Journal Article

Capilliposide A attenuates diabetic nephropathy via modulation of NF-κB/TLR4 and apoptotic pathways

Tian, Jingkui, Man, Xueli, Pan, Xin, Jin, Juan, He, Qiang, Wang, Luping, Liao, Huajun, Ma, Jiahui

2025

Overview

This study aimed to identify therapeutic targets and signaling pathways of Capilliposide A (LC-A) for diabetic nephropathy (DN) through integrated network pharmacology and experimental validation. Using a DN mouse model induced by high-fat diet (HFD) and streptozotocin (STZ), we investigated the molecular mechanisms of LC-A. The PubChem database provided the two-dimensional structure of LC-A, with subsequent identification of LC-A/DN-associated targets through intersection analysis. Core targets were determined via protein–protein interaction (PPI) network construction, followed by gene ontology enrichment and pathway analyses. Molecular docking simulations evaluated LC-A's binding affinity to DN-related targets. C57BL/6 mice receiving HFD and STZ intraperitoneal injections were treated daily with LC-A or metformin (MET) via oral gavage for 8 weeks. Weekly monitoring included body weight and blood glucose measurements. Post-treatment assessments encompassed serum lipid profiles, renal function biomarkers, inflammatory cytokines, oxidative stress markers, and renal histopathology. Western blotting, immunohistochemistry, and immunofluorescence were performed to analyze inflammatory pathway proteins and apoptosis-related factors. Network pharmacology identified TLR4, NF-κB1, STAT3, EGFR, mTOR, and MAPK as core targets involved in inflammation, oxidative stress, and apoptosis regulation. Pathway enrichment analysis revealed critical inflammatory pathways including IL-17, TNF, and Th17 cell differentiation. Molecular docking confirmed stable binding of LC-A to TLR4, NF-κB1, Bax, and Bcl-2. In vivo experiments demonstrated that LC-A significantly reduced renal injury markers (KI, SCR, BUN), lipid profiles (TG, TC), and oxidative stress (MDA), while enhancing antioxidant enzymes (SOD, GPX, CAT) in DN mice ( P  < 0.05). LC-A effectively suppressed serum inflammatory cytokines (IL-6, TNF-α, IL-1β, MCP-1, iNOS) through NF-κB pathway modulation and apoptosis regulation ( P  < 0.05). Histopathological analysis revealed attenuated renal cortical vacuolization, tubular swelling, glomerular mesangial expansion, sclerosis, and inflammatory infiltration. These findings suggest LC-A as a promising natural nephroprotective agent for DN prevention and treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154/433 / 692/163 / 692/4022 / Animals / Apoptosis / Apoptosis - drug effects / Apoptotic pathway / BAX protein / Bcl-2 protein / Body weight / Capilliposide A / Cell differentiation / Cytokines / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - metabolism / Diabetic Nephropathies - drug therapy / Diabetic Nephropathies - etiology / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - pathology / Diabetic nephropathy / Diet, High-Fat - adverse effects / Drinking water / Drug dosages / Genes / Genomes / Helper cells / High fat diet / Histopathology / Humanities and Social Sciences / Hyperglycemia / Immunofluorescence / Immunohistochemistry / Inflammation / Interleukins / Kidney - drug effects / Kidney - metabolism / Kidney - pathology / Ligands / Lymphocytes T / Male / MAP kinase / Metformin / Mice / Mice, Inbred C57BL / Molecular docking / Molecular Docking Simulation / Molecular modelling / Monocyte chemoattractant protein 1 / multidisciplinary / Nephropathy / Network Pharmacology / NF-kappa B - metabolism / NF-κB protein / NF-κB/TLR4 pathway / Ontology / Oxidative stress / Oxidative Stress - drug effects / Pathogens / Pharmacology / Protein Interaction Maps - drug effects / Proteins / Renal function / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Software / Therapeutic targets / TLR4 protein / Toll-Like Receptor 4 - metabolism / Traditional Chinese medicine / Triterpenes - chemistry / Triterpenes - pharmacology / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Western blotting