Search Results (23)

Background/Objectives: Glomerular diseases (GD) possess strong polygenic susceptibility, yet exact causal genes remain unclear because most variants identified by genome-wide association studies (GWAS) reside in non-coding regions. While transcriptome-wide association studies (TWAS) effectively decode complex traits, cross-tissue profiling for GD remains largely unexplored. Therefore, this study employs an integrative cross-tissue TWAS and Mendelian randomization framework to systematically identify and validate novel GD susceptibility genes. Methods: We conducted a systematic cross-tissue TWAS integrating Genotype-Tissue Expression (GTEx) v8 eQTL data across 49 tissues. Candidate genes were nominated using five complementary frameworks (sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)). Findings were refined via Mendelian randomization (MR), pathway enrichment, protein interaction networks, and druggability profiling. Results: We identified 21 candidate susceptibility genes for GD, with 10 genes (AGER, C6orf48, CSNK2B, CYP21A2, HLA-DRB1, HSD17B8, LST1, MICB, PRRT1, TCF19) strongly supported by MR analysis. Notably, five of these MR-prioritized genes (C6orf48, CSNK2B, HSD17B8, LST1, and PRRT1) were previously unreported. Functionally, these prioritized genes are primarily involved in immune modulation, inflammation, and steroid metabolism. Furthermore, five genes (AGER, CSNK2B, CYP21A2, HLA-DRB1 and MICB) were identified as potentially druggable targets. Conclusions: This first systematic cross-tissue TWAS of GD prioritizes a set of genetically supported susceptibility genes. By uncovering novel drivers and druggable proteins, this study advances the mechanistic understanding of GD and provides a foundation for future therapeutic development and precision nephrology. Full article

Nuclear factor kappa B (NF-κB) signaling plays a central role in inflammation, immunity, cell survival, and cancer progression. Its constitutive activation is frequently observed in breast cancer, contributing to tumor growth, treatment resistance, and metastasis. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and may modulate NF-κB signaling in a subtype-specific or -independent manner. The aim of the study was to identify miRNAs that may potentially regulate the activity of genes associated with NF-κB signaling across five molecular subtypes of breast cancer in Polish women. Tumor and matched normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (TNBC, n = 43). Expression profile of selected NF-κB-related genes were evaluated using mRNA microarrays and RT-qPCR. Protein levels were assessed by ELISA. Candidate regulatory miRNAs were identified via miRNA microarrays and validated using the miRDB database. A consistent upregulation of MAP3K7, TAB2, TNFAIP3, CSNK2A1, BCL2L1, XIAP, CXCL2, and PLAU was observed across all subtypes, suggesting activation of canonical NF-κB signaling. Downregulation of specific miRNAs, miR-1297 and miR-30a (targeting MAP3K7), miR-134 (TAB2), miR-125b (TNFAIP3), and miR-4329 (XIAP), may contribute to this deregulation. For CSNK2A1, BCL2L1, CXCL2, and PLAU, no regulatory miRNAs meeting our criteria were identified. Our study reveals a subtype-independent activation of the canonical NF-κB signaling pathway in breast cancer, underpinned by consistent upregulation of key components (at both the transcript and protein levels. Dysregulation of specific miRNAs likely contributes to this altered gene expression. These findings suggest the presence of a common NF-κB-driven oncogenic program across molecular subtypes, with potential implications for developing miRNA-based therapeutic strategies targeting inflammation, survival signaling, and treatment resistance in breast cancer. Full article

Neurodevelopmental disorders (NDDs) represent significant public health challenges due to their multifactorial etiology and clinical heterogeneity. Current treatments remain limited, highlighting the need for novel therapeutic strategies. This study aimed to identify neuroprotective natural compounds targeting NDD-associated pathways and describe an integrative computational pipeline combining in silico screening, network pharmacology, and molecular docking approaches to accelerate NDD drug discovery. An integrative computational pipeline was developed through sequential phases: (1) systematic screening of the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) for natural compounds meeting drug-likeness criteria and toxicity thresholds; (2) biological activity prediction; (3) network pharmacology analysis integrating compound targets and NDD-associated genes; (4) protein–protein interaction network construction and functional enrichment; and (5) molecular docking validation of top compounds against prioritized targets. From 2634 initial compounds, 10 met all selection criteria. Network analysis revealed significant interactions between compound targets and NDD-associated genes, with enrichment in neurodevelopment, cognition, and synaptic regulation pathways. Three key targets emerged as hubs: CSNK2B, GRIN1, and MAPK1. Molecular docking demonstrated high-affinity binding of caryophyllene oxide, linoleic acid, and tangeretin, supported by stable interactions with catalytic residues. This study identifies caryophyllene oxide, linoleic acid, and tangeretin as promising multi-target compounds for NDD intervention, with verified interactions against key neurodevelopmental targets. The integrative computational pipeline effectively bridges traditional medicine knowledge with modern drug discovery, offering a strategy to accelerate neurotherapeutic development while reducing experimental costs. These findings warrant further experimental validation of the prioritized compounds. Full article

CK2α is a kinase important for essential cellular and biological processes. CK2α is ubiquitously expressed, albeit at different tissue levels, and its transcript levels are dysregulated in disease. However, there is limited knowledge on the regulation of CK2α gene expression. The best one studied, the human CSNK2A1 (CK2α) gene promoter, contains uncharacterized binding motifs for NF-κB. Our goal was to investigate the role of NF-κB in Csnk2a1 promoter regulation. We cloned the mouse Csnk2a1 promoter which had significant sequence homology with the human CSNK2A1 promoter. Using promoter deletions, we identified a minimal promoter region containing transcription factor motifs (NF-κB, Ets-1, Sp1) consistent with those published for the CSNK2A1 promoter. Electrophoretic mobility shift assays demonstrated specific NF-κB subunit binding to the minimal promoter. NF-κB subunit transfection and extracellular NF-κB stimulation in non-tumor cell lines led to increased transactivation of the mouse minimal promoter. These data, together with data on the regulation of NF-κB by CK2 kinase activity, suggest a positive-feedback loop between CK2α and NF-κB. Non-tumor cell line re-plating and increased percent confluence upregulated Csnk2a1 transcript levels which differed from tumor cell line published data. In summary, Csnk2a1 promoter is regulated by NF-κB signaling and during cellular proliferation. Full article

Paulownia fortunei are economically important trees in China. A greening mutant was used to study greening by comparative transcriptomics and proteomics using leaf tissues from wild-type and greening mutant growing under normal conditions. Chlorophyll content analysis showed a decrease in the chlorophyll b content in the mutant line. Non-parametric transcriptome and proteome analyses were performed to screen for genes and proteins active in the regulation of P. fortunei greening. qRT-PCR was carried out to confirm 10 genes identified in the transcriptome. In the transcriptome analysis, the pathways associated with the yellow phenotype included tRNA amino acid biosynthesis, nitrogen metabolism and circadian rhythm as represented by the genes encoding Vals, gltx, aspS, NR, GluL, gdhA, phyB, CSNK2A and CSNK2B. The iTRAQ-based proteomics analysis indicated that photosynthesis and carotenoid biosynthesis were altered in the chlorophyll-deficient P. fortunei and petH, petF, atpF and Z-ISO were the key proteins dysregulated in the greening mutants compared to the wild-type. Together, the transcriptomic and iTRAQ analyses identified 10 DEGs that were perturbed in the greening mutants in the main pathways of photosynthesis, starch and sucrose metabolism, glutathione metabolism and peroxisome functions. PetJ, E3.2.1.21, GST and CAT were differentially regulated in the chlorophyll-deficient mutant. Full article

The effects of zearalenone (ZEA), a fungal toxin in food and feed, remain unclear on the mammary gland and lactation. This study examines ZEA-induced damage in lactating mice and bovine mammary epithelial cells (MAC-T), focusing on the role of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway in regulating cell proliferation and apoptosis. The results demonstrated that exposure to ZEA at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg) reduced lactation in female mice and slowed weight gain in their offspring. Hematoxylin and eosin (HE) staining and CSNK immunofluorescence staining of mammary tissue confirmed ZEA-induced mammary gland damage in vivo. Further analysis using PCNA immunohistochemistry and fluorescent TUNEL staining revealed that ZEA promoted apoptosis and decreased the proliferative capacity of mammary tissues. In vitro, 20 μM ZEA decreased MAC-T cell proliferation, increased apoptosis and oxidative stress, inhibited PI3K/AKT signaling, and decreased κ-casein (CSNK) expression. Pretreatment with a reactive oxygen species (ROS) scavenger (NAC) or PI3K/AKT activator (740-Y-P) reversed these effects, with NAC specifically restoring PI3K/AKT activity inhibited by ZEA. Overall, this study concludes that ZEA induces MAC-T cell apoptosis and disrupts proliferation via the ROS-mediated PI3K/AKT pathway, ultimately impairing lactation function. These findings highlight potential targets for managing ZEA contamination in food and its impact on lactation. Full article

Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis and progression. Notably, CC chemokines (CCLs) have been shown to either promote or inhibit angiogenesis, metastasis, and immune responses in tumors, thereby influencing cancer development and patient outcomes. However, the diagnostic and prognostic significance of CCLs in CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that the mRNA expression levels of CCL3, CCL4, and CCL26 were significantly elevated in CRC tissues compared to normal tissues, whereas CCL2, CCL5, CCL11, CCL21, and CCL28 mRNA levels were markedly downregulated. Additionally, dysregulation of CCL4, CCL5, and CCL21 was strongly associated with clinical staging, and elevated levels of CCL4, CCL11, and CCL28 were linked to significantly prolonged survival in CRC patients. Functional enrichment analysis indicated that the cellular roles of CCLs were predominantly associated with the chemokine, Wnt, and Toll-like receptor signaling pathways, as well as protein kinase activity. Furthermore, transcriptional regulation of most CCLs involved RELA and NFKB1. Key downstream targets included members of the SRC family of tyrosine kinases (HCK, LYN, and LCK), serine/threonine kinases (ATR and ATM), and others such as CSNK1G2, NEK2, and CDK2. Moreover, CCLs (CCL2, CCL3, CCL4, CCL5, CCL11, CCL21, and CCL28) exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, and dendritic cells. In conclusion, our study provides novel insights into the potential utility of CCLs as biomarkers and therapeutic targets for CRC prevention and immunotherapy. Full article

CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2. Full article

Higher-grade meningiomas (WHO grade II and III) are characterized by aggressive invasiveness and high postoperative recurrence rates. The prognosis remains inadequate even with adjuvant radiotherapy and currently there is no definitive pharmacological treatment strategy and target for malignant meningiomas. This study aims to unveil the mechanisms driving the malignant progression of meningiomas and to identify potential inhibitory targets, with significant clinical implications. Implementing techniques such as protein immunoprecipitation, mass spectrometry, RNA interference, and transcriptome sequencing, we investigated the malignancy mechanisms in meningioma cell lines IOMM-LEE and CH157-MN. Additionally, in vivo experiments were carried out on nude mice. We discovered a positive correlation between meningioma malignancy and the levels of the receptor for activated C kinase 1 (RACK1), which interacts with CSNK2B, the β subunit of casein kinase 2 (CK2), inhibiting its ubiquitination and subsequent degradation. This inhibition allows CK2 to activate the NF-κb pathway, which increases the transcription of CDK4 and cyclin D3, resulting in the transition of the cell cycle into the G2/M phase. The RACK1 inhibitor, harringtonolide (HA), significantly suppressed the malignant tendencies of meningioma cells. Our study suggests that RACK1 may play a role in the malignant progression of meningiomas, and therefore, targeting RACK1 could emerge as an effective strategy for reducing the malignancy of these tumors. Full article

Oxygen level is an important environmental factor affecting the circadian rhythm. However, little is known about the molecular mechanism by which clock genes regulate the circadian rhythm in fish under hypoxia. To explore changes in the transcription and expression of clock genes and related molecular regulatory mechanisms in pearl gentian grouper under hypoxia, liver transcriptome data were analyzed after exposure to acute hypoxic stress (dissolved oxygen 0.5 mg/L) for 1, 3, 6, and 9 h. miR-210 and m0044-5p inhibited the expression of period3 (per3) and casein kinase 1 delta b (csnk1db) in the core loop of the circadian clock, respectively. The nuclear receptor subfamily 1 group d member 1 (nr1d1) and RAR-related orphan receptor b (rorb) genes in the auxiliary loop were jointly up-regulated by three miRNAs (miR-144-3p/5p, miR-361-5p, and miR-133) and the transcription factor nuclear receptor subfamily 1 group d member 2 (Nr1d2). The pearl gentian grouper maintains the stability of circadian clock systems and normal physiological metabolism under hypoxic stress by regulating the transcriptional expression of these genes via miRNAs and transcription factors to improve hypoxic tolerance. These findings provide important basic data for future research on hypoxic tolerance in pearl gentian grouper and provide new insights into the interaction between hypoxia and the circadian rhythm in fish. Full article

Protein kinase CK2 is a Ser/Thr protein kinase that phosphorylates hundreds of substrates mainly related to survival and proliferation pathways. It has long been considered an anti-cancer drug target. However, during the recent COVID-19 pandemic, CK2 inhibitors have been repurposed as anti-SARS-CoV-2 drugs. This was based on the initial finding of CK2 among the proteins of the host cell that interact with the viral proteins and modulate the infection. Since then, several studies have deepened our understanding of the CK2/COVID-19 connection, and we deem it is time to review all the findings. Interestingly, other coronaviruses cross-talk with CK2 as well, with similarities and differences compared to the SARS-CoV-2 case. Therefore, we believe that the analysis of the effects obtained by targeting CK2 in case of coronavirus infections, both at the molecular and phenomenological level, will help in extrapolating information that could be useful not only for COVID-19 (whose pandemic emergency is hopefully turning off) but also for other infections. Full article

The most aggressive primary malignant brain tumor in adults is glioblastoma (GBM), which has poor overall survival (OS). There is a high relapse rate among patients with GBM despite maximally safe surgery, radiation therapy, temozolomide (TMZ), and aggressive treatment. Hence, there is an urgent and unmet clinical need for new approaches to managing GBM. The current study identified modules (MYC, EGFR, PIK3CA, SUZ12, and SPRK2) involved in GBM disease through the NeDRex plugin. Furthermore, hub genes were identified in a comprehensive interaction network containing 7560 proteins related to GBM disease and 3860 proteins associated with signaling pathways involved in GBM. By integrating the results of the analyses mentioned above and again performing centrality analysis, eleven key genes involved in GBM disease were identified. ProteomicsDB and Gliovis databases were used for determining the gene expression in normal and tumor brain tissue. The NetworkAnalyst and the mGWAS-Explorer tools identified miRNAs, SNPs, and metabolites associated with these 11 genes. Moreover, a literature review of recent studies revealed other lists of metabolites related to GBM disease. The enrichment analysis of identified genes, miRNAs, and metabolites associated with GBM disease was performed using ExpressAnalyst, miEAA, and MetaboAnalyst tools. Further investigation of metabolite roles in GBM was performed using pathway, joint pathway, and network analyses. The results of this study allowed us to identify 11 genes (UBC, HDAC1, CTNNB1, TRIM28, CSNK2A1, RBBP4, TP53, APP, DAB1, PINK1, and RELN), five miRNAs (hsa-mir-221-3p, hsa-mir-30a-5p, hsa-mir-15a-5p, hsa-mir-130a-3p, and hsa-let-7b-5p), six metabolites (HDL, N6-acetyl-L-lysine, cholesterol, formate, N, N-dimethylglycine/xylose, and X2. piperidinone) and 15 distinct signaling pathways that play an indispensable role in GBM disease development. The identified top genes, miRNAs, and metabolite signatures can be targeted to establish early diagnostic methods and plan personalized GBM treatment strategies. Full article

There are several studies on the deregulated gene expression profiles in kidney cancer, with varying results depending on the tumor histology and other parameters. None of these, however, have identified the networks that the co-deregulated genes (co-DEGs), across different studies, create. Here, we reanalyzed 10 Gene Expression Omnibus (GEO) studies to detect and annotate co-deregulated signatures across different subtypes of kidney cancer or in single-gene perturbation experiments in kidney cancer cells and/or tissue. Using a systems biology approach, we aimed to decipher the networks they form along with their upstream regulators. Differential expression and upstream regulators, including transcription factors [MYC proto-oncogene (MYC), CCAAT enhancer binding protein delta (CEBPD), RELA proto-oncogene, NF-kB subunit (RELA), zinc finger MIZ-type containing 1 (ZMIZ1), negative elongation factor complex member E (NELFE) and Kruppel-like factor 4 (KLF4)] and protein kinases [Casein kinase 2 alpha 1 (CSNK2A1), mitogen-activated protein kinases 1 (MAPK1) and 14 (MAPK14), Sirtuin 1 (SIRT1), Cyclin dependent kinases 1 (CDK1) and 4 (CDK4), Homeodomain interacting protein kinase 2 (HIPK2) and Extracellular signal-regulated kinases 1 and 2 (ERK1/2)], were computed using the Characteristic Direction, as well as GEO2Enrichr and X2K, respectively, and further subjected to GO and KEGG pathways enrichment analyses. Furthermore, using CMap, DrugMatrix and the LINCS L1000 chemical perturbation databases, we highlight putative repurposing drugs, including Etoposide, Haloperidol, BW-B70C, Triamterene, Chlorphenesin, BRD-K79459005 and β-Estradiol 3-benzoate, among others, that may reverse the expression of the identified co-DEGs in kidney cancers. Of these, the cytotoxic effects of Etoposide, Catecholamine, Cyclosporin A, BW-B70C and Lasalocid sodium were validated in vitro. Overall, we identified critical co-DEGs across different subtypes in kidney cancer, and our results provide an innovative framework for their potential use in the future. Full article

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them. Full article

CSNK2 tetrameric holoenzyme is composed of two subunits with catalytic activity (CSNK2A1 and/or CSNK2A2) and two regulatory subunits (CSNK2B) and is involved in skeletal muscle homeostasis. Up-to-date, constitutive Csnk2a2 knockout mice demonstrated mild regenerative impairments in skeletal muscles, while conditional Csnk2b mice were linked to muscle weakness, impaired neuromuscular transmission, and metabolic and autophagic compromises. Here, for the first time, skeletal muscle-specific conditional Csnk2a1 mice were generated and characterized. The ablation of Csnk2a1 expression was ensured using a human skeletal actin-driven Cre reporter. In comparison with control mice, first, conditional knockout of CSNK2A1 resulted in age-dependent reduced grip strength. Muscle weakness was accompanied by impaired neuromuscular transmission. Second, the protein amount of other CSNK2 subunits was aberrantly changed. Third, the number of central nuclei in muscle fibers indicative of regeneration increased. Fourth, oxidative metabolism was impaired, reflected by an increase in cytochrome oxidase and accumulation of mitochondrial enzyme activity underneath the sarcolemma. Fifth, autophagic processes were stimulated. Sixth, NMJs were fragmented and accompanied by increased synaptic gene expression levels. Altogether, knockout of Csnk2a1 or Csnk2b results in diverse impairments of skeletal muscle biology. Full article