Emad H M Hassanein1, Esam Omar Kamel2, Fares E M Ali3, Marwa Abdel-Raheim Ahmed4. 1. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt. 2. Department of Medical Histology and Cell Biology, Faculty of Medicine, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt. 3. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt. Electronic address: Faresali@azhar.edu.eg. 4. Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71526, Egypt.
Abstract
AIM: The present study was undertaken to elucidate the potential protective mechanism of berberine (BBR) and/or zinc (Zn) against methotrexate (MTX)-induced intestinal injury. METHODS: Five groups of rats were assigned; normal group (received vehicle), MTX group (20 mg/kg; i.p. single dose), and the other three groups received a single daily oral dose of BBR (50 mg/kg), Zn (5 mg/kg), and BBR plus Zn respectively, for 5 days before MTX and 5 days after. RESULTS: Our results emphasized the toxic effect of MTX on rat's intestine as shown by disturbance of oxidant/antioxidant status, down-regulation of NRF2, SIRT1, FOXO-3, Akt, and mTOR expressions, along with up-regulation of GSK-3β, JAK1, and STAT-3 expressions. Besides, severe intestinal histopathological changes were also observed. On the contrary, BBR and/or Zn produced marked protection against MTX-induced intestinal toxicity via amelioration of oxidative stress, improving NRF2, SIRT1, FOXO-3, GSK-3β, Akt, mTOR, JAK1, and STAT-3 alterations. Moreover, our treatments significantly restored histopathological abnormalities. Interestingly, combination therapy of BBR plus Zn exhibited higher effectiveness than mono-therapy. SIGNIFICANCE: BBR plus Zn could be used as a novel therapy for the treatment of MTX-induced intestinal damage through modulation of GSK-3β/NRF2, Akt/mTOR, JAK1/STAT-3, and SIRT1/FOXO-3 signaling pathways.
AIM: The present study was undertaken to elucidate the potential protective mechanism of berberine (BBR) and/or zinc (Zn) against methotrexate (MTX)-induced intestinal injury. METHODS: Five groups of rats were assigned; normal group (received vehicle), MTX group (20 mg/kg; i.p. single dose), and the other three groups received a single daily oral dose of BBR (50 mg/kg), Zn (5 mg/kg), and BBR plus Zn respectively, for 5 days before MTX and 5 days after. RESULTS: Our results emphasized the toxic effect of MTX on rat's intestine as shown by disturbance of oxidant/antioxidant status, down-regulation of NRF2, SIRT1, FOXO-3, Akt, and mTOR expressions, along with up-regulation of GSK-3β, JAK1, and STAT-3 expressions. Besides, severe intestinal histopathological changes were also observed. On the contrary, BBR and/or Zn produced marked protection against MTX-induced intestinal toxicity via amelioration of oxidative stress, improving NRF2, SIRT1, FOXO-3, GSK-3β, Akt, mTOR, JAK1, and STAT-3 alterations. Moreover, our treatments significantly restored histopathological abnormalities. Interestingly, combination therapy of BBR plus Zn exhibited higher effectiveness than mono-therapy. SIGNIFICANCE: BBR plus Zn could be used as a novel therapy for the treatment of MTX-induced intestinal damage through modulation of GSK-3β/NRF2, Akt/mTOR, JAK1/STAT-3, and SIRT1/FOXO-3 signaling pathways.
Authors: Ahmad O Babalghith; Hayder M Al-Kuraishy; Ali I Al-Gareeb; Michel De Waard; Sadiq Mohammed Al-Hamash; Sabatier Jean-Marc; Walaa A Negm; Gaber El-Saber Batiha Journal: Inflammopharmacology Date: 2022-10-02 Impact factor: 5.093