Yinchenhao Decoction Combined with Praziquantel Ameliorates Inflammation and Hepatic Fibrosis in Schistosoma japonicum-Infected Mice.

Objective: This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction (YCHD) and praziquantel (PZQ) in a Schistosoma japonicum (S. japonicum)-induced mouse model of schistosomiasis.

Methods: Six-week-old male BALB/c mice were randomly divided into five groups: control group, infected group, infected-PZQ group (I-PZQ), infected-YCHD group (I-YCHD), and infected-PZQ + YCHD group (I-PZQ + YCHD). The mice were infected with S. japonicum cercariae in infected group, I-PZQ group, I-YCHD group, and I-PZQ + YCHD group (n = 6 per group) and maintained for 63 days. From day 43 to day 63 postinfection, the mice received PZQ (150 mg/kg, intragastric gavage), YCHD (10 mL/kg, intragastric gavage), or a combination of both. The control and infected groups received equal amounts of sterile double-distilled water for the same period. At the end of the experiment, the mice were anesthetized with pentobarbital sodium and sacrificed. Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels were measured. Network pharmacology analysis was used to predict the targets of YCHD in the treatment of schistosomiasis. Histopathological analysis, Western blotting, immunofluorescence, quantitative polymerase chain reaction and flow cytometry were employed to evaluate liver pathology and molecular changes.

Results: Compared with the other groups, the I-PZQ + YCHD group presented significantly decreased serum ALT and AST levels (P < 0.001). The I-PZQ + YCHD group exhibited improved pathological changes in the liver, as evidenced by reduced area of single granuloma (P < 0.01), granuloma area (P < 0.01), and Ishak score of liver fibrosis (P < 0.01). Network pharmacology analysis suggested that YCHD may alleviate schistosomiasis-related liver injury through the modulation of the endoplasmic reticulum stress (ERS) pathway. Western blot analysis revealed that ERS-related markers, including glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1 alpha (IRE1α), X-box binding protein 1 (XBP-1), and C/EBP homologous protein (CHOP), were significantly downregulated in the I-PZQ + YCHD group (P < 0.05). Furthermore, the I-PZQ + YCHD group presented reduced hepatocyte apoptosis (P < 0.05), diminished hepatic macrophage infiltration (P < 0.05) and downregulated expression of proinflammatory cytokines (TNF-α, IL-1β and IL-6) (P < 0.05).

Conclusion: YCHD combined with PZQ reduced schistosomiasis-associated hepatic granulomatous inflammation and fibrosis by inhibiting hepatic apoptosis and ERS.