Search Results (49)

Currently, there are two major theories regarding the pathogenesis of sepsis: hyperimmune and hypoimmune. The hyperimmune theory suggests that a cytokine storm causes the symptoms of sepsis. On the contrary, the hypoimmune theory suggests that immunosuppression causes the manifestations of sepsis. By conducting a microarray analysis on peripheral leukocytes from patients with sepsis, this study found that hyperactivity of TH17 immunity was noted in sepsis patients. Innate immunity-related genes are significantly upregulated, including CD14, TLR1,2,4,5,8, HSP70, CEBP proteins, AP1 (JUNB and FOSL2), TGFB1, IL6, TGFA, CSF2 receptor, TNFRSF1A, S100A binding proteins, CCR2, FPR2, amyloid proteins, pentraxin, defensins, CLEC5A, whole complement machinery, CPD, NCF, MMP, neutrophil elastase, caspases, IgG and IgA Fc receptors (CD64, CD32), ALOX5, PTGS, LTB4R, LTA4H, and ICAM1. The majority of adaptive immunity genes were downregulated, including MHC-related genes, TCR genes, granzymes/perforin, CD40, CD8, CD3, TCR signaling, BCR signaling, T and B cell-specific transcription factors, NK killer receptors, and TH17 helper-specific transcription factors (STAT3, RORA, and REL), as well as Treg-related genes, including TGFB1, IL15, STAT5B, SMAD2/4, CD36, and thrombospondin. The findings of this study show that Th17 with Treg over-presentation play an important role in the pathophysiology of sepsis. Full article

Background: Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide. ARHL is characterized by bilateral, progressive, sensorineural hearing loss that is more pronounced at a high frequency. Conventional factors associated with ARHL include diabetes, hypertension, and a family history of hearing loss. The severity of hearing impairment varies between individuals. The defined causative molecular pathogenesis for ARHL is unknown, thus the identification of underlying pathogenic mechanisms involved in ARHL is imperative for the development of effective therapeutic approaches. Epigenetics is the study of phenotypic changes caused by the modification of gene expression rather than the alteration of a DNA sequence. While it is hypothesized that ARHL could result from undiscovered epigenetic susceptibility, there is a shortage of information on the role that epigenetic modification plays in ARHL. Here we present an investigation on the involvement of DNA methylation in ARHL. Results: Clinical, audiometric and DNA testing, and high-throughput methylation pattern screening were undertaken for ARHL patients and matched control subjects. Our results demonstrate a strong correlation between patients’ hearing measurements and methylation at CpG sites cg1140494 (ESPN) and cg27224823 (TNFRSF25). We identified 136 differentially methylated CpGs that were shared between a high and low audiometric frequency in the patient’s cohort. CpG cites in hearing loss candidate genes, KCNQ1, TMEM43, GSTM1, TCF25, and GSR, were found to be highly methylated in presbycusis patients as compared to the controls. A methylation polymerase chain reaction (PCR) assay was used to confirm methylation levels at a specific gene locus in ARHL patients and controls. Conclusions: Altered DNA methylation and its impact on gene expression has been implicated in many biological processes. By interrogating the methylation status across the genome of both hearing loss patients and those with normal hearing, our study can help to establish an association between the audiometric patterns and methylation status in ARHL, yielding new avenues for the identification of potential candidate genes for hearing loss. Full article

Introduction: Bell’s palsy is a common acute peripheral neurological disorder causing unilateral facial paralysis. Its exact etiology remains unknown, but it is linked to inflammation, immune responses, infections, and ischemia. This study explores the potential causal relationship between Bell’s palsy and peripheral blood inflammatory proteins, metabolites, and immune cell characteristics. Methods: Genetic data for Bell’s palsy were obtained from the Finnish database (version R10) and IEU OpenGWAS. A two-sample Mendelian randomization (MR) approach was applied, analyzing 4907 plasma proteins, 731 immune cell traits, 91 inflammatory proteins, and 1400 metabolites. The Finnish dataset served as the discovery cohort, while the IEU OpenGWAS dataset acted as the validation cohort. Bioinformatics analyses included protein–protein interaction (PPI) networks, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, colocalization, and Linkage Disequilibrium Score Regression (LDSC) to identify candidate proteins and explore potential therapeutic targets. Results: MR analysis identified 70 inflammatory proteins, 77 metabolites, and 26 immune cell traits as potentially causally associated with Bell’s palsy. After external validation, BLVRB, HMOX2, TNFRSF12A, DEFB128, ITM2A, VEGF-A, and DDX58 remained significantly associated (p < 0.05). PPI network analysis led to 31 candidate proteins, and six core proteins (JAK2, IL27RA, OSM, CCL19, SELL, VCAM-1) were identified. Conclusions: Our study identifies causal relationships between inflammatory proteins, metabolites, immune cells, and Bell’s palsy, highlighting that the JAK/STAT signaling pathway may be a potentially critical target for intervention in Bell’s palsy, and that its modulation may provide new directions and opportunities for therapeutic strategies and drug discovery for the disease. Full article

Breast cancer (BRCA) continues to pose a serious risk to women’s health worldwide. Neoadjuvant chemotherapy (NAC) is a critical treatment strategy. Nevertheless, the heterogeneity in treatment outcomes necessitates the identification of reliable biomarkers and prognostic models. Programmed cell death (PCD) pathways serve as a critical factor in tumor development and treatment response. However, the relationship between the diverse patterns of PCD and NAC in BRCA remains unclear. We integrated machine learning and multiple bioinformatics tools to explore the association between 19 PCD patterns and the prognosis of NAC within a cohort of 921 BRCA patients treated with NAC from seven multicenter cohorts. A prognostic risk model based on PCD-related genes (PRGs) was constructed and evaluated using a combination of 117 machine learning algorithms. Immune infiltration analysis, mutation analysis, pharmacological analysis, and single-cell RNA sequencing (scRNA-seq) were conducted to explore the genomic profile and clinical significance of these model genes in BRCA. Immunohistochemistry (IHC) was employed to validate the expression of select model genes (UGCG, BTG22, TNFRSF21, and MYB) in BRCA tissues. We constructed a PRGs prognostic risk model by using a signature comprising 20 PCD-related DEGs to forecast the clinical outcomes of NAC in BRCA patients. The prognostic model demonstrated excellent predictive accuracy, with a high concordance index (C-index) of 0.772, and was validated across multiple independent datasets. Our results demonstrated a strong association between the developed model and the survival prognosis, clinical pathological features, immune infiltration, tumor microenvironment (TME), gene mutations, and drug sensitivity of NAC for BRCA patients. Moreover, IHC studies further demonstrated that the expression of certain model genes in BRCA tissues was significantly associated with the efficacy of NAC and emerged as an autonomous predictor of outcomes influencing the outcome of patients. We are the first to integrate machine learning and bulk and scRNA-seq to decode various cell death mechanisms for the prognosis of NAC in BRCA. The developed unique prognostic model, based on PRGs, provides a novel and comprehensive strategy for predicting the NAC outcomes of BRCA patients. This model not only aids in understanding the mechanisms underlying NAC efficacy but also offers insights into personalized treatment strategies, potentially improving patient outcomes. Full article

Introduction: Immunosenescence alters TNF receptor expression (TNFR1 and TNFR2), contributing to chronic inflammation (inflamm-aging) and age-related diseases. Polymorphisms in TNFRSF1A and TNFRSF1B may influence receptor expression; however, their role in age-dependent modulation remains unclear. This study examines TNFR1/TNFR2 expression dynamics on T cells, B cells, and monocytes across different ages and evaluates the impact of genetic polymorphisms. Methods: PBMCs from 150 donors (18–60 years) were isolated via density-gradient centrifugation and cultured under spontaneous and LPS-stimulated conditions. TNFR1 and TNFR2 expression on immune cell subsets was quantified using flow cytometry with BD QuantiBRITE PE beads. SNP genotyping in TNFRSF1A and TNFRSF1B was performed via PCR with restriction analysis. Nonlinear age-related trends were assessed using polynomial approximation and inflection point analysis (Tukey’s method). Results: Among the 23 analyzed TNF system parameters, the proportion of TNFR2⁺CD3⁺ T cells increased with age, whereas TNFR1⁺ and TNFR2⁺ monocyte populations showed significant negative correlations (p < 0.05). Inflection points (~27, 34–36, and 44–45 years) indicated nonlinear dynamics in TNFRs expression during aging. TNFR2 expression on T cells gradually increased and stabilized at later ages, whereas TNFR1 and TNFR2 expression on monocytes followed distinct declining trajectories. Genetic polymorphisms influenced correlation strength, but did not alter direction, demonstrating a conserved pattern of age-related receptor expression shifts. Conclusions: TNFR expression exhibits nonlinear, age-dependent alterations across immune cells, shaped by immunosenescence and genetic variability. The identified critical age intervals represent key phases of immune remodeling, where assessing TNFR expression may provide insights into inflamm-aging mechanisms and potential targets for immune modulation. Full article

Cancer stem cells (CSCs) are a heterogeneous group of tumor cells that play a significant role in tumorigenesis, therapeutic resistance, and recurrence in liver hepatocellular carcinoma (LIHC). This study combines clinical data sets from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) with bulk RNA sequencing data. This study also features the GSE156625 single-cell RNA sequencing (scRNA) data set from the GEO to explore the prognostic significance of CSC biomarkers (BCSCs) in LIHC. In this research, we introduce a developed prognostic risk model that relies on nine specific BCSCs, including ADM, CCL5, CD274, DLGAP5, HOXD9, IGF1, S100A9, SOCS2, and TNFRSF11B. It was found that high-risk patients experience shorter overall survival rates when compared to low-risk patients. Additionally, the study characterized the composition of immune cells within the tumor microenvironment (TME) and revealed significant variations in gene-expression levels and mutation rates between different risk groups. The model suggests that liver cancer progression might be driven by immune evasion independent of PD-L1 and highlights the potential of the low-risk BCSC group being sensitive to various treatments. Our findings offer a promising foundation for personalized LIHC therapy and highlight the need for further experimental validation of the roles of these CSCs in disease progression. Full article

Osteoclasts (OCs) are important therapeutic targets in the treatment of osteoporosis. The aim of this study was to explore a novel therapeutic approach for osteoporosis using Arcyriaflavin A (ArcyA), a natural compound derived from the marine invertebrate Eudistoma sp. We systematically evaluated the effects of ArcyA on OC differentiation and function in mouse models using molecular biology assays, cellular function analyses and in vivo animal experiments. We also evaluated the efficacy of ArcyA in human cells. The TRAP staining results provide the first clear evidence of the drug’s inhibitory effect, whereby the administration of ArcyA led to a significant reduction in TRAP-positive cells compared to the control group at concentrations that were non-toxic to bone marrow macrophages. Meanwhile, a significant reduction in the number of multinucleated giant cells with more than ten nuclei was observed. Furthermore, similar TRAP staining results were reproduced in human OCs, suggesting that ArcyA has the same effect on OCs derived from human PBMCs. At the molecular level, ArcyA treatment resulted in the downregulation of genes relevant to OC differentiation (NFATc1, cFos and TNFrsf11α), fusion and survival (DCstamp and ATP6v0d2) and resorption function (CTSK, MMP9, integrin β3 and ACP5). A western blot analysis of the corresponding proteins (NFATc1, cFos, CTSK and integrin β3) further confirmed the PCR results. Furthermore, ArcyA-treated OCs produced significantly fewer resorption pits, indicating suppressed bone resorption activity. Consistent with this, in vivo experiments using an ovariectomy (OVX)-induced osteoporosis mouse model showed that ArcyA treatment significantly alleviated bone loss. Mice in the treatment groups had higher BV/TV values, and this therapeutic effect was enhanced in a dose-dependent manner. In addition, our research also showed that IκB could be a potential target for the inhibitory effect of ArcyA. In conclusion, these findings suggest that ArcyA has significant therapeutic potential for the treatment of osteoporosis by inhibiting osteoclastogenesis and bone resorption. Further studies are warranted to explore its clinical applications. Full article

The pathogenesis of the central nervous system (CNS) pathology in tick-borne encephalitis (TBE) remains unclear. We attempted to identify mediators of the blood–brain barrier (BBB) disruption in human TBE in paired serum and cerebrospinal fluid (CSF) samples from 100 TBE patients. CSF albumin quotient (Q_alb) was calculated as a measure of BBB impairment. Concentrations of cytokines, cytokine antagonists, adhesion molecules, selectins and matrix metalloproteinases (MMP) were measured with a multiplex bead assay. Single nucleotide polymorphisms (SNP) in genes MIF, TNF, TNFRSF1A, TNFRSF1B, IL-10, TLR3 and TLR4 were studied in patient blood DNA extracts and analyzed for associations with Q_alb and/or cytokine concentrations. The multivariate regression models of Q_alb were built with the soluble mediators as independent variables. The best models obtained included L-selectin, P-selectin, sVCAM, MMP7, MMP8 (or MMP9) and IL-28A as positive and IL-12p70, IL-15, IL-6Rα/IL-6 ratio and TNF-RII/TNFα ratio as negative correlates of Q_alb. The genotype did not associate with Q_alb, but polymorphism rs4149570 (in TNFRSF1A) associated with TNFα and rs1800629 (TNF) with MIF concentration. We confirm the association of the TNFα-dependent response, L-selectin and MMP8/MMP9 with BBB disruption and identify its novel correlates (IL-12, IL-15, IL-28A, MMP7). We detect no genotype associations with BBB function in TBE. Full article

Point-of-care (POC) testing has revolutionized diagnostics by providing rapid, accessible solutions outside traditional laboratory settings. However, many POC systems lack the sensitivity or multiplexing capability required for complex diseases. This study introduces an LED-based fluorescence reader designed for POC applications, enabling multiplex detection of lupus nephritis (LN) biomarkers using a biomarker microarray (BMA) slide. The reader integrates an LED excitation source, neutral density (ND) filters for precise intensity control, and onboard image processing with Gaussian smoothing and centroid thresholding to enhance signal detection and localization. Five LN biomarkers (VSIG4, OPN, VCAM1, ALCAM, and TNFRSF1B) were assessed, and performance was validated against a Genepix laser-based scanner. The LED reader demonstrated strong correlation coefficients (r = 0.96–0.98) with the Genepix system for both standard curves and patient samples, achieving robust signal-to-noise ratios and reproducibility across all biomarkers. The multiplex format reduced sample volume and allowed simultaneous analysis of multiple biomarkers. These results highlight the reader’s potential to bridge the gap between laboratory-grade precision and POC accessibility. By combining portability, cost-effectiveness, and high analytical performance, this fluorescence reader provides a practical solution for POC diagnostics, particularly in resource-limited settings, improving the feasibility of routine monitoring and early intervention for diseases requiring comprehensive biomarker analysis. Full article

Background: Among the various forms of root resorption, External Apical Root Resorption (EARR) has garnered particular attention due to its prevalence and potential complications associated with orthodontic interventions. Methods: An electronic search of literature was performed between September 2024 and December 2024 to identify all articles investigating the Role of Genetic Polymorphisms in External Apical Root Resorption Among Orthodontic Patients: Implications for Treatment Outcomes. The search was conducted using MEDLINE (National Library of Medicine)-PubMed with restrictions concerning the date of publication. In particular, we focused on the period 2014–2024 using the following keywords: gene polymorphisms AND orthodontic treatment AND apical root resorption OR external apical root resorption. This was followed by a manual search, and references were used to identify relevant articles. Results: The review showed that certain variations of the following genes may be positively associated with OIEARR: Osteopontin gene, P2RX7, IL-1β, IL-6, IL1RN, OPG, RANK, STAG2, RP1-30E17.2, SSP1, SFRP2, TNFSF11, TNFRSF11A, TNFRSF11B, VDR, CYP27B1, ACT3N, TSC2, WNT3A, LRP1, LRP6. Conversely, the IRAK1 gene has a protective function against the development of OIEARR. Conclusions: Despite these advancements, it is still not feasible to establish new guidelines and clinical protocols based on the existing research findings. The integration of genetic considerations into orthodontic practice has the potential to revolutionize treatment strategies, ensuring that they are not only effective but also respectful of each patient’s unique biological landscape. Full article

Introduction: Osteoprotegerin (OPG), encoded by the TNFRSF11B gene, is linked to the development of breast cancer via several pathways, including interactions with the receptor activator of nuclear factor-κB (RANK) ligands, apoptosis-inducing proteins like TRAIL, and genetic variations such as single nucleotide polymorphisms (SNPs), directly altering gene expression. This review aims to investigate the role of OPG expression in breast cancer. Methods: A comprehensive literature search was conducted using PubMed Medline, Google Scholar, and ScienceDirect. Only full-text English publications from inception to September 2024 were included. Results: Studies have demonstrated that certain SNPs in the OPG gene, specifically rs3102735 and rs2073618, are linked to a higher risk of breast cancer development. Additionally, OPG’s function as a TRAIL decoy receptor may inhibit the death of cancer cells. Furthermore, OPG in the serum and its interactions with BRCA mutations are being investigated for their potential influence on breast cancer progression. Studies have found that OPG promotes tumorigenesis by enhancing cell proliferation, angiogenesis, and aneuploidy in normal mammary epithelial cells. Moreover, OPG mediates the tumor-promoting effects of interleukin-1 beta and may serve as a biomarker for breast cancer risk, particularly in BRCA1 mutation carriers, through its role in dysregulated RANK signaling. Lastly, the use of recombinant OPG in mouse models has been found to exert anti-tumor effects. Conclusions: In this review, the role of OPG in breast cancer is examined. OPG has a multifaceted role in breast cancer tumorigenesis and exerts its effects through genetic variations (SNPs), interactions with TNF-related apoptosis-inducing ligand (TRAIL), and the modulation of the pro-tumorigenic microenvironment effects of angiogenesis, cell survival, and metastasis. Additionally, OPG’s dual role as a tumor suppressor and promoter serves as a possible therapeutic target to enhance apoptosis, limit bone metastasis, and modulate the tumor microenvironment. Whilst much is now known, further studies are necessary to fully delineate the role of OPG. Full article

Receptors for advanced glycation end products (RAGE) are multiligand cell surface receptors found most abundantly in lung tissue. This study sought to evaluate the role of RAGE in lung development by using a transgenic (TG) mouse model that spatially and temporally controlled RAGE overexpression. Histological imaging revealed that RAGE upregulation from embryonic day (E) 15.5 to E18.5 led to a thickened alveolar parenchyma and reduced alveolar surface area, while RAGE overexpression from E0 to E18.5 caused a significant loss of tissue and decreased architecture. Mitochondrial dysfunction was a hallmark of RAGE-mediated disruption, with decreased levels of anti-apoptotic BCL-W and elevated pro-apoptotic BID, SMAC, and HTRA2, indicating compromised mitochondrial integrity and increased intrinsic apoptotic activity. Extrinsic apoptotic signaling was similarly dysregulated, as evidenced by the increased expression of TNFRSF21, Fas/FasL, and Trail R2 in E0-18.5 RAGE TG mice. Additionally, reductions in IGFBP-3 and IGFBP-4, coupled with elevated p53 and decreased p27 expression, highlighted disruptions in the cell survival and cycle regulatory pathways. Despite the compensatory upregulation of inhibitors of apoptosis proteins (cIAP-2, XIAP, and Survivin), tissue loss and structural damage persisted. These findings underscore RAGE’s role as a pivotal modulator of lung development. Specifically, the timing of RAGE upregulation significantly impacts lung development by influencing pathways that cause distinct histological phenotypes. This research may foreshadow how RAGE signaling plausibly contributes to developmental lung diseases. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. While the precise causes of AD remain unclear, emerging evidence suggests that messenger RNA (mRNA) dysregulation contributes to AD pathology and risk. This study examined exosomal mRNA expression profiles of 15 individuals diagnosed with AD and 15 healthy controls from Barranquilla, Colombia. Utilizing advanced bioinformatics and machine learning (ML) techniques, we identified differentially expressed mRNAs and assessed their predictive power for AD diagnosis and AD age of onset (ADAOO). Our results showed that ENST00000331581 (CADM1) and ENST00000382258 (TNFRSF19) were significantly upregulated in AD patients. Key predictors for AD diagnosis included ENST00000311550 (GABRB3), ENST00000278765 (GGTLC1), ENST00000331581 (CADM1), ENST00000372572 (FOXJ3), and ENST00000636358 (ACY1), achieving > 90% accuracy in both training and testing datasets. For ADAOO, ENST00000340552 (LIMK2) expression correlated with a delay of ~12.6 years, while ENST00000304677 (RNASE6), ENST00000640218 (HNRNPU), ENST00000602017 (PPP5D1), ENST00000224950 (STN1), and ENST00000322088 (PPP2R1A) emerged as the most important predictors. ENST00000304677 (RNASE6) and ENST00000602017 (PPP5D1) showed promising predictive accuracy in unseen data. These findings suggest that mRNA expression profiles may serve as effective biomarkers for AD diagnosis and ADAOO, providing a cost-efficient and minimally invasive tool for early detection and monitoring. Further research is needed to validate these results in larger, diverse cohorts and explore the biological roles of the identified mRNAs in AD pathogenesis. Full article

Aryl Hydrocarbon Receptor (AHR) signaling is crucial for regulating the biotransformation of xenobiotics and physiological processes like inflammation and immunity. Meanwhile, Thalassophryne nattereri Peptide (TnP), a promising anti-inflammatory candidate from toadfish venom, demonstrates therapeutic effects through immunomodulation. However, its influence on AHR signaling remains unexplored. This study aimed to elucidate TnP’s molecular mechanisms on the AHR–cytochrome P450, family 1 (CYP1) pathway upon injury-induced inflammation in wild-type (WT) and Ahr2-knockdown (KD) zebrafish larvae through transcriptomic analysis and Cyp1a reporters. TnP, while unable to directly activate AHR, potentiated AHR activation by the high-affinity ligand 6-Formylindolo [3,2-b]carbazole (FICZ), implying a role as a CYP1A inhibitor, confirmed by in vitro studies. This interplay suggests TnP’s ability to modulate the AHR-CYP1 complex, prompting investigations into its influence on biotransformation pathways and injury-induced inflammation. Here, the inflammation model alone resulted in a significant response on the transcriptome, with most differentially expressed genes (DEGs) being upregulated across the groups. Ahr2-KD resulted in an overall greater number of DEGs, as did treatment with the higher dose of TnP in both WT and KD embryos. Genes related to oxidative stress and inflammatory response were the most apparent under inflamed conditions for both WT and KD groups, e.g., Tnfrsf1a, Irf1b, and Mmp9. TnP, specifically, induces the expression of Hspa5, Hsp90aa1.2, Cxcr3.3, and Mpeg1.2. Overall, this study suggests an interplay between TnP and the AHR-CYP1 pathway, stressing the inflammatory modulation through AHR-dependent mechanisms. Altogether, these results may offer new avenues in novel therapeutic strategies, such as based on natural bioactive molecules, harnessing AHR modulation for targeted and sustained drug effects in inflammatory conditions. Full article

ERβ has been assigned a tumor suppressor role in many cancer types. However, as conflicting findings emerge, ERβ’s tissue-specific expression and functional role have remained elusive. There remains a notable gap in compact and comprehensive analyses of ESR2 mRNA expression levels across diverse tumor types coupled with an exploration of its potential gene network. In this study, we aim to address these gaps by presenting a comprehensive analysis of ESR2 transcriptomic data. We distinguished cancer types with significant changes in ESR2 expression levels compared to corresponding healthy tissue and concluded that ESR2 influences patient survival. Gene Set Enrichment Analysis (GSEA) distinguished molecular pathways affected by ESR2, including oxidative phosphorylation and epithelial–mesenchymal transition. Finally, we investigated genes displaying similar expression patterns as ESR2 in tumor tissues, identifying potential co-expressed genes that may exert a synergistic effect on clinical outcomes, with significant results, including the expression of ACIN1, SYNE2, TNFRSF13C, and MDM4. Collectively, our results highlight the significant influence of ESR2 mRNA expression on the transcriptomic landscape and the overall metabolism of cancerous cells across various tumor types. Full article