Identification Of Therapeutic Targets Research Articles

Enhanced sensitivity and scalability with a Chip-Tip workflow enables deep single-cell proteomics.

Single-cell proteomics (SCP) promises to revolutionize biomedicine by providing an unparalleled view of the proteome in individual cells. Here, we present a high-sensitivity SCP workflow named Chip-Tip, identifying >5,000 proteins in individual HeLa cells. It also facilitated direct detection of post-translational modifications in single cells, making the need for specific post-translational modification-enrichment unnecessary. Our study demonstrates the feasibility of processing up to 120 label-free SCP samples per day. An optimized tissue dissociation buffer enabled effective single-cell disaggregation of drug-treated cancer cell spheroids, refining overall SCP analysis. Analyzing nondirected human-induced pluripotent stem cell differentiation, we consistently quantified stem cell markers OCT4 and SOX2 in human-induced pluripotent stem cells and lineage markers such as GATA4 (endoderm), HAND1 (mesoderm) and MAP2 (ectoderm) in different embryoid body cells. Our workflow sets a benchmark in SCP for sensitivity and throughput, with broad applications in basic biology and biomedicine for identification of cell type-specific markers and therapeutic targets.

The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation

Neuroinflammation is a blanket term that describes the body’s complex inflammatory response in the central nervous system (CNS). It encompasses a phenotype shift to a proinflammatory state, the release of cytokines, the recruitment of peripheral immune cells, and a wide variety of other processes. Neuroinflammation has been implicated in nearly every major CNS disease ranging from Alzheimer’s disease to brain cancer. Understanding and modeling neuroinflammation is critical for the identification of novel therapeutic targets in the treatment of CNS diseases. Unfortunately, the translation of findings from non-human models has left much to be desired. This review systematically discusses the role of human pluripotent stem cell (hPSC)-derived glia and supporting cells within the CNS, including astrocytes, microglia, oligodendrocyte precursor cells, pericytes, and endothelial cells, to describe the state of the field and hope for future discoveries. hPSC-derived cells offer an expanded potential to study the pathobiology of neuroinflammation and immunomodulatory cascades that impact disease progression. While much progress has been made in the development of models, there is much left to explore in the application of these models to understand the complex inflammatory response in the CNS.

Establishment and characterization of a new mouse gastric carcinoma cell line, MCC

BackgroundThe aim of this study was to establish a primary mouse gastric carcinoma cell line.MethodsGastric adenocarcinoma in the body region was induced in immunocompetent BALB/c mice using N-Methyl-N-nitrosourea and a 2% NaCl solution. Fresh gastric cancer tissue samples were cultured in 1640 medium supplemented with 10% fetal bovine serum for primary culture and subculture. Cellular morphology was assessed via light microscopy, and a cell growth curve was established. Genomic and proteomic analyses were conducted to characterize the molecular features of the cell lines. This cell line demonstrated a 100% success rate in forming subcutaneous tumors in BALB/c mice. By integrating proteomic profiles from clinical gastric cancer patients and the murine subcutaneous tumor model, several molecular targets suitable for preclinical investigation were identified. Trametinib, a MEK inhibitor, was employed as a model compound in our preclinical study.ResultsA novel gastric carcinoma cell line, designated MCC, was established from BALB/c mice. This cell line exhibited a doubling time of approximately 33 h. Genomic and proteomic analyses identified mutations frequently observed in clinical gastric cancer patients, such as Kras, Egfr, and Ccnd3. Additionally, MCC overexpresses proteins, including SLC1A5, MCM6, and ITGA2, which are significantly upregulated in gastric cancer tissues compared to adjacent non-cancerous tissues. The MCC cell line demonstrated stable tumorigenicity in immunocompetent BALB/c mice, forming subcutaneous tumors that closely resemble the proteomic profile of clinical gastric cancer samples. This high concordance facilitated the identification of several potential therapeutic targets for gastric cancer. Preclinical studies with trametinib revealed that treatment effectively inhibited gastric cancer growth, likely mediated through the activation of immune cells, particularly neutrophils and T cells.ConclusionsThe MCC cell line serves as an indispensable model for gastric cancer research, offering a robust platform for investigating tumor development and progression. Its exceptional tumorigenic capacity and strong concordance with clinical proteomic profiles underscore its significance in translational research, facilitating the discovery of novel therapeutic targets and elucidation of molecular pathways critical for developing effective treatment strategies.

Systematic identification of pathological mechanisms, prognostic biomarkers and therapeutic targets by integrating lncRNA expression variation in salivary gland mucoepidermoid carcinoma

Biologicalprocesses intricately intertwine with tumorigenesis, significantly influencing treatment outcomes and prognosis. However, the mechanisms fostering mucoepidermoid carcinoma (MEC) remain inadequately elucidated. This research utilizes expression profiles of lncRNAs from clinical MEC tissues and matched normal glandular tissues, integrating public data to explore the biological mechanisms and immune microenvironment characteristics of tumorigenesis. Gene set enrichment analysis identified key pathways, and a customized epithelial-mesenchymal transition (EMT) score elucidated the relationship between pathological processes and prognosis, while an immune signature revealed tumor microenvironment characteristics. MECs exhibited significant enrichment in EMT pathway, with key genes such as Secretogranin II, tissue factor pathway inhibitor 2, and periostin identified as contributors to the EMT process. High EMT scores correlated with upregulated EMT and immune response activity, indicating poor prognosis. Single-sample gene set enrichment analysis unveiled the tumors’ immune infiltration signature, suggesting active antigen presentation and a positive immune response for immunotherapy. Additionally, SLC2A1-AS1 and CERS6-AS1 were identified as potential mediators of EMT and the immune environment. This study provides insights into the biological processes of MEC tumorigenesis and identifies potential therapeutic targets for future research.

Long Non-Coding RNAs in Diabetic Cardiomyopathy: Potential Function as Biomarkers and Therapeutic Targets of Exercise Training.

Recent studies emphasize the beneficial effects of exercise on diabetic cardiomyopathy (DCM), adding to the growing body of evidence that underscores the role of exercise in improving health outcomes. Despite this, a notable gap persists in the number of healthcare providers who actively prescribe exercise as a therapeutic intervention for DCM management. In addition, exercise modulates the expression of lncRNAs, which play a pivotal role in DCM progression. Further investigation into this relationship may facilitate the identification of novel biomarkers and therapeutic targets for DCM. This review consolidates recent advances in identifying lncRNAs biomarkers in DCM, summarizing the current knowledge on dysregulated lncRNAs and their molecular mechanisms. Additionally, it offers new insights into the mechanistic roles of lncRNAs, highlighting their potential as biomarkers and therapeutic targets for DCM. Overall, this review aims to inform future research and reinforce the significance of addressing diabetes-related cardiovascular diseases to potentially improve clinical outcomes.

G Protein Regulation by RGS Proteins in the Pathophysiology of Dilated Cardiomyopathy.

Regulators of G protein signaling (RGS) proteins finetune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, kidney, heart, and the vasculature. Impaired regulation of G protein signaling by RGS proteins is implicated in the pathogenesis of several human diseases including various forms of cardiomyopathy such as hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Both genetic and non-genetic changes that impinge on G protein signaling in cardiomyocytes are implicated in the etiology of DCM, and there is accumulating evidence that such genetic and non-genetic changes affecting G protein signaling in cell types other than cardiomyocytes could serve as a DCM trigger in humans. This review discusses and highlights mammalian RGS proteins and their roles in cardiac physiology and disease, with specific focus on the current understanding of the etiology of DCM and the pathogenic roles of RGS proteins that are prominently expressed in the cardiovascular system. Growing evidence suggests that defects in G protein regulation by RGS proteins in the cardiovascular system likely contribute to cardiomyocyte structural damage and decreased contractile function that hallmark DCM. Further studies that enhance the understanding of the dynamics of G protein regulation by RGS proteins in several cell types in the myocardium and the vasculature are critical to gaining more insight into the etiology of DCM and heart failure, and to the identification of novel therapeutic targets.

Identification and Validation of Potential Biomarkers and Therapeutic Targets of COVID-19-related Depression.

The prevalence of depression in COVID-19 patients is notably high, disrupting daily life routines and compounding the burden of other chronic health conditions. In addition, to elucidate the connection between COVID-19 and depression, we conducted an analysis of commonly differentially expressed genes [co-DEGs], uncovering potential biomarkers and therapeutic avenues specific to COVID-19-related depression. We obtained gene expression profiles from the Gene Expression Omnibus [GEO] database with strategic keyword searches ["COVID-19", "depression," and "SARS"]. We used functional enrichment analysis of the co-DEGs to decipher their likely biological roles. Then, we utilized protein-protein interaction [PPI] network analysis to identify hub genes among the co- DEGs. These findings were validated via an independent third-party dataset. Our analysis of blood samples from COVID-19 patients revealed 10,716 upregulated genes and 10,319 downregulated genes. In addition, by applying the same approach to depression samples, we identified 571 upregulated and 847 downregulated genes. Furthermore, by intersecting these datasets, we extracted 121 upregulated and 175 downregulated co-DEGs. Through PPI network construction and hub gene selection, we identified MPO, ARG1, CD163, FCGR1A, ELANE, LCN2, and CR1 as co-upregulated hub genes and MRPL13, RPS23, and MRPL1 as co-downregulated hub genes. The incorporation of third-party datasets revealed that these hub genes are specific targets of SARS-CoV-2, not generic viral response mechanisms. The identification of potential biomarkers represents a groundbreaking strategy for assessing and treating depression in the context of COVID-19, with the potential to reduce its prevalence among these patients. However, to fully harness this potential, additional clinical research is paramount.

Early differentiation of committed erythroid cells defined by miR-144/451 expression.

Before committing to an erythroid cell lineage, hematopoietic stem cells differentiate along a myeloid cell pathway to generate megakaryocyte-erythroid biopotential progenitor cells in bone marrow. Recent studies suggest that erythroid progenitors (EryPs) could be generated at the level of common myeloid progenitors (CMPs). However, due to a lack of suitable markers, little is known about the early differentiation of these committed EryP cells during CMP development. Herein, using miR-144/451-eGFP knock-in mice, we found that early differentiation of committed erythroid cells could be defined by miR-144/451 expression within CMPs. Single-cell RNA sequencing showed that miR-144/451+ progenitors had obvious differentiation characteristics of erythroid lineage cells and diverged from megakaryocyte and other myeloid cell lineages. These progenitors exclusively gave rise to erythroid cells, both in vitro and in vivo, and the commitment to an erythroid cell lineage was accompanied by loss of CD53 expression. Our findings will facilitate further understanding of the molecular mechanisms governing erythroid development and support the identification of therapeutic targets for diseases related to erythrocyte development.

Glycosaminoglycan Adenogenesis Factors: Immunohistochemical Expression in Endometriosis Tissues Compared with the Endometrium.

Endometriosis is a chronic inflammatory pathology estrogen-dependent. It is a condition affecting 5%-10% of women of reproductive age worldwide. Recent evidence indicating an embryological origin of endometriosis has provided new insights into its pathogenesis and potential therapeutic approaches. In this study, we compared the immunohistochemical expression of extracellular matrix molecules involved in the interaction between epithelium and stroma in endometriotic lesions and normal endometrial tissue. A total of 41 cases were analyzed. We examined the immunohistochemical expression of chondroitin sulfate proteoglycan 4 (CSPG4), keratan sulfate, chondroitin sulfate (CS-56), hyaluronic acid, and heparan sulfate (HEP). Our results showed higher expression of CSPG4 and CS-56 in epithelial endometriosis samples compared with normal endometrial tissue, while HEP, keratan sulfate, and hyaluronic acid showed decreased expression in epithelial endometriosis samples relative to normal endometrial tissue. Additionally, endometriotic stroma exhibited more frequent low intensity of hyaluronic acid and HEP compared with normal endometrial stroma. Investigating the levels of these molecules in eutopic and ectopic endometrial tissues enables the identification of potential therapeutic targets, and the development of novel treatments aimed at disrupting the adhesive and invasive properties of endometriotic lesions.

Single-nucleus transcriptome profiling provides insights into the pathophysiology of adhesive arachnoiditis.

Adhesive arachnoiditis (AA) is a rare form of chronic degenerative pathology associated with persistent inflammation in the arachnoid matter of the spinal cord. Despite the existing knowledge, the detailed pathological mechanisms underlying AA are not fully understood. This study aimed to elucidate through comprehensive single nuclei RNA sequencing (snRNA-seq) to delineate the transcriptomic landscape of AA. From six arachnoid membrane samples, a total of 52,886 cells met the quality control standards for analysis. The main cell populations identified with specific gene markers were as follows: fibroblasts, glial cells, microglial cells, endothelial cells, mural cells, plasma cells, and T cells. Downstream analysis of fibroblasts, glial cells, and microglial cells was performed. Notably, fibroblast subsets 1 and 3 demonstrated a strong association with AA. Among them, subcluster 3 demonstrated elevated expression of genes COL1A1, COL3A1, and FN1, indicative of enhanced Wnt/β-catenin and extracellular matrix (ECM) synthesis pathways. Subcluster 3 was predicted to progressively transform into subcluster 1. In subcluster 1, there was a significant upregulation of genes such as BMP and ALPL, signaling enhanced activation of calcification-related pathways. This was highly relevant to end-stage arachnoid ossification formation. After being activated, microglial cells transformed into inflammatory disease-associated microglial cells and continued to express high levels of chemokines CCL2, CCL4, IL-1β, and other inflammatory factors NAMPT, INPP5D and NLRP3. This might be the main reason why AA recurrence is frequently observed in patients. These insights enhance our understanding of the pathological progression of AA and may contribute to the identification of novel therapeutic targets.

Emerging biomarkers in Gaucher disease.

Gaucher disease (GD) is a rare lysosomal disorder characterized by the accumulation of glycosphingolipids in macrophages resulting from glucocerebrosidase (GCase) deficiency. The accumulation of toxic substrates, which causes the hallmark symptoms of GD, is dependent on the extent of enzyme dysfunction. Accordingly, three distinct subtypes have been recognized, with type 1 GD (GD1) as the common and milder form, while types 2 (GD2) and 3 (GD3) are categorized as neuronopathic and severe. Manifestations variably include hepatosplenomegaly, anemia, thrombocytopenia, easy bruising, inflammation, bone pain and other skeletal pathologies, abnormal eye movements and neuropathy. Although the molecular basis of GD is relatively well understood, currently used biomarkers are nonspecific and inadequate for making finer distinctions between subtypes and in evaluating changes in disease status and guiding therapy. Thus, there is continued effort to investigate and identify potential biomarkers to improve GD diagnosis, monitoring and potential identification of novel therapeutic targets. Here, we provide a comprehensive review of emerging biomarkers in GD that can enhance current understanding and improve quality of life through better testing, disease management and treatment.

A transcriptomic analysis of the interplay of ferroptosis and immune filtration in endometriosis and identification of novel therapeutic targets.

Endometriosis is an inflammatory disease, involving immune cell infiltration and production of inflammatory mediators. Ferroptosis has recently been recognized as a mode of controlled cell death and the iron overload and peroxidative environment prevailing in the ectopic endometrium facilitates the occurrence of ferroptosis. In the current investigation, gene expression data was obtained from the dataset GSE7305.The variation in infiltration of immune cells amongst the samples with endometriosis and normal tissue was analysed using the CIBERSORTx tool which revealed higher infiltration of T cells gamma delta, macrophages M2, B cells naïve, T cells CD4 memory resting cells, plasma cells, T cells CD8 and mast cells activated in the tissue samples with endometriosis. An overlap of the differentially expressed genes (DEGs) and ferroptosis related genes revealed 32 ferroptosis related DEGs (FR-DEGs). GO and KEGG pathway analysis showed the FR-DEGs to be enriched in ferroptosis. The PPI network of the FR-DEGs was constructed and TP53, HMOX1, CAV1, CDKN1A, CD44, EPAS1, SLC2A1, MAP3K5, GCLC and FANCD2 were identified as the hub genes. Pearson correlation revealed significant correlation between the hub genes and infiltrating immune cells in endometriosis, thereby suggesting existence of a regulatory crosstalk between immune responses and ferroptosis in endometriosis. Hub gene- miRNA network analysis revealed that 7 of the 10 hub genes were targets of 3 miRNAs -hsa-miR-20a-5p, hsa-miR-16-5p and hsa-miR-17-5p, thereby providing further insight into the regulatory mechanisms underlying disease progression. Predictive analysis and cross validation studies revealed TP53 and CDKN1A as common targets of hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-20a-5p, thereby revealing their regulatory roles in ferroptosis and immune modulatory pathways relevant to endometriosis. The present study indicates an important role of both immune dysregulation and ferroptosis in the pathogenesis of endometriosis and identifies ferroptosis related hub genes and their miRNA regulators as favourable novel targets for further studies and therapeutic interventions.

Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer.

Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.

Clinical Molecular Testing for Clonal Relatedness of Second Melanoma Tumors.

Patients with melanoma can develop second tumors representing either metastases or new primary melanoma. This distinction has profound implications for management. Although clinicopathologic features are often sufficient, molecular assays can support the presence or absence of clonal relatedness in challenging cases. However, the potential for false-positive and false-negative results in this context is not well described. To evaluate clinical molecular assays used to determine whether melanoma tumors represent primary-metastasis pairs or unrelated tumors. We identified clinical cases at our institution in which paired melanocytic tumors were analyzed for clonal relatedness by molecular assays. Results were compared against data sets and/or controls to establish the likelihood that paired tumors were clonally related. In total, 12 pairs were evaluated by single-nucleotide polymorphism (SNP) array, targeted next-generation sequencing (NGS), or both. SNP array predicted relatedness in 5 of 9 cases and unrelatedness in 4 cases. In SNP comparisons, whole-chromosomal and arm-level changes were often nonspecific (coincidentally similar between unrelated tumors). Targeted NGS predicted relatedness in 2 of 4 cases and unrelatedness in 1 case, and was equivocal/noncontributory in 1 case. For targeted NGS, nonspecific (coincidentally similar) results were related to recurrent oncogenic drivers or pairs lacking detected oncogene mutations. The genome-wide analysis provided by SNP array was optimal for assessment of clonality. Targeted NGS can be informative but may be equivocal in some cases. The choice of assay may rely upon considerations including the amount of DNA, likelihood of distinctive mutations, and need for therapeutic target identification.

Bioisosteric replacement of pyridoxal‐5′‐phosphate to pyridoxal‐5′‐tetrazole targeting Bacillus subtilisGabR

AbstractAntimicrobial resistance is a significant cause of mortality globally due to infections, a trend that is expected to continue to rise. As existing treatments fail and new drug discovery slows, the urgency to develop novel antimicrobial therapeutics grows stronger. One promising strategy involves targeting bacterial systems exclusive to pathogens, such as the transcription regulator protein GabR. Expressed in diverse bacteria including Escherichia coli, Bordetella pertussis, and Klebsiella pneumoniae, GabR has no homolog in eukaryotes, making it an ideal therapeutic target. Bacillus subtilis GabR (bsGabR), the most studied variant, regulates its own transcription and activates genes for GABA aminotransferase (GabT) and succinic semialdehyde dehydrogenase (GabD). This intricate regulatory system presents a compelling antimicrobial target with the potential for agonistic intervention to disrupt bacterial gene expression and induce cellular dysfunction, especially in bacterial stress responses. To explore manipulation of this system and the potential of this protein as an antimicrobial target, an in‐depth understanding of the unique PLP‐dependent transcription regulation is critical. Herein, we report the successful structural modification of the cofactor PLP and demonstrate the biochemical reactivity of the PLP analog pyridoxal‐5′‐tetrazole (PLT). Through both spectrophotometric and X‐ray crystallographic analyses, we explore the interaction between bsGabR and PLT, together with a synthesized GABA derivative (S)‐4‐amino‐5‐phenoxypentanoate (4‐phenoxymethyl‐GABA or 4PMG). Most notably, we present a crystal structure of the condensed, external aldimine complex within bsGabR. While PLT alone is not a drug candidate, it can act as a probe to study the detailed mechanism of GabR‐mediated function. PLT employs a tetrazole moiety as a bioisosteric replacement for phosphate in PLP. In addition, the PLP‐4PMG adduct observed in the structure may serve as a novel chemical scaffold for subsequent structure‐based antimicrobial design.

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy

A mini review of leveraging biobanking in the identification of novel biomarkers in neurological disorders: insights from a rapid single-cell sequencing pipeline.

Recent successes in the identification of biomarkers and therapeutic targets for diagnosing and managing neurological diseases underscore the critical need for cutting-edge biobanks in the conduct of high-caliber translational neuroscience research. Biobanks dedicated to neurological disorders are particularly timely, given the increasing prevalence of neurological disability among the rising aging population. Translational research focusing on disorders of the central nervous system (CNS) poses distinct challenges due to the limited accessibility of CNS tissue pre-mortem. Nevertheless, technological breakthroughs, including single-cell and single-nucleus methodologies, offer unprecedented insights into CNS pathophysiology using minimal input such as cerebrospinal fluid (CSF) cells and brain biopsies. Moreover, assays designed to detect factors that are released by CNS resident cells and diffuse into the CSF and/or bloodstream (such as neurofilament light chain [NfL], glial fibrillar acidic protein [GFAP] and amyloid beta peptides), and systemic factors that cross the blood-brain barrier to target CNS-specific molecules (e.g., autoantibodies that bind either the NMDA receptor [NMDAR] or myelin oligodendrocyte glycoprotein [MOG]), are increasingly deployed in clinical research and practice. This review provides an overview of current biobanking practices in neurological disorders and discusses ongoing challenges to biomarker discovery. Additionally, it outlines a rapid consenting and processing pipeline ensuring fresh paired blood and CSF specimens for single-cell sequencing that might more accurately reflect in vivo pathways. In summary, augmenting biobank rigor and establishing innovative research pipelines using patient samples will undoubtedly accelerate biomarker discovery in neurological disorders.

Research progress and application status of organoid in breast cancer subtypes

Breast cancer (BC) is a prevalent malignant tumor that poses a significant health risk to women. The complexity of basic BC research and clinical treatment is influenced by multiple factors, including age, fertility, hormone metabolism, molecular subtypes, and tumor grading and staging. Traditional in vitro models often fall short of meeting modern research demands, whereas organoids—an emerging 3D primary culture technology—offer a unique platform that better replicates the tumor microenvironment (TME). Coupled with advances in high-throughput sequencing technologies, organoids have become increasingly valuable in biological and chemical research. Currently, the most widely used organoid model in BC research is the patient-derived organoid (PDO) model, which is generated directly from original tumor tissues. This paper aims to summarize the current status of PDO models across various BC subtypes, highlighting recent advances in genetics, mechanisms of drug resistance, identification of new therapeutic targets, and approaches to personalized treatment. In conclusion, the development of clinical precision medicine urgently requires in vitro models capable of accurately simulating the unique molecular subtypes of patients. This review will examine the challenges and future prospects of organoid models in BC research, offering new insights into the fundamental mechanisms of BC and paving the way for more effective personalized therapies.

Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.

Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.

Discovery of Glucose Metabolism-Associated Genes in Neuropathic Pain: Insights from Bioinformatics.

Metabolic dysfunction has been demonstrated to contribute to diabetic pain, pointing towards a potential correlation between glucose metabolism and pain. To investigate the relationship between altered glucose metabolism and neuropathic pain, we compared samples from healthy subjects with those from intervertebral disc degeneration (IVDD) patients, utilizing data from two public datasets. This led to the identification of 412 differentially expressed genes (DEG), of which 234 were upregulated and 178 were downregulated. Among these, three key genes (Ins, Igfbp3, Plod2) were found. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated the enrichment of hub genes in pathways such as the positive regulation of the ErbB signaling pathway, monocyte activation, and response to reactive oxygen species; thereby suggesting a potential correlation between these biological pathways and pain sensation. Further analysis identified three key genes (Ins, Igfbp3, and Plod2), which showed significant correlations with immune cell infiltration, suggesting their roles in modulating pain through immune response. To validate our findings, quantitative real-time polymerase chain reaction (qPCR) analysis confirmed the expression levels of these genes in a partial sciatic nerve ligation (PSNL) model, and immunofluorescence studies demonstrated increased immune cell infiltration at the injury site. Behavioral assessments further corroborated pain hypersensitivity in neuropathic pain (NP) models. Our study sheds light on the molecular mechanisms underlying NP and aids the identification of potential therapeutic targets for future drug development.