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Norcantharidin Ameliorates Experimental Ulcerative Colitis Through Epigenetic and Metabolic Reprogramming Involving
Eman H Yousef1, Samia S Hawas2, Mohamed M Salama3
1Department of Pharmacology and Biochemistry (Biochemistry), Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
Abstract:
Ulcerative colitis (UC) is a chronic inflammatory disorder associated with cytokine imbalance, epigenetic alterations, and metabolic-redox dysfunction. Despite the widespread use of mesalazine (5-ASA), therapeutic limitations remain. Norcantharidin (NCTD), a synthetic cantharidin analogue, may provide multi-target protection against UC. Experimental colitis was induced in male Sprague-Dawley rats by intrarectal administration of 4% acetic acid (AA). Rats received oral NCTD (10 mg/kg), 5-ASA (100 mg/kg), or their combination for 8 days. Disease severity was assessed by disease activity index, body weight, colon length, colon weight/length ratio, and histopathology. Colonic biomarkers were evaluated using ELISA, qRT-PCR, Western blotting, and immunohistochemistry. Fe2+ and malondialdehyde (MDA) were measured as indicators of iron accumulation and lipid peroxidation. Molecular docking suggested that NCTD may adopt plausible binding poses within the binding pockets of AMPK, SIRT1, and DNMT1, providing structural support for potential protein-ligand interactions. NCTD significantly ameliorated AA-induced colitis, improving clinical and histological outcomes. These effects were associated with reduced IL-6, TNF-α, DNMT1, Fe2+, and MDA levels, restoration of SOCS3, activation of p-AMPK/SIRT1/FOXO3a signaling, and enhancement of Nrf2/HO-1 defenses. Combined NCTD/5-ASA treatment produced greater clinical and histological protection, with differential effects on molecular markers. Docking studies suggested favorable interactions of NCTD with AMPK, SIRT1, and DNMT1. NCTD treatment was associated with protection against experimental colitis, linked to modulation of inflammatory, epigenetic, metabolic, and antioxidant pathways.
Insights
Norcantharidin (NCTD) effectively treats experimental ulcerative colitis (UC) by reducing inflammation and improving gut health. This novel compound offers multi-target protection, potentially overcoming limitations of current mesalazine (5-ASA) therapies for UC patients.
Area of Science:
- Gastroenterology
- Pharmacology
- Molecular Biology
Background:
- Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by cytokine imbalance, epigenetic changes, and metabolic dysfunction.
- Current treatments like mesalazine (5-ASA) have limitations, necessitating novel therapeutic strategies.
- Norcantharidin (NCTD), a cantharidin analogue, shows potential for multi-target protection against UC.
Purpose of the Study:
- To investigate the therapeutic efficacy of Norcantharidin (NCTD) in a rat model of experimental colitis.
- To elucidate the underlying molecular mechanisms of NCTD's protective effects against ulcerative colitis.
- To compare the efficacy of NCTD, 5-ASA, and their combination in managing colitis.
Main Methods:
- Experimental colitis was induced in rats using acetic acid (AA).
- Animals were treated with NCTD, 5-ASA, or combination therapy.
- Disease activity, colon histology, and colonic biomarkers (cytokines, epigenetic markers, oxidative stress indicators) were assessed.
- Molecular docking was employed to predict NCTD interactions with key proteins (AMPK, SIRT1, DNMT1).
Main Results:
- NCTD significantly ameliorated acetic acid-induced colitis, improving clinical and histological outcomes.
- NCTD treatment reduced pro-inflammatory cytokines (IL-6, TNF-α), DNMT1, iron accumulation (Fe2+), and lipid peroxidation (MDA).
- NCTD restored SOCS3, activated AMPK/SIRT1/FOXO3a signaling, and enhanced Nrf2/HO-1 antioxidant pathways. Combined therapy showed enhanced protection.
Conclusions:
- Norcantharidin (NCTD) demonstrates significant protective effects against experimental colitis.
- NCTD modulates inflammatory, epigenetic, metabolic, and antioxidant pathways, offering multi-target therapeutic potential.
- NCTD represents a promising candidate for ulcerative colitis treatment, potentially superior to or synergistic with 5-ASA.
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