Document Type : Original Article

Authors

Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran, ‎Iran

Abstract

Background: Cadmium (Cd) is an environmental pollutant known to be toxic to lung tissue. Crocin is an active phytochemical of saffron with antioxidant properties. Because of this characteristic, it is hypothesized that crocin can reduce the harmful effects of toxic chemicals. The current study aimed to investigate the crocin intervention on the expression of NRAS, KRAS, c-FOS, and c-JUN genes in the lung tissues of Cd-treated rats.
Methods: In this study, 40 Wistar rats (180±30 g) were randomly divided into four groups: the control group, received food and water; the crocin-treated group, received 15 mg/kg crocin orally; the Cd-treated group, received 20 mg/kg Cd by gastric gavage; and the complex group, treated by crocin and cadmium with previously mentioned concentrations. After eight weeks daily administered, the rats were euthanized, and their lungs were extracted to assess NRAS, KRAS, c-FOS, and c-JUN gene expressions by Real-Time PCR. Data were computed by GraphPad Prism (v.8). One-way ANOVA test was used as statistical analysis, and P<0.05 was considered statistically significant.
Results: The results revealed that the Cd consumption raised the expression of all four genes in lung tissue (c-JUN, KRAS P<0.001, NRAS P<0.01, and c-FOS P<0.05). Crocin significantly reduced the expression of c-JUN (P<0.0001), c-FOS, and NRAS (P<0.05) genes.
Conclusion: The data obtained from the current study indicated that crocin could reduce the expression of c-FOS, c-JUN, and NRAS as vital players in cell proliferation.  

Graphical Abstract

Evaluating the Effect of Crocin on NRAS, KRAS, c-FOS, and c-JUN Genes Expressions in Lung Tissue of Cadmium-Treated Rats

Keywords

Main Subjects

  1. Soltanbeigi A, Dastyar N, Khajoei Nejad F, Shokri S. (2022). Medicinal Herbs Affecting Cancers in Iran and the World. Plant Biotechnol Persa, 4: 1–3. [Google Scholar], [Publisher]
  2. Osada H, Takahashi T. (2002). Genetic Alterations of MultipleTumor Suppressors and Oncogenes in the Carcinogenesis and Progression of Lung Cancer. Oncogene, ‎‎21: 7421–7434. [Crossref], [Google Scholar], [Publisher]
  3. Globocan. (2020). Lung Fact Sheet. In: Obs. Glob. do Câncer. https://gco.iarc.fr/today. [Publisher
  4. Urman A, Dean Hosgood H. (2015). Lung Cancer Risk, Genetic Variation, and Air Pollution. EBioMedicine, 2: 491–492. [Crossref], [Google Scholar], [Publisher]
  5. Shankar A, Dubey A, Saini D, Singh M, Prasad C P, Roy S, Bharati S J, Rinki M, Singh N, Seth T, Khanna M, Sethi N, Kumar S, Sirohi B, Mohan A, Guleria R, Rath G K. (2019). Environmental and Occupational Determinants of Lung Cancer. Transl lung cancer Res, ‎‎8: S31–S49. [Crossref], [Google Scholar], [Publisher]
  6. Waalkes M P. (2003). Cadmium Carcinogenesis. Mutat Res, 533: 107–120. ‎‎[Crossref], [Google Scholar], [Publisher]
  7. Branca J J V, Fiorillo C, Carrino D, Paternostro F, Taddei N, Gulisano M, Pacini A, Becatti M. (2020). Cadmium-Induced Oxidative Stress: Focus on the Central Nervous System. Antioxidants, 9: 492. [Crossref], [Google Scholar], [Publisher]
  8. Zhu Y, Costa M. (2020). Metals and Molecular Carcinogenesis. Carcinogenesis, ‎‎41: 1161–1172. [Crossref], [Google Scholar], [Publisher]
  9. Jing Y, Liu L Z, Jiang Y, Zhu Y, Guo N L, Barnett J, Rojanasakul Y, Agani F, Jiang B H. ‎‎(2012). Cadmium Increases HIF-1 and VEGF Expression Through ROS, ERK, and AKT Signaling  Pathways and Induces Malignant Transformation of Human Bronchial Epithelial Cells. Toxicol Sci., 125: 10–19. [Crossref], [Google Scholar], [Publisher]
  10. Chandler J D, Wongtrakool C, Banton S A, Li S, Orr M L, Barr D B, Neujahr D C, Sutliff R L, Go Y M, Jones D P. (2016). Low-dose Oral Cadmium Increases Airway Reactivity and Lung Neuronal Gene Expression in Mice. Physiol Rep, 4: e12821. ‎‎[Crossref], [Google Scholar], [Publisher]
  11. Abdel-Rahman O. (2016). Targeting the MEK Signaling Pathway in Non-Small Cell Lung Cancer (NSCLC) Patients with RAS Aberrations. Ther Adv Respir Dis, 10: 265–274. ‎‎[Crossref], [Google Scholar], [Publisher]
  12. Guin S, Ru Y, Wynes M W, Mishra R, Lu X, Owens C, Barόn A E, Vasu V T, Hirsch F R, Kern J A, Theodorescu D. (2013). Contributions of KRAS and RAL in Non–Small-Cell Lung Cancer Growth and Progression. J Thorac Oncol, 8: 1492–1501. ‎‎[Crossref], [Google Scholar], [Publisher]
  13. Shao W, Li S, Li L, Lin K, Liu X, Wang H, Wang H, Wang D. (2019). Chemical Genomics Reveals Inhibition of Breast Cancer Lung Metastasis by Ponatinib via c-Jun. Protein Cell, 10: 161–177. [Crossref], [Google Scholar], [Publisher]
  14. Huff M O, Todd S L, Smith A L, Elpers J T, Smith A P, Murphy R D, Bleser-Shartzer A S, Hoerter J E, Radde B N, Klinge C M. (2016). Arsenite and Cadmium Activate MAPK/ERK via Membrane Estrogen Receptors and G-Protein  Coupled Estrogen Receptor Signaling in Human Lung Adenocarcinoma Cells. Toxicol Sci., 152: 62–71. ‎‎[Crossref], [Google Scholar5], [Publisher]
  15. Shukla G S, Shukla A, Potts R J, Osier M, Hart B A, Chiu J F. (2000). Cadmium-Mediated Oxidative Stress in Alveolar Epithelial Cells Induces the  Expression of Gamma-Glutamylcysteine Synthetase Catalytic Subunit and Glutathione S-Transferase Alpha and pi Isoforms: Potential Role of Activator Protein-1. Cell Biol Toxicol., 16: 347–362.‎ ‎[Crossref], [Google Scholar], [Publisher]
  16. Kotecha R, Takami A, Espinoza J L. (2016). Dietary Phytochemicals and Cancer Chemoprevention: a Review of the Clinical  Evidence. Oncotarget, 7: 52517–52529. ‎ ‎[Crossref], [Google Scholar], [Publisher]
  17. Benetou V, Lagiou A, Lagiou P. (2015). Chemoprevention of Cancer: Current Evidence and Future Prospects. F1000Res, 4: 916. ‎ ‎[Crossref], [Google Scholar], [Publisher]
  18. Howes M J R, Simmonds M S J. (2014). The Role of Phytochemicals as Micronutrients in Health and Disease. Curr Opin Clin Nutr Metab Care., 17 (6): 558-566. [Crossref], [Google Scholar], [Publisher]
  19. Murakami A. (2009). Chemoprevention with Phytochemicals Targeting Inducible ‎Nitric Oxide Synthase. Forum of Nutrition., 61: 193–203. [Crossref], [Google Scholar], [Publisher]
  20. Rameshrad M, Razavi B M, Hosseinzadeh H. (2018). Saffron and its Derivatives, Crocin, Crocetin and Safranal: a patent review. Expert Opin Ther Pat, 28: 147–165.[Crossref], [Google Scholar], [Publisher]
  21. Abdullaev F I, Espinosa-Aguirre J J. (2004). Biomedical Properties of Saffron and its Potential Use in Cancer Therapy and Chemoprevention Trials. Cancer Detect Prev, 28: 426–‎‎432. [Crossref], [Google Scholar], [Publisher]
  22. Kustiawan P M. (2021). A Reviw of Effectiveness of Red betel Leaves (Piper crocatum) as Antihyperglysemic Activities. Plant Biotechnol Persa, 3(2): 39–47. [Google Scholar], [Publisher]
  23. Andjelkovic M, Djordjevic A B, Antonijevic E, Antonijevic B, Stanic M, Kotur-Stevuljevic J, Spasojevic-Kalimanovska V, Jovanovic M, Boricic N, Wallace D, Bulat Z. ‎‎(2019). Toxic Effect of Acute Cadmium and Lead Exposure in Rat Blood, Liver, and Kidney. Int J Environ Res Public Health, 16: 274. [Crossref], [Google Scholar], [Publisher]
  24. Margaritis I, Angelopoulou K, Lavrentiadou S, Mavrovouniotis I C, Tsantarliotou M, ‎Taitzoglou I, Theodoridis A, Veskoukis A, Kerasioti E, Kouretas D, Zervos I. (2020). Effect ‎of Crocin on Antioxidant Gene Expression, Fibrinolytic Parameters, Redox Status and ‎Blood Biochemistry in Nicotinamide-Streptozotocin-Induced Diabetic Rats. J of Biol Res-Thessaloniki, 27.‎ ‎[Crossref], [Google Scholar], [Publisher]
  25. Colapietro A, Mancini A, D’Alessandro A M, Festuccia C. (2019). Crocetin and Crocin from Saffron in Cancer Chemotherapy and Chemoprevention. Anticancer Agents Med Chem, 19: 38–47. [Crossref], [Google Scholar], [Publisher]
  26. Abdullaev F I. (2002). Cancer Chemopreventive and Tumoricidal Properties of Saffron (Crocus sativus L.). Exp Biol Med, 227: 20–25.‎ ‎[Crossref], [Google Scholar], [Publisher]
  27. Hashemzaei M, Mamoulakis C, Tsarouhas K, Georgiadis G, Lazopoulos G, Tsatsakis A, Shojaei Asrami E, Rezaee R. (2020). Crocin: A Fighter against Inflammation and Pain. Food Chem Toxicol an Int J Publ Br Ind Biol Res Assoc, 143: 111521.[Crossref], [Google Scholar], [Publisher]
  28. Jiao L, Bi L, Lu Y, Wang Q, Gong Y, Shi J, Xu L. (2018). Cancer Chemoprevention and Therapy Using Chinese Herbal Medicine. Biol Proced Online, 20: 1. [Crossref], [Google Scholar], [Publisher]
  29. Luevano J, Damodaran C. (2014). A Review of Molecular Events of Cadmium-‎Induced Carcinogenesis. J Environ Pathol Toxicol Oncol, 33: 183–194. ‎[Crossref], [Google Scholar], [Publisher]
  30. Gimple R C, Wang X. (2019). RAS: Striking at the Core of the Oncogenic Circuitry. Front Oncol, 9: 965. [Crossref], [Google Scholar], [Publisher]
  31. Matthews C, Colburn N, Young M. (2007). AP-1 a Target for Cancer Prevention. Curr Cancer Drug Targets, 7: 317–324. [Crossref], [Google Scholar], [Publisher]
  32. Ashrafi M, Bathaie S Z, Abroun S, Azizian M. (2015). Effect of Crocin on Cell Cycle Regulators in N-Nitroso-N-Methylurea-Induced Breast Cancer in Rats. DNA Cell Biol, ‎‎34: 684–691. [Crossref], [Google Scholar], [Publisher]
  33. Bakshi H A, Hakkim F L, Sam S, Javid F, Rashan L. (2018). Dietary Crocin Reverses Melanoma Metastasis. J Biomed Res, 32: 39–50. [Crossref], [Google Scholar], [Publisher]
  34. Hadipour M, Kaka G, Bahrami F, Meftahi G H, Pirzad Jahromi G, Mohammadi A, Sahraei H. (2018). Crocin Improved Amyloid Beta Induced Long-Term Potentiation and Memory Deficits in the Hippocampal CA1 Neurons in Freely Moving Rats. Synapse, 72: e22026.‎ ‎[Crossref], [Google Scholar], [Publisher]
  35. Fu L, Pan F, Jiao Y. (2017). Crocin Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption by Suppressing NF-κB Signaling Pathway Activation. Immunobiology, ‎‎222: 597–603. [Crossref], [Google Scholar], [Publisher]
  36. Shi L, Zhao S, Chen Q, Wu Y, Zhang J, Li N. (2018). Crocin Inhibits RANKL-Induced ‎Osteoclastogenesis by Regulating JNK and NF-κB Signaling Pathways. Mol Med Rep., ‎‎17: 7947–7951. ‎[Crossref], [Google Scholar], [Publisher]