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PubMed2026

Identification and expression validation of key genes of Xiaozhengtongluo formula in the treatment of diabetic nephropathy by Mendelian randomization.

Xiaozhengtongluo formula (XZTL) has a positive effect on the treatment of diabetic nephropathy (DN), but its mechanism is not fully understood. Therefore, it is important to explore the key genes of XZTL in the treatment of DN. Differentially expressed genes (DEGs) between DN and control obtained from GSE96804, drug target genes of XZTL, and disease target genes of DN obtained from public databases were intersected. Genes of intersection were defined as candidate genes. Next, Mendelian randomization (MR) analysis was used to ascertain the causal associations between candidate genes and DN. Afterwards, key genes were confirmed through receiver operating characteristic (ROC) curve analysis and expression validation. Subsequently, enrichment analysis, molecular regulatory network analysis, and molecular docking were conducted. Finally, experimental verification of the expression levels of key genes was performed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Altogether, 29 candidate genes were screened via MR analysis, identifying APOD, IGFBP3, and LPL as significantly associated with DN. IGFBP3 and APOD were risk factors, whereas LPL was protective. Consistent expression trends across training and validation datasets defined them as key genes. All three were co-enriched in 26 pathways, including oxidative phosphorylation. Regulatory networks showed MIR497HG/hsa-miR-19a-3p regulated IGFBP3, and NEAT1/hsa-miR-29a-3p regulated LPL; IGFBP3 and LPL were co-targeted by SP3 and SP1. Molecular docking revealed APOD-baicalein, LPL-oleic acid, and IGFBP3-quercetin binding, suggesting therapeutic potential. RT-qPCR confirmed aberrant expression of these genes in DN, which was normalized by XZTL intervention. In this study, three key genes (APOD, IGFBP3, and LPL) of XZTL in the treatment of DN were finally obtained, providing mechanistic clues for understanding XZTL's multi-target mechanism and providing experimentally tractable candidate targets for DN molecular subtyping, targeted therapeutic development, and precision medicine approaches in TCM.

Diabetic Nephropathies↗

PubMed2025

A multifaceted investigation into the impact of m6A methylation-related genes on pancreatic cancer, integrating insights from various databases and foundational experimental research.

BACKGROUND: Despite advances in surgical techniques, immunotherapy, the mortality rate associated with pancreatic cancer (PC) has been on the rise in recent years. Understanding the importance of RNA N6-methyladenosine (m6A) in PC is critical for prognosis, tumor microenvironment, and immunotherapy efficacy. The study aims to identify m6A methylation regulators that play an important role in the development and progression of PC by mining databases. The effect of insulin-like growth factor-binding protein 3 (IGFBP3) on pancreatic tumors was explored, and the related mechanisms were explored. METHODS: We analyzed the expression of m6A regulators in PC by digging deeper into the datasets of The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, and analyzed its relationship with the prognosis of patients with PC, looking for m6A methylation regulators that play an important role in the development and progression of PC. Reuse the ConsensusClusterPlus package, Cox analysis, and unsupervised clustering to delineate three distinct m6A clusters - designated as m6A cluster A, m6A cluster B, and m6A cluster C single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses evaluated the different pathway roles of these clusters in the development and progression of PC. Finally, the cell lines with IGFBP3 overexpression and knockdown were constructed by lentivirus transfection, the transfection effect was identified by WB, and the effects of IGFBP3 overexpression/knockdown on the survival and growth of PC cell lines were verified by cell cloning experiments and cell counting kit-8 experiments, and the possible related pathways were explored by KEGG. RESULTS: Most m6A regulatory factors are highly expressed in PC, and their high expression is negatively correlated with the prognosis of patients with PC. Furthermore, m6A regulatory factors may influence the occurrence and development of PC through metabolic pathways, stroma activation pathways, immune regulatory processes, and the immune microenvironment. Finally, the overexpression of IGFBP3 promoted the growth of PC cells, and vice versa. CONCLUSIONS: Most m6A regulatory factors are differentially expressed in PC and are associated with the prognosis of patients with PC, potentially influencing the occurrence and development of PC through pathways such as the immune microenvironment. The overexpression of IGFBP3 can promote the growth of PC cells and vice versa.

IGFBP3↗

PubMed1992

Endothelial cells express insulin-like growth factor-binding proteins 2 to 6.

Cultured endothelial cells have been shown to produce insulin-like growth factor-binding proteins (IGFBPs); however, the identity of these BPs has not been defined. We now demonstrate that cultured bovine endothelial cells produce IGFBP2, IGFBP3, and IGFBP4 and have mRNA specific for IGFBP2, -3, -4, -5 and -6. DNA probes for bovine IGFBP2-6 were obtained by polymerase chain reaction (PCR) amplification of cDNA from bovine large vessel pulmonary artery and aortic endothelial cells as well as omental and periaortic fat microvessel cells, using oligonucleotide primers whose sequences were based on the reported cDNA sequences of IGFBP2-6. The PCR-derived probes were labeled with 32P and used for Northern blot analysis of RNAs obtained from the four bovine endothelial cell types. Transcripts corresponding to IGFBP2-6 were found in RNA from large vessel endothelial cells (bovine pulmonary artery and bovine aorta) and microvessel cells (periaortic and omental fat). The PCR-derived probe for IGFBP4 was used to screen a bovine pulmonary artery cDNA library for a full-length bovine IGFBP4 cDNA clone. One positive clone, containing a single EcoRI insert of approximately 2.0 kilobases, was selected for further characterization by DNA sequence analysis. This clone contained an open reading frame encoding a 258-amino acid protein that was 97% identical to human IGFBP4, 268 basepairs of 5'-untranslated region, and a longer 1044 basepairs of 3'-untranslated region. IGFBP4 protein was purified from bovine pulmonary artery-conditioned medium, shown to have N-terminal amino acid sequence DEAIHCPPCSEEKLARCR (identical to human IGFBP4) and to be secreted in glycosylated and nonglycosylated forms. Immunoblots further demonstrated that microvessel cells, at early passage, secrete predominantly IGFBP2 and IGFBP3, while large vessel cells, at early and late passages, secrete IGFBP3 and IGFBP4. Thus, cultured bovine endothelial cells synthesize and secrete IGFBP2, IGFBP3, and IGFBP4 and have mRNA encoding IGFBP2-6. The production of specific IGFBPs by endothelial cells raises the interesting possibility that the vascular endothelium contributes to circulating and tissue levels of specific IGFBPs in vivo.

Adipose Tissue↗

PubMed2025

Novel insights into hypoxia-driven transcriptomic and epigenetic landscapes in grade 3 meningioma.

BACKGROUND: Meningiomas are among the most prevalent central nervous system (CNS) tumors, with up to 20% of cases exhibiting recurrence or aggressive behavior. Hypoxia is a key driver of malignant transformation and therapeutic resistance, yet its molecular basis in meningioma remains poorly understood. METHODS: We conducted integrative transcriptomic and epigenomic profiling of IOMM-Lee cells (grade 3 meningioma) cultured under hypoxic (0.2% O₂) and normoxic conditions. RNA-sequencing and Illumina MethylationEPIC v2.0 data were analyzed in R using DESeq2 and minfi, respectively. Functional enrichment, transcription-factor binding analysis, and pathway mapping (clusterProfiler, enrichR) were performed. Findings were cross-validated in public meningioma datasets, in Indian meningioma patient cohort and cell line via RT-qPCR, and azacytidine-based demethylation assay. Functional role of the candidate gene was elucidated in vitro via cellular assays. RESULTS: Hypoxia triggered a canonical HIF1A-driven transcriptional program activating glycolytic and angiogenic pathways while downregulating genes associated with DNA repair and replication in meningioma. Several differentially expressed genes (DEGs) were identified as known oncogenes, tumor-suppressors, or associated with immune regulation and stemness. Promoter motif analysis identified HIF1, SP1, TP53, BRCA1, and E2F1 as enriched transcriptional regulators. We validated hypoxia and HIF1-mediated regulation of some of the top DEGs. DNA-methylation analysis revealed epigenetic silencing of RTN4IP1 and ZBTB7C under hypoxia, reversible upon azacytidine treatment. Integrative comparison with patient datasets highlighted SLITRK2, PDE4C, SGCD, and LRP1B as hypoxia-responsive genes associated with poor prognosis. Several hypoxia-regulated genes also showed significant correlation with known hypoxia biomarkers, VEGFA and CA9. IGFBP3 and NDRG1 were among the top hypoxia-associated upregulated genes, and IGFBP3 expression was linked to advanced meningioma grades. Knockdown of IGFBP3 via siRNA in hypoxia-treated IOMM-Lee cells was associated with reduced cell proliferation and migration. CONCLUSIONS: This study presents the first integrated transcriptomic–epigenomic landscape of hypoxia in grade 3 meningioma, uncovering regulatory networks and candidate biomarkers with prognostic and therapeutic potential. These findings provide a foundation for future translational studies targeting hypoxia-driven tumor progression in meningioma.

Humans↗

PubMed2026

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.

Despite the substantial variability in physical function among older adults, the molecular mechanisms remain poorly characterized, particularly within skeletal muscle. This study aimed to determine the patterns of DNA methylation in skeletal muscle associated with physical function in healthy older adults. We analyzed DNA methylation (EPIC v2 array; 875,554 CpG sites) in skeletal muscle from 92 healthy older adults (median age 74; 62% female). Associations were examined across five phenotypes: Short Physical Performance Battery (SPPB), 6-min walk test (6MWT), handgrip strength, perceived disability (PAT-D), and lifestyle health (modified Life's Essential 8). Linear regression models adjusted for age, sex, race, BMI, and muscle fiber composition. Genomic inflation corrected via the BACON method (FDR < 0.05). Gene set enrichment analysis was performed on suggestive hits (FDR < 0.1). We identified significant differentially methylated probes (DMPs) and regions (DMRs) across all phenotypes: SPPB (70 DMPs, 22 DMRs), 6MWT (16 DMPs, 566 DMRs), handgrip strength (2 DMRs), PAT-D (19 DMPs, 1 DMR), and lifestyle health (2 DMPs). DMRs largely overlapped promoters. Identified genes overlapped known musculoskeletal and neurological GWAS hits, including RUNX2 and FOXL1 (bone mineral density), IGFBP3 (muscle mass), and NEK1 and SHANK1 (neurological function). Enrichment analysis revealed that 6MWT-associated genes relate to nervous and skeletal system development, while handgrip-associated genes involve cytoskeletal dynamics and protein assembly. Epigenetic variation in aging skeletal muscle is associated with physical function. The enrichment of pathways related to nervous and musculoskeletal development suggests specific epigenetic mechanisms underlying functional decline, offering potential targets for intervention in older adults.

DNA methylation↗

PubMed1991

Structure and localization of the human insulin-like growth factor-binding protein 2 gene.

Insulin-like growth factor binding proteins (IGFBPs) are extracellular proteins that specifically bind IGF and modulate their effects. The human IGFBP2 gene was studied and shown to be localized to chromosome 2 region q33-q34, by somatic cell hybrid analysis and in situ hybridization. Structural characterization of the gene showed that it consists of four exons with three introns of lengths 27.0, 1.0, and 1.9 kilobase-pairs. Comparison of the encoded protein sequence of each exon in IGFBP1, 2, and 3 reveals the highest amino acid identity, 28%, in exon 1, while the lowest was found in exon 2. However, pairwise sequence comparisons demonstrate 50% identity between the protein sequences encoded by exon 4 in IGFBP1 and 2, while their respective identities with IGFBP3 are only 25 and 30%.

Amino Acid Sequence↗

PubMed2025

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.

The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

Humans↗

PubMed1992

Anatomy of the pituitary insulin-like growth factor system.

In situ hybridization was used to map patterns of gene expression for components of the insulin-like growth factor (IGF) system, including IGF-I and -II, IGF-binding proteins 1-5 (IGFBP1-5), the IGF-I receptor, and GH in the rat pituitary. IGF-I mRNA was concentrated in isolated cells scattered throughout the gland with features typical of nonendocrine folliculo-stellate cells. IGF-II mRNA was abundant in neural (NL) and intermediate lobe (IL) capillaries, and low levels were present in endocrine cells of anterior lobe (AL) and IL. IGFBP1 mRNA was not detected in the pituitary. IGFBP2 mRNA was concentrated in epithelial cells lining AL follicles and in astroglial-like cells (pituicytes) of the NL. IGFBP3 mRNA was localized in isolated cells scattered throughout the AL and NL. IGFBP4 mRNA was relatively abundant in NL pituicytes and was diffusely expressed in the AL. IGFBP5 mRNA was equally abundant in NL and AL, and was localized in folliculo-stellate and epithelial cells of the AL and pituicytes and capillaries of the NL. Neither IGF-I nor IGFBP1-5 were detected in the IL. IGF-I receptor mRNA was abundant and homogeneously distributed throughout the AL and IL, compatible with expression by endocrine cells. There was overlap, but no particular correlation, between IGF system gene expression and GH-producing cells, which were clustered in the dorsal-lateral wings of the AL. In summary, IGF system gene expression is bountiful in the rat pituitary, but does not correlate with sites of GH synthesis. IGF-I receptor mRNA, which might have been expected to localize to somatotrophs, appears to be equally abundant in all of the endocrine cells of both AL and IL; the other constituents of the IGF system are localized in connective tissue and support elements that demonstrate no special anatomical relationship to somatotrophs. Finally, there is remarkably abundant gene expression for IGFBP2, -4, and -5 in the NL.

Animals↗

PubMed2026

Prognostic value of genes associated with metastasis and propionate metabolism in rectal cancer.

BACKGROUND: Research indicates that alterations in propionate metabolic pathways play a critical role in cancer development and invasion. Postoperative metastatic recurrence remains a major cause of mortality in patients with rectal cancer. However, propionate metabolism-related genes (PMRGs) in rectal cancer remain insufficiently characterized. Therefore, this study aimed to identify prognostic biomarkers associated with lymph node metastasis and propionate metabolism and construct a risk‑prediction model for rectal cancer via bioinformatic analyses. METHODS: The Cancer Genome Atlas-Rectum Adenocarcinoma (TCGA-READ) and GSE87211 datasets, together with a curated PMRGs gene set, were used in this study. Pearson correlation analysis was performed to assess associations between overlapping genes (differentially expressed genes between READ and normal tissues, as well as between N0 and N1-N2 stages) and PMRGs, leading to the identification of candidate genes. Functional enrichment analyses were subsequently conducted to characterize the biological roles of these candidates. Prognostic biomarkers were identified using univariate Cox regression combined with least absolute shrinkage and selection operator (LASSO) regression, and a prognostic model was constructed accordingly. Independent prognostic validation was then performed. In addition, immune checkpoint profiling and immunotherapy response analyses were conducted across risk subgroups. Single-gene Gene Set Enrichment Analysis (GSEA) was applied to elucidate the pathways associated with the identified biomarkers. Finally, drug sensitivity analyses were performed. RESULTS: A total of 157 candidate genes were identified through the analytical pipeline. Functional enrichment analysis indicated that these genes were primarily involved in inflammatory response regulation and tumor necrosis factor (TNF) signaling pathways. Five prognostic biomarkers were subsequently identified and incorporated into a predictive model. External validation using the GSE87211 cohort confirmed the robustness of the model. Risk score and disease status were identified as independent prognostic factors. Six immune checkpoint molecules exhibited differential expression between risk groups. Correlation analyses revealed that the risk score was positively associated with most immune checkpoint genes. Single-gene GSEA demonstrated that the biomarkers were mainly enriched in ribosomal biogenesis and cell adhesion molecule-related pathways. Furthermore, 51 therapeutic agents exhibited significantly different half-maximal inhibitory concentration (IC50) values between risk subgroups. CONCLUSIONS: This study identified five biomarkers (CCL24, IGFBP3, ODC1, PYGM, and VKORC1) associated with lymph node metastasis and propionate metabolism pathways, providing a potential foundation for prognostic prediction in patients with rectal cancer.

Rectal cancer↗

PubMed1991

[Somatomedins].

Somatomedins or insulin-like growth factors (IGFs) are two polypeptides (IGF I and IGF II) whose structure shows great homology with proinsulin. Mostly synthetized by the liver but also by many tissues, they circulate in blood bound to specific binding proteins (IGFBPs). IGFBP3, a 120 to 150 kDa complex, carries over 95% of blood IGFs and its production is stimulated by growth hormone (hGH). On the contrary, IGFBP1, a 40 to 50 kDa protein, increases in case of hGH-deficiency. An IGFBP of 34 kDa, which is the major BP in cerebrospinal fluid but also present in blood, shows a great affinity for IGF II whereas the others BPs show similar affinities for both IGFs. Little is known about the other BP, IGFBP2. Two receptors can be found in most tissues: type 1, which binds IGFs and insulin, type 2, which binds IGF II preferentially to IGF I but not insulin. Type 1 IGF receptor has structural and enzymatic (phosphorylation of one of its own sub-units) similarities with the insulin receptor and mediates the action of IGF I. Type 2 receptor has an homology with the bovine cation-dependent mannose-6-phosphate receptor and has no known function. Liver production of IGF I is mainly under the control of hGH and other factors such as diet; other tissues are less or not at all under the control of hGH. The blood levels of IGF I raise from birth to the end of puberty, then decrease and remain almost stable during adulthood. The activity of IGF I on skeletal growth is well established and the determination of its plasma levels by radioimmunoassay is of great clinical utility in the diagnosis of growth disorders. IGF I levels in blood are high in case of acromegaly, low in hGH-deficiency, undernutrition, hypothyroidy and renal failure. IGF I acts in an autocrine/paracrine way and probably endocrine sometimes. How IGF II synthesis is regulated is not well known, in any case, IGF II has no effect on growth and the regulation of its secretion is hardly influenced by hGH, its blood levels remain unchanged in acromegaly and are irregularly diminished in hGH-deficiency. Moreover, IGF I and II promote cellular growth and differentiation. This activity could be of great importance during fetal life.

Animals↗