechanisms involved in the development of MI is limited. Therefore, the present study attempts to analyze the peripheral blood transcriptome information of MI patients and unveil the key genes involved in the pathogenesis of MI. Methods: Total RNA was extracted from the blood sample for illumine sequencing, and raw data obtained were subjected to quality control (QC) using the FastQC tool, followed by trimming of raw data by the fastp tool. Further processed high-quality data were aligned onto the human reference genome using HISAT2 aligner. Gene quantification was done using the feature Counts plugin in the subread package. The raw read counts were given as input to the differential expression analysis (DESeq2) R package for the computation of differentially expressed genes. Gene set enrichment analysis for gene ontology was done using the clusterProfiler R package. Results: A total of 609 genes were significantly expressed in the present study, of which 561 genes were upregulated and 48 genes were downregulated. This study presents overall changes in genes involved in different categories such as biological processes, molecular functions, and cellular components in responses to MI. Conclusions: The significantly deregulated genes identified in the present study not only indicate the molecular and cellular changes but also suggest the scope for the detection of specific gene markers for MI.

Discerning Endoscopic Severity of Inflammatory Bowel Disease by Scoping the Peripheral Blood Transcriptome

Background and AimsUlcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory bowel diseases (IBD) with an incompletely understood etiology and pathogenesis. Identification of suitable drug targets and assessment of disease severity are crucial for optimal management. MethodsUsing RNA-sequencing, we investigated differential gene expression in peripheral blood samples from IBD-patients and non-inflamed controls, analysed pathway enrichment, and identified genes whose expression correlated with endoscopic disease severity. ResultsNeutrophil degranulation emerged as the most significant pathway across all IBD sample types. Signalling by interleukins was prominent in patients with active intestinal inflammation, but also enriched in CD and UC patients without intestinal inflammation. Nevertheless, genes correlated to endoscopic disease severity implicated the primary cilium in CD patients, and translation and focal adhesion in UC patients. Moreover, several of these genes were located in genome-wide associated loci linked to IBD, cholesterol levels, blood cell counts, and levels of markers assessing liver and kidney function. These genes also suggested connections to intestinal epithelial barrier dysfunction, contemporary IBD drug treatment, and new actionable drug targets. A large number of genes associated with endoscopic disease severity corresponded to non-coding RNAs. ConclusionsThis study revealed biological pathways associated with IBD disease state and endoscopic disease severity, thus providing insights into the underlying mechanisms of IBD pathogenesis as well as identifying potential biomarkers and therapies. Peripheral blood might constitute a suitable non-invasive diagnostic sample type, in which gene expression profiles might serve as indicators of ongoing mucosal inflammation, and thus guide personalized treatment decisions.

Comparative analysis of peripheral whole blood transcriptome from asymptomatic carriers reveals upregulation of subsets of surface proteins implicated in Plasmodium falciparum phenotypic plasticity

The molecular mechanism underlying Plasmodium falciparum's persistence in the asymptomatic phase of infection remains largely unknown. However, large-scale shifts in the parasites' gene expression during asymptomatic infections may enhance phenotypic plasticity, maximizing their fitness and leading to the persistence of the asymptomatic infections. To uncover these mechanisms, we aimed to identify parasite genetic factors implicated in asymptomatic infections through whole transcriptome analysis. We analyzed publicly available transcriptome datasets containing asymptomatic malaria (ASM), uncomplicated malaria (SM), and malaria-naïve (NSM) samples from 35 subjects for differentially expressed genes (DEGs) and long noncoding RNAs. Our analysis identified 755 and 1773 DEGs in ASM vs SM and NSM, respectively. These DEGs revealed sets of genes coding for proteins of unknown functions (PUFs) upregulated in ASM vs SM and ASM, suggesting their role in underlying fundamental molecular mechanisms during asymptomatic infections. Upregulated genes in ASM vs SM revealed a subset of 24 clonal variant genes (CVGs) involved in host-parasite and symbiotic interactions and modulation of the symbiont of host erythrocyte aggregation pathways. Moreover, we identified 237 differentially expressed noncoding RNAs in ASM vs SM, of which 11 were found to interact with CVGs, suggesting their possible role in regulating the expression of CVGs. Our results suggest that P. falciparum utilizes phenotypic plasticity as an adaptive mechanism during asymptomatic infections by upregulating clonal variant genes, with long noncoding RNAs possibly playing a crucial role in their regulation. Thus, our study provides insights into the parasites' genetic factors that confer a fitness advantage during asymptomatic infections.

Leveraging transcriptomics to develop bronchopulmonary dysplasia endotypes: a concept paper

ImpactBronchopulmonary dysplasia has multiple definitions that are currently based on phenotypic characteristics. Using an unsupervised machine learning approach, we created BPD subclasses (e.g., endotypes) by clustering whole microarray data. T helper 17 cell differentiation was the most significant pathway differentiating the BPD endotypes.IntroductionBronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Discovery of BPD endotypes in an unbiased format, derived from the peripheral blood transcriptome, may uncover patterns underpinning this complex lung disease.MethodsAn unsupervised agglomerative hierarchical clustering approach applied to genome-wide expression of profiling from 62 children at day of life five was used to identify BPD endotypes. To identify which genes were differentially expressed across the BPD endotypes, we formulated a linear model based on least-squares minimization with empirical Bayes statistics.ResultsFour BPD endotypes (A, B,C,D) were identified using 7,319 differentially expressed genes. Across BPD endotypes, 5,850 genes had a p value < 0.05 after multiple comparison testing. Endotype A consisted of neonates with a higher gestational age and birthweight. Endotypes B-D included neonates between 25 and 26 weeks and a birthweight range of 640 to 940 g. Endotype D appeared to have a protective role against BPD compared to Endotypes B and C (36% vs. 62% vs. 60%, respectively). The most significant pathway focused on T helper 17 cell differentiation.ConclusionBioinformatic analyses can help identify BPD endotypes that associate with clinical definitions of BPD.

Early transcriptional responses to human enteric fever challenge.

Enteric fever, caused by oral infection with typhoidal Salmonella serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal Salmonella, there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0.05). Gene sets relating to neutrophils, monocytes, and innate immunity were over-represented (false discovery rate <0.05). Estimating cell proportions from gene expression data suggested a possible increase in activated monocytes 12 hours post-challenge (P = 0.036, paired Wilcoxon signed-rank test). Furthermore, plasma TNF-α rose following exposure (P = 0.011, paired Wilcoxon signed-rank test). There were no significant differences in gene expression (false discovery rate <0.05) in the 12 hours response between those who did and did not subsequently develop clinical or blood culture confirmed enteric fever or between vaccination groups. Together, these results demonstrate early perturbation of the peripheral blood transcriptome after enteric fever challenge and provide initial insight into early mechanisms of protection.

Integration of transcriptomics and metabolomics reveals the responses of the maternal circulation and maternal-fetal interface to LPS-induced preterm birth in mice.

Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological and pathological changes. In this study, we hypothesize that inflammation can cause changes in mRNA expression and metabolic stability in the placenta, decidua, chorioamniotic membrane, uterus and peripheral blood, ultimately leading to PTB. To comprehensively assess the effects of inflammation on mRNA expression and metabolite production in different tissues of pregnancy, we used a mouse PTB model by intraperitoneally injecting lipopolysaccharide (LPS) and integrated transcriptomics and metabolomics studies. Our analysis identified 152 common differentially expressed genes (DEGs) and 8 common differentially expressed metabolites (DEMs) in the placenta, decidua, chorioamniotic membrane, uterus, and peripheral blood, or placenta and uterus after LPS injection, respectively. Our bioinformatics analysis revealed significant enrichment of the NOD-like receptor signaling pathway (mmu04621), TNF signaling pathway (mmu04668), IL-17 signaling pathway (mmu04657), and NF-kappa B signaling pathway in the transcriptomics of different tissues, and Hormone synthesis, Lysosome, NOD-like receptor signaling pathway, and Protein digest and absorption pathway in metabolomics. Moreover, we found that several upstream regulators and master regulators, including STAT1, STAT3, and NFKB1, were altered after exposure to inflammation in the different tissues. Interaction network analysis of transcriptomics and metabolomics DEGs and DEMs also revealed functional changes in mice intraperitoneally injected with LPS. Overall, our study identified significant and biologically relevant alterations in the placenta, decidua, chorioamniotic membrane, uterus, peripheral blood transcriptome and the placenta and uterus metabolome in mice exposed to LPS. Thus, a comprehensive analysis of different pregnancy tissues in mice intraperitoneally injected with LPS by combining transcriptomics and metabolomics may help to systematically understand the local and systemic changes associated with PTB caused by inflammation.

A burns and COVID-19 shared stress responding gene network deciphers CD1C-CD141- DCs as the key cellular components in septic prognosis

Differential body responses to various stresses, infectious or noninfectious, govern clinical outcomes ranging from asymptoma to death. However, the common molecular and cellular nature of the stress responsome across different stimuli is not described. In this study, we compared the expression behaviors between burns and COVID-19 infection by choosing the transcriptome of peripheral blood from related patients as the analytic target since the blood cells reflect the systemic landscape of immune status. To this end, we identified an immune co-stimulator (CD86)-centered network, named stress-response core (SRC), which was robustly co-expressed in burns and COVID-19. The enhancement of SRC genes (SRCs) expression indicated favorable prognosis and less severity in both conditions. An independent whole blood single-cell RNA sequencing of COVID-19 patients demonstrated that the monocyte-dendritic cell (Mono-DC) wing was the major cellular source of SRC, among which the higher expression of the SRCs in the monocyte was associated with the asymptomatic COVID-19 patients, while the quantity-restricted and function-defected CD1C-CD141-DCs were recognized as the key signature which linked to bad consequences. Specifically, the proportion of the CD1C-CD141-DCs and their SRCs expression were step-wise reduced along with worse clinic conditions while the subcluster of CD1C-CD141-DCs from the critical COVID-19 patients was characterized of IFN signaling quiescence, high mitochondrial metabolism and immune-communication inactivation. Thus, our study identified an expression-synchronized and function-focused gene network in Mono-DC population whose expression status was prognosis-related and might serve as a new target of diagnosis and therapy.

RNA-Seq Analysis of Peripheral Whole Blood from Dairy Bulls with High and Low Antibody-Mediated Immune Responses-A Preliminary Study.

Enhancing the immune response through breeding is regarded as an effective strategy for improving animal health, as dairy cattle identified as high immune responders are reported to have a decreased prevalence of economically significant diseases. The identification of differentially expressed genes (DEGs) associated with immune responses might be an effective tool for breeding healthy dairy cattle. In this study, antibody-mediated immune responses (AMIRs) were induced by the immunization of hen egg white lysozyme (HEWL) in six Chinese Holstein dairy bulls divided into high- and low-AMIR groups based on their HEWL antibody level. Then, RNA-seq was applied to explore the transcriptome of peripheral whole blood between the two comparison groups. As a result, several major upregulated and downregulated genes were identified and attributed to the regulation of locomotion, tissue development, immune response, and detoxification. In addition, the result of the KEGG pathway analysis revealed that most DEGs were enriched in pathways related to disease, inflammation, and immune response, including antigen processing and presentation, Staphylococcus aureus infection, intestinal immune network for IgA production, cytokine-cytokine receptor interaction, and complement and coagulation cascades. Moreover, six genes (BOLA-DQA5, C5, CXCL2, HBA, LTF, and COL1A1) were validated using RT-qPCR, which may provide information for genomic selection in breeding programs. These results broaden the knowledge of the immune response mechanism in dairy bulls, which has strong implications for breeding cattle with an enhanced AMIR.

Analysis of the influence of pyroptosis-related genes on molecular characteristics in patients with acute myocardial infarction.

Pyroptosis is a newly identified mode of programmed cell death, but the potential role in patients with acute myocardial infarction (AMI) remains unclear. In this study, bioinformatics methods were used to identify differentially expressed genes from peripheral blood transcriptome data between normal subjects and patients with AMI which were downloaded by the Gene Expression Omnibus database. Comparing Random Forest (RF) and Support Vector Machine (SVM) training algorithms were used to identify pyroptosis-related genes, predicting patients with AMI by nomogram based on informative genes. Moreover, clustering was used to amplify the feature of pyroptosis, in order to facilitate analysis distinct biological differences. Diversity analysis indicated that a majority of pyroptosis-related genes are expressed at higher levels in patients with AMI. The receiver operating characteristic curves show that the RF model is more responsive than the SVM machine learning model to the pyroptosis characteristics of these patients in vivo. We obtained a column line graph diagnostic model which was developed based on 19 genes established by the RF model. After the consensus clustering algorithm of single sample Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, the results for them found that pyroptosis-related genes mediate the activation of multiple immune cells and many inflammatory pathways in the body. We used RF and SVM algorithms to determine 19 pyroptosis-related genes and evaluate their immunological effects in patients with AMI. We also constructed a series of by nomogram related to pyroptosis-related genes to predict the risk of developing AMI.

High diagnostic potential of short and long read genome sequencing with transcriptome analysis in exome-negative developmental disorders

Exome sequencing (ES) has become the method of choice for diagnosing rare diseases, while the availability of short-read genome sequencing (SR-GS) in a medical setting is increasing. In addition, new sequencing technologies, such as long-read genome sequencing (LR-GS) and transcriptome sequencing, are being increasingly used. However, the contribution of these techniques compared to widely used ES is not well established, particularly in regards to the analysis of non-coding regions. In a pilot study of five probands affected by an undiagnosed neurodevelopmental disorder, we performed trio-based short-read GS and long-read GS as well as case-only peripheral blood transcriptome sequencing. We identified three new genetic diagnoses, none of which affected the coding regions. More specifically, LR-GS identified a balanced inversion in NSD1, highlighting a rare mechanism of Sotos syndrome. SR-GS identified a homozygous deep intronic variant of KLHL7 resulting in a neoexon inclusion, and a de novo mosaic intronic 22-bp deletion in KMT2D, leading to the diagnosis of Perching and Kabuki syndromes, respectively. All three variants had a significant effect on the transcriptome, which showed decreased gene expression, mono-allelic expression and splicing defects, respectively, further validating the effect of these variants. Overall, in undiagnosed patients, the combination of short and long read GS allowed the detection of cryptic variations not or barely detectable by ES, making it a highly sensitive method at the cost of morecomplex bioinformatics approaches. Transcriptome sequencing is a valuable complement for the functional validation of variations, particularly in the non-coding genome.

The Effects of a Multi-Ingredient Supplement Containing Wasabia Japonica Extract, Theacrine, and Copper (I) Niacin Chelate on Peripheral Blood Mononuclear Cell DNA Methylation, Transcriptomics, and Sirtuin Activity

Herein, we determined if a multi-ingredient supplement (NAD3; 312 mg of combined Wasabia japonica extract, theacrine, and copper (I)niacin chelate) versus a placebo (CTL) affected peripheral blood mononuclear (PMBC) transcriptomic, DNA methylation, and sirtuin activity profiles in middle-aged adults after 12 weeks of supplementation. Several mRNAs demonstrated interactions (n = 148 at ±1.5-fold change, p &lt; 0.01), and more stringent filtering indicated that 25 mRNAs were upregulated and 29 were downregulated in the NAD3 versus CTL group. Bioinformatics on these 64 mRNAs suggested that DNA conformational alterations may have been promoted with NAD3 supplementation, and this was corroborated with more CpG sites being hypermethylated (p &lt; 0.001) in the CTL versus the NAD3 group when examining pre- to post-intervention changes (369 versus 35). PBMC SIRT activity decreased in CTL participants (p &lt; 0.001), but not in NAD3 participants (p = 0.289), and values at 12 weeks trended higher in NAD3 participants (p = 0.057). Interestingly, the pre- to post- changes in SIRT activity values significantly correlated with changes in PBMC NAD+: NADH values obtained from a previous investigation in these participants (r = 0.534, p = 0.015). In conclusion, the current mRNA and DNA methylation data indirectly suggest that NAD3 supplementation may affect PBMC DNA conformation, while other direct assays suggest that NAD3 supplementation maintains SIRT activity through the potential maintenance of NAD+: NADH levels. However, these results are preliminary due to limited n-sizes and the study being performed in middle-aged adults.

Identification of new candidate drugs for primary Sjögren's syndrome using a drug repurposing transcriptomic approach.

To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes. Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database. We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated. This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

WCN23-0771 Identification of Key Biomarkers and Immune Cell Infiltration in IgA Nephropathy by Peripheral Blood Transcriptome Analysis

WCN23-0771 Identification of Key Biomarkers and Immune Cell Infiltration in IgA Nephropathy by Peripheral Blood Transcriptome Analysis

Bioinformatic Analyses of Peripheral Blood Transcriptome Identify Altered Neutrophil-Related Pathway and Different Transcriptomic Profiles for Acute Pancreatitis in Patients with and without Chylomicronemia Syndrome.

Acute pancreatitis (AP) is a serious inflammatory condition of the pancreas that can be associated with chylomicronemia syndrome (CS). Currently, no study has explored the differences between non-CS-associated AP and CS-associated AP in terms of gene expression. Transcriptomic profiles of blood samples from patients with AP were retrieved from GSE194331 (non-CS-associated) and GSE149607 (CS-associated). GSE31568 was used to examine the linkage between non-CS-associated AP and the expression of micro RNAs (miRNAs). Differentially expressed genes (DEGs) were identified, a gene regulatory network was constructed, and hub genes were defined. Subsequently, single-sample gene set enrichment analysis (ssGSEA) scores of hub genes were calculated to represent their regulatory-level activity. A total of 1851 shared DEGs were identified between non-CS-associated and CS-associated AP. Neutrophils were significantly enriched in both conditions. In non-CS-associated AP, miRNAs including hsa-miR-21, hsa-miR-146a, and hsa-miR-106a demonstrated a lower expression level as compared with the healthy control. Furthermore, the expression patterns and regulatory activities were largely opposite between non-CS-associated and CS-associated AP, with significantly lower estimated neutrophils in the latter case. In summary, we found that the regulation of neutrophils was altered in AP. There was a different gene expression pattern and lower estimated neutrophil infiltration in CS-associated AP. Whether these findings are clinically significant requires further investigation.