Jing Liang | PubMed Health

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↗

PubMed2026

Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage.

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of prostate cancers but it is not understood how cells adapt to declining activity of this major transcription elongation kinase. To probe this response, we developed a cell line resistant to an inhibitor targeting CDK12 and its paralog, CDK13. CDK13 can compensate for the loss of CDK12, which is why we used the dual inhibitor THZ531. Targeted drug screening of the parental and resistant cell lines revealed cross-resistance to other transcriptional kinases but no clear acquired point of vulnerability. Using genome-wide mapping of mRNA-stabilization based on metabolic labelling of RNA, we report selective mRNA stabilization of factors promoting oxidative phosphorylation in the resistant cells. We go on to show that loss of CDK12 activity enhances ATP production both in cell line models and in patient tumours. Finally, we show that dual inhibition of CDK12/13 results in excessive phosphorylation of the DNA damage H2AX in prostate cancer cells but not in our CDK12/13 inhibitor-resistant model system. In brief, we propose that inactivation of CDK12 rewires cellular energy metabolism to suppress DNA damage.

Humans↗