Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear.Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests.Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD.Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2.Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.

Exploring the Protective Effect and Mechanism of Buddlejae Flos on Sodium Selenite-Induced Cataract in Rats by Network Pharmacology, Molecular Docking, and Experimental Validation

“…The Traditional Chinese Medicine Systems Pharmacology (TCMSP, https://tcmspw.com/tcmspsearch.php ) database was employed for screening the bioactive components of Buddlejae Flos [ 19 ]. In accordance to ADME, drug similarity (DL) > 0.18 and oral bioavailability (OB) 30% were established as threshold for screening (absorption, distribution, metabolism, and excretion) parameters [ 20 , 21 ]. To ensure reliable and comprehensive data, data collected from published literature were used to complement findings from TCMSP [ 22 – 24 ].…”

The effects and underlying mechanisms of medicine and food homologous flowers on the prevention and treatment of related diseases

“…In conclusion, CCT can inhibit oxidative stress, reduce inflammation and upregulate the expression of Nrf2 and HO‐1. It is a potential biologically active component for the treatment of NAFLD (Xu et al, 2021).…”

“…Homogenous" catalog. It contains flavonoids such as saffron glycosides and terpenoids such as saffron acid and saffron aldehyde (Li et al, 2004;Tung & Shoyama, 2013) It is a potential biologically active component for the treatment of NAFLD (Xu et al, 2021).…”

Therapeutic Effect of Costunolide in Autoimmune Hepatitis: Network Pharmacology and Experimental Validation

“…Network pharmacology was proposed by integrating network biology and polypharmacology [ 16 ]. It is capable of describing complexities among biological systems, drugs, and diseases from a network perspective, which has been applied in many studies to explore the molecular mechanism of drugs [ 17 , 18 , 19 , 20 , 21 ]. In this study, we investigated the effect of costunolide in two murine models of AIH: Concanavalin A (ConA)-induced acute immune-mediated hepatitis and human Cytochrome P4502D6 (CYP2D6) plasmid injection-induced chronic autoimmune hepatitis [ 22 ].…”