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Role of Combination Treatment of Aspirin and Zinc in DMH-DSS-induced Colon Inflammation, Oxidative Stress and Tumour Progression in Male BALB/c Mice

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Abstract

Colitis-associated colorectal cancer serves as a prototype of inflammation-associated cancers which is linked with repeated cycles of inflammation and DNA repair deficits. Several preclinical and clinical data reported that aspirin has a chemo-preventive effect in colorectal cancer and is associated with dose-dependent side effects. Furthermore, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in the combined administration of aspirin and zinc-mediated protection against colitis-associated colorectal cancer deserves further investigation. For the induction of colitis-associated colorectal cancer, male BALB/c mice were administered 1,2-dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) were administered for 8 weeks. Combination of aspirin and zinc as intervention significantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various inflammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase-2 (COX-2) and interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression significantly decreased, and antioxidant enzymes nuclear factor erythroid 2–related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) significantly increased as evaluated by immunohistochemistry and western blot analysis.

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Data Availability

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Abbreviations

CACC:

Colitis-associated colorectal cancer

DMH:

1,2-Dimethylhydrazine

DSS:

Dextran sulphate sodium

NFκBp65:

Nuclear factor kappa light chain enhancer of activated B cells

COX-2:

Cyclooxygenase-2

IL-6:

Interleukin-6

PCNA:

Proliferating cell nuclear antigen

STAT3:

Signal transducer and activator of transcription 3

Nrf-2:

Nuclear factor erythroid 2–related factor 2

IBD:

Inflammatory bowel disease

MPO:

Myeloperoxidase

Caspase-1:

Cysteine aspartases

SOD:

Superoxide dismutase

DAI:

Disease activity index

BSA:

Bovine serum albumin

MT:

Metallothionein

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Acknowledgements

The authors are grateful for the financial assistance received from the Department of Science and Technology (DST), New Delhi (SERB File Number: CRG/2020/000412). Furthermore, we also acknowledge the National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, for providing financial assistance to undertake the present study.

Funding

The authors are grateful for the financial assistance received from the Department of Science and Technology (DST), New Delhi (SERB File Number: CRG/2020/000412). Furthermore, the authors are thankful to the National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, India, for providing financial assistance to carry out the present study.

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  1. Facility for Risk Assessment and Intervention Studies, Dept. of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India, 160062

    Singothu Siva Nagendra Babu, Shivani Singla & Gopabandhu Jena

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Singothu Siva Nagendra Babu conceived, performed the experiments and analysed the data. Shivani Singla wrote all the sections of the manuscript. G.B. Jena conceived the idea, reviewed the manuscript and administered the project. Finally, all the authors have read and approved the manuscript.

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Correspondence to Gopabandhu Jena.

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12011_2022_3241_MOESM1_ESM.tif

Supplementary file1 Supplementary Fig. 1. Representative photomicrographs showing different stages of colitis-associated colorectal cancer stained with methylene blue (0.05%v/v). The lesions were slightly elevated with darkly stained and larger crypts from the surrounding normal mucosa. Normal mucosa characterised with regular round crypts; ACF with dysplasia characterised with enlarged and elongated crypts and the lumen was dilated, thickened and closed along with elongated to oval hyperchromatic nuclei with loss of nuclear polarity; Carcinoma stage exhibits highly pleomorphic nuclei with increased stratification, higher degree of mucin depletion and increased mitotic activity. (TIF 16427 KB)

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Babu, S.S.N., Singla, S. & Jena, G. Role of Combination Treatment of Aspirin and Zinc in DMH-DSS-induced Colon Inflammation, Oxidative Stress and Tumour Progression in Male BALB/c Mice. Biol Trace Elem Res 201, 1327–1343 (2023). https://doi.org/10.1007/s12011-022-03241-3

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