Ethnopharmacological relevance: Coptidis Rhizome (CR), a cornerstone medicinal herb, is routinely used to treat metabolic diseases for centuries in China. However, the potential mechanism has not been completely elucidated. Preceding investigation has reported that berberine in CR can bind to hemoglobin (Hb) and utilize erythrocyte-Hb self-assembly drug delivery system to significantly upregulate HO-1 expression.
Aim of the study: This study was designed in a pioneering endeavor to explore the therapeutic potential and underlying mechanism of CR in dexamethasone- and fructose-induced glycolipid metabolism disorders (GLD) rat models.
Material and methods: The major elements of CR were identified by high performance liquid chromatograph (HPLC). Dexamethasone- and fructose-induced rat GLD model was constructed. Glucolipid metabolism, oxidative status, and insulin sensitivity were investigated. Histopathological, transcriptomic, in silico simulations, immunofluorescence, immunohistochemistry, and Western blotting analyses were performed to gain further mechanism insight.
Results: HPLC analysis revealed that berberine, palmatine, coptisine, epiberberine, and jatrorrhizine were detected in CR, with berberine as the most abundant. Administration of CR favorably regulated the organ indexes, and significantly improved glucose metabolism by decreasing the FBG and GSP levels along with improved OGTT. CR promoted insulin sensitivity by suppressing the increased levels of FINS, HOMA-IR and ISI, and concomitantly improving ITT. Furthermore, CR normalized lipid metabolism by decreasing the elevated TG, TC and LDL-C levels. Additionally, CR effectively ameliorated histopathological deterioration in pancreatic and hepatic tissues and reduced serum ALT and AST activities. CR also ameliorated oxidative stress by remarkably lowering hepatic ROS fluorescence intensity and serum MDA content, whereas enhancing SOD and CAT enzymatic activity, and T-AOC level. Hepatic transcriptomics analysis revealed the oxidative stress-related gene HMOX1 encoding HO-1 and AMPK pathway critically involved in the therapeutic effect of CR. Furthermore, CR was found to significantly up-regulate the protein expression levels of HO-1, NQO1 and p-AMPK. On the other hand, in silico simulations indicated that strong van der Waals forces interaction between these alkaloids and HO-1. Notably, CR exhibited potent HO-1 agonistic activity comparable to the HO-1 inducer hemin, as manifested by enhanced HMOX1 mRNA level, HO-1 expression level, cytoplasmic HO-1 fluorescence intensity, carbon monoxide production, and reduced heme level, which were the markers of erythrocyte metabolism. Administration of CR or hemin significantly improved fasting glycemia, blood fat, insulin sensitivity, and antioxidant capacity. Nevertheless, these effects were observably reversed by the HO-1 inhibitor zinc protoporphyrin (ZnPP).
Conclusion: CR effectively ameliorated insulin resistance, hyperglycemia, and dyslipidemia, and its mechanism of action may be at least partially, mediated through HO-1 activation via erythrocyte metabolic regulation. This study provided further evidences for the historical use of CR in the therapy of metabolic diseases. These results highlighted the potential of CR as a novel HO-1 agonist for the development of innovative treatments for GLD.
Keywords: Coptidis rhizome; Erythrocyte metabolism; HO-1; Insulin resistance; Metabolic disorder.
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