Potential Therapeutic Drug Research Articles

Bioinformatics and experimental validation were combined to explore lactylation-related biomarkers in HBV-associated acute liver failure.

Currently, hepatitis B virus-related acute liver failure (HBV-ALF) has limited treatment options. Studies have shown that histone lactylation plays a role in the progression of liver-related diseases. Therefore, it is essential to explore lactylation-related gene (LRGs) biomarkers in HBV-ALF to provide new information for the treatment of HBV-ALF. Two HBV-ALF-related datasets (GSE38941 and GSE14668) and 65 LRGs were used. First, the differentially expressed genes (DEGs) were derived from differential expression analysis, the key module genes from weighted gene co-expression network analysis; and LRGs were used to intersect to obtain the candidate genes. Subsequently, the feature genes obtained from least absolute shrinkage and selection operator regression analysis and support vector machine analysis were intersected to obtain the candidate key genes. Among them, genes with consistent and significant expression trends in both GSE38941 and GSE14668 were used as biomarkers. Subsequently, biomarkers were analyzed for functional enrichment, immune infiltration, and sensitive drug prediction. In this study, five candidate genes (PIGM, PIGA, EGR1, PIGK, and PIGL) were identified by intersecting 6461 DEGs and 2496 key module genes with 65 LRGs. We then screened four candidate key genes from the machine learning algorithm, among which PIGM and PIGA were considered biomarkers in HBV-ALF. Moreover, the results of enrichment analysis showed that the significant enrichment signaling pathways for biomarkers included allograft rejection and valine, leucine, and isoleucine degradation. Thereafter, 11 immune cells differed significantly between groups, with resting memory CD4+ T cells having the strongest positive correlation with biomarkers. Methylphenidate hydrochloride is a potential therapeutic drug for PIGM. Two genes, PIGM and PIGA, were identified as biomarkers related to LRGs in HBV-ALF, providing a basis for understanding HBV-ALF pathogenesis.

Study of the role of leukocyte telomere length-related lncRNA NBR2 in Alzheimer's disease.

Alzheimer's Syndrome (AD) is a neurodegenerative disease that is prevalent in middle-aged and elderly people. As the disease progresses, patients gradually lose the ability to take care of themselves, which brings a heavy burden to the family. There is a link between leukocyte telomere length (LTL) and cognitive ability. To search for possible pathogenic mechanisms and potential therapeutic agents, we demonstrated a causal link between LTL and AD using Mendelian randomization analysis (MR). The expression of the target gene NBR2 and the downstream mRNA GJA1 and GJA1-related genes, pathway enrichment, and association with immune cells were further explored. Using the gene cluster-drug target interaction network, we obtained potential therapeutic drugs. Our study provides evidence for a causal link between AD and LTL, suggesting medicines that may treat and alleviate AD symptoms.

Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

The crucial role of beta-catenin in the osteoprotective effect of semaglutide in an ovariectomized rat model of osteoporosis.

Postmenopausal osteoporosis is a common chronic medical illness resulting from an imbalance between bone resorption and bone formation along with microarchitecture degeneration attributed to estrogen deficiency and often accompanied by other medical conditions such as weight gain, depression, and insomnia. Semaglutide (SEM) is a recently introduced GLP-1 receptor agonist (GLP-1RA) for the treatment of obesity and type 2 diabetes mellitus by mitigating insulin resistance. It has been discovered that the beneficial effects of GLP-1 are associated with alterations in lipolysis, adipogenesis, and anti-inflammatory processes. GLP-1 analogs transmit signals directly to adipose tissue. Mesenchymal stem cells (MSCs) are multidisciplinary cells that originate from bone marrow, migrate to injury sites, and promote bone regeneration. MSCs can differentiate into osteoblasts, adipose cells, and cartilage cells. Our aim is to investigate the role of semaglutide on bone formation and the Wnt signaling pathway. Osteoporosis was induced in female rats by ovariectomy, and the ovariectomized rats were treated with alendronate as standard treatment with a dose of 3mg/kg orally and semaglutide with two doses (150 mcg/kg and 300 mcg/kg) S.C. for 10 successive weeks. Semaglutide ameliorates bone detrimental changes induced by ovariectomy. It improves bone microarchitecture and preserves bone mineral content. Semaglutide ameliorates ovariectomy-induced osteoporosis and increases the expression of β-catenin, leading to increased bone formation and halted receptor activator of nuclear factor kappa-Β ligand (RANKL's) activation. Semaglutide can be used as a potential prophylactic and therapeutic drug against osteoporosis, possibly by activating Wnt signaling and decreasing bone resorption.

Novel insights into immunopathogenesis and crucial biomarkers between primary open‐angle glaucoma and systemic lupus erythematosus

AbstractGlaucoma is the primary factor underlying irreversible blindness. Recent studies suggest that the risk of glaucoma significantly increases in patients with systemic lupus erythematosus (SLE); however, the mechanism underlying this association remains unclear. Therefore, this study aimed to identify novel common biomarkers and potential therapeutic drugs for SLE and glaucoma. GSE27276, GSE50772, and GSE148371 datasets were sourced from the gene expression omnibus (GEO) database. An integrated analysis of the datasets for both diseases identified biomarkers and thoroughly examined their biological roles and molecular mechanisms using differential expression analysis (DEA), weighted gene co‐expression network analysis (WGCNA), gene enrichment analysis, machine learning, microRNA (miRNA) and transcription factor analyses, immune infiltration analyses, and single‐cell transcriptome analysis. Concurrently, molecular docking was used to forecast potential drugs targeting these biomarkers. Finally, reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR) was performed in human trabecular meshwork stem cells to validate the five identified biomarkers. The 10 key genes identified through DEA and WGCNA were predominantly involved in immune, inflammatory, and autophagy pathways. Additionally, machine learning identified five biomarkers, and we established associated transcription factors and miRNA regulatory networks. Immune infiltration analysis indicated an elevated presence of immune cells, including macrophages, T cells, and B cells, in both conditions. Furthermore, the DSigDB database yielded 10 potential therapeutic agents, three of which showed strong binding potential to the biomarkers via molecular docking. The RT‐qPCR results confirmed the trend in gene expression. This study uncovered a new link between SLE and primary open‐angle glaucoma, identifying biomarkers and mechanisms of immunopathogenesis for future research and treatment strategies.

Nicotinamide Mononucleotide: Research Process in Cardiovascular Diseases.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that plays a crucial role in diverse biological processes, including energy metabolism, gene expression, DNA repair, and mitochondrial function. An aberrant NAD+ level mediates the development of cardiovascular dysfunction and diseases. Both in vivo and in vitro studies have demonstrated that nicotinamide mononucleotide (NMN), as a NAD+ precursor, alleviates the development of cardiovascular diseases such as heart failure, atherosclerosis, and myocardial ischemia/reperfusion injury. Importantly, NMN has suggested pharmacological activities mostly through its involvement in NAD+ biosynthesis. Several clinical studies have been conducted to investigate the efficacy and safety of NMN supplementation, indicating its potential role in cardiovascular protection without significant adverse effects. In this review, we systematically summarize the impact of NMN as a nutraceutical and potential therapeutic drug on cardiovascular diseases and emphasize the correlation between NMN supplementation and cardiovascular protection.

In vitro cytotoxicity assessment of phenolic extracts from grapevine bunch stem and cane by-products for their potential use as phytotherapeutic agents

Aim: In the present study, bunch stem and cane extracts (Vitis vinifera L. cv. Malbec) rich in phenolic compounds (PCs) like flavonoids, phenolic acids, and stilbenes are studied as potential anticancer candidates. Methods: Twenty-three PCs were quantified by liquid chromatography-diode array fluorescence detection (LC-DAD-FLD). In vitro cytotoxic activity of both extracts on healthy (HBL-100) and colorectal cancer (HCT-116) human cell lines was assessed by 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay. Results: Cane extract did not show cytotoxic effect for the tested lines, which can be considered as an advantage for its application in the pharmaceutical industry. Conversely, the bunch stem extract showed a dose-dependent cytotoxic effect on HCT-116 and an IC50 of 680 µg/mL after 48 h of incubation; but not reported cytotoxic activity on the healthy cell line, evidencing a beneficial selective activity. The reported results encourage further investigation of these extracts as potential preventive and/or therapeutic drugs, or their combined use with chemotherapeutic treatments that lead to a potential dose reduction. Conclusions: The results preliminarily demonstrated that the extracts have potential anticancer properties or do not cause damage at the cellular level, encouraging their application as functional/nutraceutical or phytotherapeutic agents.

Huperzine A targets Apolipoprotein E: A potential therapeutic drug for diabetic nephropathy based on omics analysis

AimsDiabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) without curative interventions currently. Huperzine A (Hup A), a natural alkaloid, has demonstrated significant hypoglycemic and anti-inflammatory effects. We aim to investigate the protective effects of Hup A on DN and explore the underlying mechanisms MethodsWe applied STZ induced diabetic rats as DN model and leveraged combination analysis of the transcriptome, metabolome, microbiome, and network pharmacology (NP). The total effect of Hup A on DN was detected (i.e. urine protein, renal tissue structure) and the differential genes were further verified at the level of diabetic patients, db/db mice and cells. Clinical data and small interfering RNA (siRNA)-Apoe were adopted. ResultsHup A alleviated kidney injury in DN rats. Transcriptomics data and Western blot indicated that the improvement in DN was primarily associated with Apoe and Apoc2. Additionally, metabolomics data demonstrated that DN-induced lipid metabolism disruption was regulated by Hup A, potentially involving sphingosine. Hup A also enriched microbial diversity and ameliorated DN-induced microbiota imbalance. Spearman's correlation analysis demonstrated significant associations among the transcriptome, metabolome, and microbiome. Apoe level was positively correlated with clinical biomarkers in DN patients. Si-Apoe also played protective role in podocytes. NP analysis also suggested that Hup A may treat DN by modulating lipid metabolism, microbial homeostasis, and apoptosis, further validating our findings. ConclusionsCollectively, we provide the first evidence of the therapeutic effect of Hup A on DN, indicating that Hup A is a potential drug for the prevention and treatment of DN.

Effect of calcium concentration on metastasis of hepatocellular carcinoma cells cultured in alginate gel beads

Changes in sodium alginate and calcium ion concentrations have a considerable impact on the structural properties of calcium alginate gel (ALG) beads, consequently influencing the biological characteristics of the cells encapsulated within them. This study aimed to examine the effects of calcium on the metastatic potential of hepatocellular carcinoma (HCC) cells encapsulated in ALG beads. The results showed that the invasion ability of HCC cells significantly increased when they were encapsulated in beads prepared with a calcium concentration of 200 mM compared to those prepared with a calcium concentration of 50 mM. Furthermore, the expression levels of genes related to metastasis were significantly elevated in ALG beads prepared with a calcium concentration of 200 mM. Specifically, the expression of activated matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and urokinase-type plasminogen activator system proteins was found to be high. Conversely, the expression of phosphatase and tensin homolog deleted on chromosome 10 was observed to be significantly reduced. These findings indicate that manipulating the calcium ion concentration during the fabrication of ALG beads enables the generation of three-dimensional HCC cells with varying metastatic capacities. This model offers a valuable tool for investigating the mechanisms underlying liver cancer metastasis and screening potential therapeutic drugs.

Alpinia officinarum Hance extract relieved sepsis-induced myocardial ferroptosis and inflammation by inhibiting lncRNA MIAT/TRAF6/NF-κB axis.

Sepsis is generally triggered by a dysfunctional host response to infection, and it can result in life-threatening organ dysfunction. Alpinia officinarum Hance (AO) exhibits regulatory functions in some diseases. However, whether AO extract (AOE) plays a promoting role in sepsis--triggered myocardial injury is unclear. This study was aimed at investigating the regulatory effects of AOE on myocardial ferroptosis and inflammation in sepsis, and the regulation effects on the lncRNA MIAT/TRAF6/NF-κB axis. Lipopolysaccharide (LPS) was used to treat mice for establishing an in vivo sepsis model. The pathological changes in heart tissues were observed through hematoxylin-eosin (HE) staining. The levels of CK-MB, cTnl, MDA, SOD, IL-1β, IL-18, IL-6, and TNF-α in serum were detected through enzyme-linked immunosorbent assay (ELISA). The level of Fe2+ was assessed, and the protein expressions (ACSL4, GPX4, TRAF6, p-P65, and P65) were examined through western blot. The expressions of lncRNA MIAT and TRAF6 were measured through real-time quantitative polymerase chain reaction (RT-qPCR). Our results demonstrated that AOE treatment ameliorated sepsis-triggered myocardial damage by reducing the disordered cardiomyocytes, the destroyed sarcolemma, and the CK-MB and cTnl levels. In addition, AOE treatment inhibited sepsis-induced myocardial ferroptosis and inflammation by regulating Fe2+, ACSL4, GPX4, IL-1β, IL-18, IL-6, and TNF-α levels. Moreover, the improvement effect of AOE was strengthened with the increase in the dose of AOE (25, 50, 100 mg/kg). It was also revealed that AOE treatment retarded the lncRNA MIAT/TRAF6/NF-κB axis. Rescue assays manifested that overexpression of MIAT reduced the cardioprotective effect of AOE. In conclusion, AOE relieved sepsis-induced myocardial ferroptosis and inflammation by inhibiting lncRNA MIAT/TRAF6/NF-κB axis. These findings may provide a potential therapeutic drug for the treatment of sepsis.

Bioinformatics screening and verification of ischemic stroke-related key genes and drug prediction.

Stroke is one of the major causes of disability and death worldwide. The lack of effective medical treatment for stroke heightens the need for new therapeutic targets. In this study, we obtained two microarray data sets from the Gene Expression Omnibus (GEO) database and identified differential genes (DEGs) between MCAO and control groups. Then, enrichment analysis of the DEGs was performed using DAVID and Metascape. The results show 27 DEGs shared between the two datasets. The functional enrichment analysis showed that these genes are mainly enriched in immune response, complement and coagulation cascades, apoptotic processes. The four hub genes (C1qc, Fcgr2b, C1qb, and Cd14) were screened out using the Cytoscape. Next, real-time PCR and Western blot analysis showed that expression of C1q and CD14 increased at 14 days after tMCAO. Furthermore, we took eight small molecule compounds with the lowest score using Cmap and studied their background characteristics. These results are built on a meta-analysis of data, which are generally accessible from the online space. Finally, we evaluated the protective effect of the rolipram through behavior tests after tMCAO, and results showed that the rolipram significantly attenuated neurobehavioral dysfunction at 14 days after brain ischemia. The present results provide novel insights into the biological process and potential therapeutic drugs involved in stroke.

Unraveling Shared Diagnostic Biomarkers of Fibromyalgia in Ankylosing Spondylitis: Evidence from Comprehensive Bioinformatic Analysis and Experimental Validation.

Fibromyalgia (FM) is a commonly encountered disease featuring chronic generalized pain, sleep disorder, and physical fatigue. Ankylosing spondylitis (AS) causes chronic lumbodorsalgia involving the sacroiliac joint, often clinically complicated with FM. Nevertheless, the pathophysiology of FM secondary to AS is still lacking. Gene expression data of the whole blood in FM and AS patients were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were evaluated employing the "limma" package. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to explore common pathways. Weighted gene correlation network analysis (WGCNA) was adopted to screen key gene modules. Three machine learning algorithms were performed to refine the intersected genes. Single sample gene set enrichment analysis (ssGSEA) was applied to explore the relationships between hub genes and immune cells. The dependability of hub gene expressions in clinical blood specimens was verified by RT-PCR. Molecular docking was conducted to predict small molecular compounds targeting hub genes. DEG analysis screened 419 shared up-regulated and 179 shared down-regulated genes in FM and AS. A total of 143 common genes in positive modules of AS and FM were identified via WGCNA. Six key genes (CETN3, CACNA1E, OGT, QRFPR, SCOC, DIAPH1) were obtained by intersecting the WGCNA-derived shared genes and up-regulated DEGs. CETN3 and CACNA1E were refined as hub genes via three machine-learning algorithms and they showed excellent diagnostic value for FM and AS. However, ssGSEA exhibited different immune cell infiltration patterns in FM and AS. Gabapentin enacarbil was recognized as a potential therapeutic drug for AS-FM patients. This study reveals the shared hub genes in AS and FM. Meanwhile, these results were confirmed in clinical samples. CETN3 and CACNA1E may become potential diagnostic biomarkers and therapeutic targets for patients with AS complicated by FM.

Radiotracers for Molecular Imaging of Angiotensin-Converting Enzyme 2.

Angiotensin-converting enzymes (ACE) are well-known for their roles in both blood pressure regulation via the renin-angiotensin system as well as functions in fertility, immunity, hematopoiesis, and many others. The two main isoforms of ACE include ACE and ACE-2 (ACE2). Both isoforms have similar structures and mediate numerous effects on the cardiovascular system. Most remarkably, ACE2 serves as an entry receptor for SARS-CoV-2. Understanding the interaction between the virus and ACE2 is vital to combating the disease and preventing a similar pandemic in the future. Noninvasive imaging techniques such as positron emission tomography and single photon emission computed tomography could noninvasively and quantitatively assess in vivo ACE2 expression levels. ACE2-targeted imaging can be used as a valuable tool to better understand the mechanism of the infection process and the potential roles of ACE2 in homeostasis and related diseases. Together, this information can aid in the identification of potential therapeutic drugs for infectious diseases, cancer, and many ACE2-related diseases. The present review summarized the state-of-the-art radiotracers for ACE2 imaging, including their chemical design, pharmacological properties, radiochemistry, as well as preclinical and human molecular imaging findings. We also discussed the advantages and limitations of the currently developed ACE2-specific radiotracers.

Gut microecology: effective targets for natural products to modulate uric acid metabolism.

Gut microecology,the complex community consisting of microorganisms and their microenvironments in the gastrointestinal tract, plays a vital role in maintaining overall health and regulating various physiological and pathological processes. Recent studies have highlighted the significant impact of gut microecology on the regulation of uric acid metabolism. Natural products, including monomers, extracts, and traditional Chinese medicine formulations derived from natural sources such as plants, animals, and microorganisms, have also been investigated for their potential role in modulating uric acid metabolism. According to research, The stability of gut microecology is a crucial link for natural products to maintain healthy uric acid metabolism and reduce hyperuricemia-related diseases. Herein, we review the recent advanced evidence revealing the bidirectional regulation between gut microecology and uric acid metabolism. And separately summarize the key evidence of natural extracts and herbal formulations in regulating both aspects. In addition,we elucidated the important mechanisms of natural products in regulating uric acid metabolism and secondary diseases through gut microecology, especially by modulating the composition of gut microbiota, gut mucosal barrier, inflammatory response, purine catalyzation, and associated transporters. This review may offer a novel insight into uric acid and its associated disorders management and highlight a perspective for exploring its potential therapeutic drugs from natural products.

Identification of RCAN1’s role in hepatocellular carcinoma using single-cell analysis

BackgroundThe regulator of calcineurin 1 (RCAN1) is expressed in multiple organs, including the heart, liver, brain, and kidney, and is closely linked to the pathogenesis of cardiovascular diseases, Down syndrome, and Alzheimer’s disease. It is also implicated in the development of various organ tumors; however, its potential role in hepatocellular carcinoma (HCC) remains poorly understood. Therefore, the objective of this study was to investigate the potential mechanisms of RCAN1 in HCC through bioinformatics analysis.MethodsWe conducted a joint analysis based on the NCBI and TCGA databases, integrating both bulk transcriptome and single-cell analyses to examine the principal biological functions of RCAN1 in HCC, as well as its roles related to phenotype, metabolism, and cell communication. Subsequently, an RCAN1-overexpressing cell line was established, and the effects of RCAN1 on tumor cells were validated through in vitro experiments. Moreover, we endeavored to identify potential related drugs using molecular docking and molecular dynamics simulations.ResultsThe expression of RCAN1 was found to be downregulated in 19 types of cancer tissues and upregulated in 11 types of cancer tissues. Higher levels of RCAN1 expression were associated with improved patient survival. RCAN1 was predominantly expressed in hepatocytes, macrophages, endothelial cells, and monocytes, and its high expression not only closely correlated with the distribution of cells related to the HCC phenotype but also with the distribution of HCC cells themselves. Additionally, Rcan1 may directly or indirectly participate in metabolic pathways such as alanine, aspartate, and glutamate metabolism, as well as butanoate metabolism, thereby influencing tumor cell proliferation and migration. In vitro experiments confirmed that RCAN1 overexpression promoted apoptosis while inhibiting proliferation and invasion of HCC cells. Through molecular docking of 1615 drugs, we screened brompheniramine as a potential target drug and verified our results by molecular dynamics.ConclusionIn this study, we revealed the relationship between RCAN1 and HCC through bioinformatics methods, verified that RCAN1 can affect the progress of the disease through experiments, and finally identified potential therapeutic drugs through drug molecular docking and molecular dynamics.

The novel peptide PEP-Z-2 potentially treats renal fibrosis in vivo and in vitro by regulating TGF-β/Smad/AKT/MAPK signaling

Renal fibrosis is a process in which excessive deposition of extracellular matrix leads to an increase in tissue hardness and gradual destruction of the renal parenchyma. Chronic kidney disease (CKD) commonly progresses to end-stage renal disease (ESRD), ultimately leading to renal failure. This disease has high incidence and mortality rates, but to date, effective treatment options are lacking. PEP-Z-2 is a collagen peptide isolated from redlip croaker scales and may have potential fibroprotective activity. In this study, PEP-Z-2 was found to alleviate unilateral ureteral obstruction (UUO)- and folic acid (FA)-induced kidney injury in a mouse model, reduce collagen deposition in tissues, normalize renal function, reduce the expression of fibrosis markers, reduce reactive oxygen species (ROS) production, and restore the balance of the oxidant/antioxidant system. In vitro experiments also demonstrated that PEP-Z-2 inhibits the TGF-β-induced differentiation of fibroblasts and renal tubular epithelial cells into myofibroblasts and reduces the production of extracellular matrix (ECM) proteins such as fibronectin, Col I, and α-SMA, demonstrating notable therapeutic effects on renal fibrosis. This effect is achieved by regulating the TGF-β/Smad/AKT/MAPK pathway. Our research suggested that PEP-Z-2 is a potential therapeutic drug for renal fibrosis, and peptides from aquatic organisms may constitute a new class of candidate drugs for the treatment of renal fibrosis and even other types of organ fibrosis.

Identification of key immune-related genes and potential therapeutic drugs in diabetic nephropathy based on machine learning algorithms

BackgroundDiabetic nephropathy (DN) is a major contributor to chronic kidney disease. This study aims to identify immune biomarkers and potential therapeutic drugs in DN.MethodsWe analyzed two DN microarray datasets (GSE96804 and GSE30528) for differentially expressed genes (DEGs) using the Limma package, overlapping them with immune-related genes from ImmPort and InnateDB. LASSO regression, SVM-RFE, and random forest analysis identified four hub genes (EGF, PLTP, RGS2, PTGDS) as proficient predictors of DN. The model achieved an AUC of 0.995 and was validated on GSE142025. Single-cell RNA data (GSE183276) revealed increased hub gene expression in epithelial cells. CIBERSORT analysis showed differences in immune cell proportions between DN patients and controls, with the hub genes correlating positively with neutrophil infiltration. Molecular docking identified potential drugs: cysteamine, eltrombopag, and DMSO. And qPCR and western blot assays were used to confirm the expressions of the four hub genes.ResultsAnalysis found 95 and 88 distinctively expressed immune genes in the two DN datasets, with 14 consistently differentially expressed immune-related genes. After machine learning algorithms, EGF, PLTP, RGS2, PTGDS were identified as the immune-related hub genes associated with DN. In addition, the mRNA and protein levels of them were obviously elevated in HK-2 cells treated with glucose for 24 h, as well as their mRNA expressions in kidney tissues of mice with DN.ConclusionThis study identified 4 hub immune-related genes (EGF, PLTP, RGS2, PTGDS), as well as their expression profiles and the correlation with immune cell infiltration in DN.

Modelling and drug targeting of a myeloid neoplasm with atypical 3q26/MECOM rearrangement using patient-specific iPSCs.

Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment.

Stack-HDAC3i: A high-precision identification of HDAC3 inhibitors by exploiting a stacked ensemble-learning framework

Epigenetics involves reversible modifications in gene expression without altering the genetic code itself. Among these modifications, histone deacetylases (HDACs) play a key role by removing acetyl groups from lysine residues on histones. Overexpression of HDACs is linked to the proliferation and survival of tumor cells. To combat this, HDAC inhibitors (HDACi) are commonly used in cancer treatments. However, pan-HDAC inhibition can lead to numerous side effects. Therefore, isoform-selective HDAC inhibitors, such as HDAC3i, could be advantageous for treating various medical conditions while minimizing off-target effects. To date, computational approaches that use only the SMILES notation without any experimental evidence have become increasingly popular and necessary for the initial discovery of novel potential therapeutic drugs. In this study, we develop an innovative and high-precision stacked-ensemble framework, called Stack-HDAC3i, which can directly identify HDAC3i using only the SMILES notation. Using an up-to-date benchmark dataset, we first employed both molecular descriptors and Mol2Vec embeddings to generate feature representations that cover multi-view information embedded in HDAC3i, such as structural and contextual information. Subsequently, these feature representations were used to train baseline models using nine popular ML algorithms. Finally, the probabilistic features derived from the selected baseline models were fused to construct the final stacked model. Both cross-validation and independent tests showed that Stack-HDAC3i is a high-accuracy prediction model with great generalization ability for identifying HDAC3i. Furthermore, in the independent test, Stack-HDAC3i achieved an accuracy of 0.926 and Matthew’s correlation coefficient of 0.850, which are 0.44–6.11% and 0.83–11.90% higher than its constituent baseline models, respectively.

Identification of a Novel Activated NK-Associated Gene Score Associated with Diagnosis and Biological Therapy Response in Ulcerative Colitis

Introduction: Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. Methods: Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the “Batch correction” and “Robust rank aggregation” (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by “AddModuleScore” and “AUCell.” Results: Immune infiltration analysis revealed a higher abundance of activated NK cells in noninflamed UC tissues (ssGSEA, p < 0.001; CIBERSORT, p < 0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (p < 0.001) and in biological therapy nonresponders (NR) tissues before treatment (golimumab, p < 0.05; ustekinumab, p < 0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, p < 0.05; ustekinumab, p < 0.001). Conclusion: This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment.