Anat Cell Biol.  2022 Dec;55(4):483-496. 10.5115/acb.22.088.

Morphological, ultrastructural, and biochemical changes induced by sodium fluoride in the tongue of adult male albino rat and the ameliorative effect of resveratrol

• El-Bestawy EM
• Tolba AM
• Rashad WA

• KMID: 2537468
• DOI: http://doi.org/10.5115/acb.22.088

Abstract

Little knowledge is available about the effects of fluoride exposure on the tongue. This study evaluated the effects of sodium fluoride (NaF) on the tongue ultrastructure and detected the ameliorative effects of resveratrol. Forty adult albino rats were separated into 4 groups: the control group was given a balanced diet and purified water. The NaF treated group: received 10 mg/kg/d dissolved in 2.5 ml distilled water once daily for 30 days orally. The NaF+resveratrol group: received NaF 10 mg/ kg/d orally together with resveratrol in a dose of 30 mg/kg daily for 30 days. The resveratrol group was subjected to resveratrol in a dose of 30 mg/kg/d by oral gavage for 30 days. Sections were stained with hematoxylin & eosin, and Masson’s trichrome. Tumor necrosis factor α immunohistochemical study and electron microscopic examinations were done. The oxidative stress markers malondialdehyde, antioxidant reduced glutathione, and the total antioxidant capacity were measured. The NaF group revealed ulceration, necrotic muscle fibers, distorted papillae and a significant increase in malondialdehyde level, and a significant decrease in glutathione and the total antioxidant levels. In the NaF+resveratrol group, pathological changes were less, and the oxidant levels were decreased by the administration of resveratrol with NaF. In conclusion, NaF adversely affects the ultrastructure of the adult rat tongue and resveratrol can ameliorate this effect.

Keyword

Sodium flouride; Resveratrol; Tongue; Rat; Electron microscopy

Figure

• 

  Fig. 1 A photomicrograph shows the gross morphological changes of the albino rat tongue induced by sodium fluoride and their amelioration by resveratrol. (A) Control group shows a normal appearance of the rat tongue. (B) NaF treated group, displays a red tongue with marked congestion of the dorsal surface over the intermolar prominence (im) and ulcers (arrows) on the anterior part of the dorsal surface. (C) NaF+resveratrol group shows marked improvement but still shows some congestion in the posterior part of the dorsal surface over the intermolar prominence (im). (D) Resveratrol group exhibits a normal appearance of the rat tongue which looks like the control group. NaF, sodium fluoride.

• 

  Fig. 2 H&E-stained sections show the pathological changes of the albino rat tongue induced by sodium fluoride and their amelioration by resveratrol. The control group (A–D): (A, B) Long pointed filiform papillae (F) with overlaying keratinized layer (arrows), lamina propria (l), the muscle layer fibers (M) arranged in the different directions (curved arrows), serous (sg) and mucous (mg) lingual glands. (C) Mushroom-shaped fungiform papilla (Fg) with centrally situated taste bud (arrowhead). (D) Muscle fibers are arranged in the different directions (curved arrows) with vesicular nuclei (N). The NaF treated group (E–H): (E, F) Atrophied and short filiform papilla (F*) with a flattened end (F**), inflammatory aggregations (thick arrow) in the lamina propria (l), and the muscle layer (M). The necrotic muscle fibers (crossed curved arrow) and complete necrotic areas with substance loss (star). (G) Deformed fungiform papillae (Fg) with degenerated taste bud (arrowhead) and several vacuolations (v). (H) Separation (*) and fragmentation of the muscle fibers (dotted arrow), necrotic muscle fibers (crossed curved arrow) with pyknotic nuclei (N*), complete necrotic areas with substance loss (star), congested blood capillaries (c), lymphatic capillaries (c*). NaF+resveratrol group (I–L): (I, J) Filiform papillae (F) are less atrophied, some filiform papillae with a flattened end (F**), keratinized layer (arrow), lamina propria (l), muscle layer (M), normal muscle layer fibers (curved arrow), necrotic muscle fibers (crossed curved arrow), complete necrotic areas with substance loss (star), adipose tissue (x). (K) Less deformed fungiform papilla (Fg) with normal centrally situated taste bud (arrowhead). (L) Normal muscle layer fibers (curved arrow) with vesicular nuclei (N), necrotic muscle fibers (crossed curved arrow), fragmented muscle fibers (dotted arrow), and adipose tissue (x). The resveratrol group (M–P): (M, N) Long pointed filiform papillae (F) with overlaying, lamina propria (l), the muscle layer fibers (M). (O) Mushroom-shaped fungiform papilla (Fg) with centrally situated taste bud (arrowhead). (P) Muscle fibers are arranged in the different directions (curved arrow) with vesicular nuclei (N), and adipose tissue (x). H&E staining; (A, E, I, M) ×100, scale bars=200 µm; (B–D, F, G, J–L, N–P) ×400, scale bars=50 µm.

• 

  Fig. 3 The albino rat tongue sections reveal the collagen fibers and tumor necrosis factor α (TNF-α) immune expression changes induced by sodium fluoride and their amelioration by resveratrol. (A) Control group shows a little amount of blue-stained collagen fibers (arrow) in the lamina propria. (B) NaF treated group shows an excess amount of blue-stained collagen fibers (arrow) in the lamina propria. (C) NaF+resveratrol group shows a moderate amount of the blue-stained collagen fibers (arrow) in the lamina propria. (D) Resveratrol group shows a little amount of the blue-stained collagen fibers (arrow) in the lamina propria. (E) Control group shows a negative TNF-α immunoreaction in the papillary epithelium (arrow), the lamina propria (curved arrow), and the muscle fibers (thick arrow). (F) NaF treated group displays a strong positive cellular cytoplasmic TNF-α immunoreaction in the papillary epithelium (arrow), the lamina propria (curved arrow), and the muscle fibers (thick arrow). (G) NaF+resveratrol group displays a weak positive cellular cytoplasmic TNF-α immunoreaction in the papillary epithelium (arrow) and a moderate positive immunoreaction in the lamina propria (curved arrow) and the muscle fibers (thick arrow). (H) Resveratrol group exhibits a negative cellular cytoplasmic TNF-α immunoreaction in the papillary epithelium (arrow), the lamina propria (curved arrow), and the muscle fibers (thick arrow). (A–D) Masson’s trichrome staining, ×100, scale bars=200 µm; (E–H) TNF-α immunohistochemical staining, ×400, scale bars=50 µm; Inset higher magnification figures: ×1,000, scale bars=20 µm.

• 

  Fig. 4 A scanning electron photomicrograph shows the pathological changes of the albino rat tongue induced by sodium fluoride and their amelioration by resveratrol. The control group (A, B): (A) Numerous elongated filiform papillae (F) with pointed tip (arrow) oriented in one direction (×270, scale bar=50 µm). (B) Fungiform papillae (Fg) are seen among the filiform papillae (F) with a taste pore (curved arrow) on its surface (×350, scale bar=50 µm). NaF treated group (C–F): (C, D) Filiform papillae (F) with flattened tip (arrows) and epithelial exfoliation in the filiform papillae (dotted arrows), clarified also in the inset figure which shows higher magnification view. The fungiform papillae (Fg) with a taste pore (curved arrow) on its surface show epithelial exfoliation (arrowheads) (C: ×270, scale bar=50 µm; the inset figure: ×1,400, scale bar=10 µm; D: ×370, scale bar=50 µm). (E, F) Wide areas of papillary loss (stars) and markedly distorted filiform papillae (F) with loss of its elongated appearance and typical features (thick arrow), other papillae with extensive exfoliations (dotted arrows) with flattened tip (arrow) (E: ×250, scale bar=100 µm; F: ×750, scale bar=20 µm). NaF+resveratrol group (G, H): (G) Filiform papillae (F) with preserved elongated appearance and pointed tips (arrows) and a minor exfoliation (dotted arrow) in the filiform papillae (×350, scale bar=50 µm). (H) Minor epithelial exfoliation (dotted arrow) in the filiform papillae with pointed tip (arrow). The fungiform papillae (Fg) show little epithelial exfoliation (arrowhead) (×500, scale bar=50 µm). Resveratrol group (I, J): The numerous elongated filiform papillae (F) with pointed tips (arrows) oriented in one direction and the fungiform papillae (Fg) were seen among the filiform papillae (I: ×200, scale bar=100 µm; J: ×450, scale bar=50 µm).

• 

  Fig. 5 A transmission electron photomicrograph shows the pathological changes in the albino rat tongue induced by sodium fluoride and their amelioration by resveratrol. Control group (A, B): (A) Parallel myofibrils (f), well-recognized z lines (arrowhead), and the mitochondria (m) between the myofibrils. (B) Euchromatic oval nucleus (N), mitochondria (m) below the sarcolemma (curved arrow), parallel myofibrils (f), and well-recognized z lines (arrowhead). NaF treated group (C–E): (C) Atrophied, widely separated (*) and fragmented (arrows) myofibrils, areas with myofibrils loss (star), poorly observed to absent z lines (arrowhead), small and fragmented mitochondria (m). (D) Pyknotic nucleus (N), atrophied widely separated (*) and fragmented (arrows) myofibrils, areas with myofibrils loss (star), poorly observed to absent z lines (arrowhead), small and fragmented mitochondria (m). (E) Congested blood vessel (BV), atrophied, widely separated (*), and fragmented myofibrils (arrow). NaF+resveratrol group (F, G): (F) Parallel myofibrils (f), well-recognized z lines (arrowhead), mitochondria (m) between the myofibrils. Some atrophied myofibrils with little separation (*), a small area with myofibrils loss (star). (G) Euchromatic oval nucleus (N), Parallel myofibrils (f), well-recognized z lines (arrowhead), mitochondria (m). (H) Resveratrol group shows parallel myofibrils (f), well recognized z lines (arrowhead), mitochondria (m) between the myofibrils. (A–D, F, G) ×4,000, scale bar=5 µm; (E) ×6,000, scale bar=10 µm; (H) ×10,000, scale bar=2 µm.

• 

  Fig. 6 Bar chart showing (A) Statistical comparison of the tongue weight, area percentage (AP) of the collagen fibers, and the optical density (OD) of tumor necrosis factor α immune-reaction among the 4 groups using one way ANOVA test and least significant difference (LSD) post-hoc test. (B) Statistical comparison of the malondialdehyde (MDA), reduced glutathione (GSH), and the total antioxidant capacity tissue levels of the tongue among the 4 groups using one way ANOVA test and LSD post-hoc test. Comparison in relation to the control group, ***P<0.001; comparison in relation to the NaF treated group, ##P<0.01, ###P<0.001.

Reference

References

1. Gao J, Tian X, Yan X, Wang Y, Wei J, Wang X, Yan X, Song G. 2021; Selenium exerts protective effects against fluoride-induced apoptosis and oxidative stress and altered the expression of Bcl-2/caspase family. Biol Trace Elem Res. 199:682–92. DOI: 10.1007/s12011-020-02185-w. PMID: 32613488.

2. Abed KF, Alwakeel SS. 2007; Mineral and microbial contents of bottled and tap water in Riyadh, Saudi Arabia. Middle East J Sci Res. 2:151–6.

3. Pendrys DG. 2001; Fluoride ingestion and oral health. Nutrition. 17:979–80. DOI: 10.1016/S0899-9007(01)00686-4. PMID: 11744358.

4. Al-hayani A, Elshal EB, Aal IHA, Al-Shammeri E. 2013; Does vitamin E protect against sodium fluoride toxicity on the cerebellar cortex of albino rats? Middle East J Sci Res. 16:1019–26.

5. Fung KF, Zhang ZQ, Wong JWC, Wong MH. 1999; Fluoride contents in tea and soil from tea plantations and the release of fluoride into tea liquor during infusion. Environ Pollut. 104:197–205. DOI: 10.1016/S0269-7491(98)00187-0.

6. Jacinto-Alemán LF, Hernández-Guerrero JC, Trejo-Solís C, Jiménez-Farfán MD, Fernández-Presas AM. 2010; In vitro effect of sodium fluoride on antioxidative enzymes and apoptosis during murine odontogenesis. J Oral Pathol Med. 39:709–14. DOI: 10.1111/j.1600-0714.2010.00918.x. PMID: 20738751.

7. Rahmani S, Rezaei M. 2020; Toxicity of fluoride on isolated rat liver mitochondria. J Fluor Chem. 239:109636. DOI: 10.1016/j.jfluchem.2020.109636.

8. O'Neil MJ, Smith A, Heckelman PE, Budavari S. 2001. The Merck index: an encyclopedia of chemicals, drugs, and biologicals. 13th ed. Merck;Whitehouse Station: DOI: 10.1016/j.jfluchem.2020.109636.

9. Ahmed SK, Kalleny NK, El Moneim Attia AA, Elkateb LA. 2015; The possible protective role of chromium chloride against sodium fluoride-induced changes in the structure of the cerebellar cortex of the adult male albino rat. Egypt J Histol. 38:402–14. DOI: 10.1097/01.EHX.0000464785.45283.40.

10. Mondal K, Nath S. 2015; Fluoride contamination on aquatic organisms and human body at Purulia and Bankura district of West Bengal, India. Bull Environ Pharmacol Life Sci. 4:112–4.

11. Dhar V, Bhatnagar M. 2009; Physiology and toxicity of fluoride. Indian J Dent Res. 20:350–5. DOI: 10.4103/0970-9290.57379. PMID: 19884722.

12. Yan X, Yang X, Hao X, Ren Q, Gao J, Wang Y, Chang N, Qiu Y, Song G. 2015; Sodium fluoride induces apoptosis in H9c2 cardiomyocytes by altering mitochondrial membrane potential and intracellular ROS level. Biol Trace Elem Res. 166:210–5. DOI: 10.1007/s12011-015-0273-z. PMID: 25707396.

13. Al Badawi MH, Mahmoud OM, Salem NA. 2016; Therapeutic potential of omega-3 against sodium fluoride toxicity on the cerebellar cortex of adult male albino rats. Egypt J Histol. 39:170–8. DOI: 10.1097/01.EHX.0000490005.17183.4f.

14. Basha MP, Begum S, Madhusudhan N. 2014; Antioxidants in the management of fluoride induced neural oxidative stress in developing rats. Int J Pharm Sci Res. 5:201–6.

15. El-Khair DMA, El-Safti FENA, El-Habeby MM, El-Kholy WB, El-Sherif NM. 2016; Effect of sodium fluoride on the grey matter of spinal cord in the albino rat and the protective role of green tea extract. Anatomy. 10:114–33. DOI: 10.2399/ana.16.017.

16. Kanagaraj VV, Panneerselvam L, Govindarajan V, Ameeramja J, Perumal E. 2015; Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: a possible mechanism. Biofactors. 41:90–100. DOI: 10.1002/biof.1203. PMID: 25845575.

17. Shivarajashankara Y, Shivashankara A, Bhat PG, Rao SH. 2001; Effect of fluoride intoxication on lipid peroxidation and antioxidant systems in rats. Fluoride. 34:108–13.

18. Oliveira BV, Barros Silva PG, Nojosa Jde S, Brizeno LA, Ferreira JM, Sousa FB, Mota MR, Alves AP. 2016; TNF-alpha expression, evaluation of collagen, and TUNEL of Matricaria recutita L. extract and triamcinolone on oral ulcer in diabetic rats. J Appl Oral Sci. 24:278–90. DOI: 10.1590/1678-775720150481. PMID: 27383710. PMCID: PMC5022216.

19. Chamani G, Zarei MR, Mehrabani M, Mehdavinezhad A, Vahabian M, Ahmadi-Motamayel F. 2017; Evaluation of honey as a topical therapy for intraoral wound healing in rats. Wounds. 29:80–6. PMID: 28054920.

20. Al-Ayed MS, Asaad AM, Qureshi MA, Attia HG, AlMarrani AH. 2016; Antibacterial activity of Salvadora persica L. (Miswak) extracts against multidrug resistant bacterial clinical isolates. Evid Based Complement Alternat Med. 2016:7083964. DOI: 10.1155/2016/7083964. PMID: 26904146. PMCID: PMC4745819.

21. Nalagoni CSR, Karnati PR. 2016; Protective effect of resveratrol against neuronal damage through oxidative stress in cerebral hemisphere of aluminum and fluoride treated rats. Interdiscip Toxicol. 9:78–82. DOI: 10.1515/intox-2016-0009. PMID: 28652849. PMCID: PMC5458107.

22. Zeng XX, Deng J, Xiang J, Dong YT, Cao K, Liu XH, Chen D, Ran LY, Yang Y, Guan ZZ. 2019; Resveratrol attenuated the increased level of oxidative stress in the brains and the deficit of learning and memory of rats with chronic fluorosis. Fluoride. 52:149–60.

23. Agustina F, Sofro ZM, Partadiredja G. 2019; Subchronic administration of high-dose sodium fluoride causes deficits in cerebellar Purkinje cells but not motor coordination of rats. Biol Trace Elem Res. 188:424–33. DOI: 10.1007/s12011-018-1420-0. PMID: 29951727.

24. Sharma C, Suhalka P, Bhatnagar M. 2018; Curcumin and resveratrol rescue cortical-hippocampal system from chronic fluoride-induced neurodegeneration and enhance memory retrieval. Int J Neurosci. 128:1007–21. DOI: 10.1080/00207454.2018.1458727. PMID: 29607689.

25. Suvarna SK, Layton C, Bancroft JD. 2013. Bancroft's theory and practice of histological techniques. 7th ed. Churchill Livingstone;Philadelphia: p. 173–214.

26. Rau E, Gostev A, Shiqiu Z, Phang D, Chan D, Thong D, Wong W. 2001; Comparative analysis of scanning electron microscopy techniques for semiconductors: electron-beam-induced potential method, single-contact electron-beam-induced current method, and thermoacoustic detection. Russ Microelectron. 30:207–18. DOI: 10.1023/A:1011336726819.

27. Ayache J, Beaunier L, Boumendil J, Ehret G, Laub D. 2010. Sample preparation handbook for transmission electron microscopy techniques. Springer;New York: DOI: 10.1007/978-1-4419-5975-1.

28. Erel O. 2004; A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 37:277–85. DOI: 10.1016/j.clinbiochem.2003.11.015. PMID: 15003729.

29. Mistretta CM, Bradley RM. 2021; The fungiform papilla is a complex, multimodal, oral sensory organ. Curr Opin Physiol. 20:165–73. DOI: 10.1016/j.cophys.2021.01.012. PMID: 33681545. PMCID: PMC7928430.

30. Hsu PC, Wu HK, Huang YC, Chang HH, Chen YP, Chiang JY, Lo LC. 2019; Gender- and age-dependent tongue features in a community-based population. Medicine (Baltimore). 98:e18350. DOI: 10.1097/MD.0000000000018350. PMID: 31860990. PMCID: PMC6940112.

31. Abayomi TA, Ofusori DA, Ayoka OA, Odukoya SA, Omotoso EO, Amegor FO, Ajayi SA, Ojo GB, Oluwayinka OP. 2009; A comparative histological study of the tongue of rat (Rattus norvegicus), bat (Eidolon Helvum) and pangolin (Manis tricuspis). Int J Morphol. 27:1111–9. DOI: 10.4067/S0717-95022009000400026.

32. Maynard RL, Downes N. Maynard RL, Downes N, editors. 2019. Alimentary canal or gastrointestinal tract. Anatomy and Histology of the Laboratory Rat in Toxicology and Biomedical Research. Academic Press;London: p. 147–58. DOI: 10.1016/B978-0-12-811837-5.00013-7.

33. Osman HI, Abd El Razek N, Koura SA. 2006; Histological changes of rat lingual papillae due to chromium toxicity and the protective role of vitamin E. Egypt Dent J. 52:193–200.

34. Yang M, Zhao HP, Yang J. 2021; Effect of toothpaste containing emulsifier 30 and sodium lauryl sulfate surfactant on the integrity of oral epithelium. Shanghai Kou Qiang Yi Xue. 30:312–5. Chinese. PMID: 34476452.

35. Song C, Fu B, Zhang J, Zhao J, Yuan M, Peng W, Zhang Y, Wu H. 2017; Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway. Sci Rep. 7:672. Erratum in: Sci Rep 2018;8:7737. DOI: 10.1038/s41598-017-00796-3. PMID: 28386112. PMCID: PMC5429606. PMID: 2e9952cb85b44fb7992773223c598e75.

36. Kaeffer B. 2010; Exfoliated epithelial cells: potentials to explore gastrointestinal maturation of preterm infants. Rev Bras Saude Matern Infant. 10:13–24. DOI: 10.1590/S1519-38292010000100002.

37. Schwab M. 2011. Encyclopedia of Cancer. Springer-Verlag;Berlin: DOI: 10.1007/978-3-642-16483-5.

38. Maurer JK, Cheng MC, Boysen BG, Anderson RL. 1990; Two-year carcinogenicity study of sodium fluoride in rats. J Natl Cancer Inst. 82:1118–26. DOI: 10.1093/jnci/82.13.1118. PMID: 2359138.

39. Lu Y, Luo Q, Cui H, Deng H, Kuang P, Liu H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. 2017; Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging (Albany NY). 9:1623–39. DOI: 10.18632/aging.101257. PMID: 28657544. PMCID: PMC5509460.

40. Aronson JK. Aronson JK, editor. 2016. Tumor necrosis factor alfa. Meyler's Side Effects of Drugs. 16th ed. Elsevier;Amsterdam: p. 230–32. DOI: 10.1016/B978-0-444-53717-1.01608-5.

41. Fujita M, Shannon JM, Morikawa O, Gauldie J, Hara N, Mason RJ. 2003; Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta. Am J Respir Cell Mol Biol. 29:669–76. DOI: 10.1165/rcmb.2002-0046OC. PMID: 12816730.

42. Adkins EA, Brunst KJ. 2021; Impacts of fluoride neurotoxicity and mitochondrial dysfunction on cognition and mental health: a literature review. Int J Environ Res Public Health. 18:12884. DOI: 10.3390/ijerph182412884. PMID: 34948493. PMCID: PMC8700808. PMID: 67631e9742a448988bc9f0e69088df9b.

43. Peng W, Xu S, Zhang J, Zhang Y. 2019; Vitamin C attenuates sodium fluoride-induced mitochondrial oxidative stress and apoptosis via Sirt1-SOD2 pathway in F9 cells. Biol Trace Elem Res. 191:189–98. DOI: 10.1007/s12011-018-1599-0. PMID: 30565018.

44. Suen DF, Norris KL, Youle RJ. 2008; Mitochondrial dynamics and apoptosis. Genes Dev. 22:1577–90. DOI: 10.1101/gad.1658508. PMID: 18559474. PMCID: PMC2732420.

45. Miyazono Y, Hirashima S, Ishihara N, Kusukawa J, Nakamura KI, Ohta K. 2018; Uncoupled mitochondria quickly shorten along their long axis to form indented spheroids, instead of rings, in a fission-independent manner. Sci Rep. 8:350. DOI: 10.1038/s41598-017-18582-6. PMID: 29321618. PMCID: PMC5762872.

46. Arnoult D. 2007; Mitochondrial fragmentation in apoptosis. Trends Cell Biol. 17:6–12. DOI: 10.1016/j.tcb.2006.11.001. PMID: 17116393.

47. Davis MA, Jeffery EH. Haschek WM, Rousseaux CG, Wallig MA, editors. 2002. Organelle biochemistry and regulation of cell death. Handbook of Toxicologic Pathology. 2nd ed. Academic Press;Orlando: p. 67–81. DOI: 10.1016/B978-012330215-1/50005-3.

48. Mittal M, Flora SJ. 2006; Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice. Chem Biol Interact. 162:128–39. DOI: 10.1016/j.cbi.2006.05.018. PMID: 16828073.

49. Holley AK, Bakthavatchalu V, Velez-Roman JM, St Clair DK. 2011; Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci. 12:7114–62. DOI: 10.3390/ijms12107114. PMID: 22072939. PMCID: PMC3211030.

50. Hassan HA, Abdel-Aziz AF. 2010; Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats. Food Chem Toxicol. 48:1999–2004. DOI: 10.1016/j.fct.2010.05.018. PMID: 20472017.

51. Nabavi SM, Nabavi SF, Eslami S, Moghaddam AH. 2012; In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chem. 132:931–5. DOI: 10.1016/j.foodchem.2011.11.070.

52. Panneerselvam L, Subbiah K, Arumugam A, Senapathy JG. 2013; Ferulic acid modulates fluoride-induced oxidative hepatotoxicity in male Wistar rats. Biol Trace Elem Res. 151:85–91. DOI: 10.1007/s12011-012-9534-2. PMID: 23149809.

53. Powers SK, Smuder AJ, Judge AR. 2012; Oxidative stress and disuse muscle atrophy: cause or consequence? Curr Opin Clin Nutr Metab Care. 15:240–5. DOI: 10.1097/MCO.0b013e328352b4c2. PMID: 22466926. PMCID: PMC3893113.

54. Ranneh Y, Ali F, Akim AM, Hamid HA, Khazaai H, Fadel A. 2017; Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review. Appl Biol Chem. 60:327–38. DOI: 10.1007/s13765-017-0285-9.

55. Johar D, Roth JC, Bay GH, Walker JN, Kroczak TJ, Los M. 2004; Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz Akad Med Bialymst. 49:31–9. PMID: 15631311.

56. Amaral SL, Azevedo LB, Buzalaf MAR, Fabricio MF, Fernandes MS, Valentine RA, Maguire A, Zohoori FV. 2018; Effect of chronic exercise on fluoride metabolism in fluorosis-susceptible mice exposed to high fluoride. Sci Rep. 8:3211. DOI: 10.1038/s41598-018-21616-2. PMID: 29453343. PMCID: PMC5816643.

57. Vohra P. 1973; Fluoride tolerance of Japanese quail. Poult Sci. 52:391–3. DOI: 10.3382/ps.0520391. PMID: 4709783.

58. Tunali-Akbay T, Sehirli O, Ercan F, Sener G. 2010; Resveratrol protects against methotrexate-induced hepatic injury in rats. J Pharm Pharm Sci. 13:303–10. DOI: 10.18433/J30K5Q. PMID: 20816014. PMID: a6d9cfed1b2d4db283065b89439b7c5e.

59. Atmaca N, Atmaca HT, Kanici A, Anteplioglu T. 2014; Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol. 70:191–7. DOI: 10.1016/j.fct.2014.05.011. PMID: 24857819.

60. Pignet AL, Schellnegger M, Hecker A, Kohlhauser M, Kotzbeck P, Kamolz LP. 2021; Resveratrol-induced signal transduction in wound healing. Int J Mol Sci. 22:12614. DOI: 10.3390/ijms222312614. PMID: 34884419. PMCID: PMC8657598. PMID: 635432d94c2c4077ad907ce84256f1b0.

61. Alarcon de la Lastra C, Villegas I, Martin AR. Aggarwal BB, Shishodia S, editors. 2006. Resveratrol as an Antioxidant. Resveratrol in Health and Disease. CRC Press;Boca Raton: p. 33–56. DOI: 10.1201/9781420026474-3.

62. Konyalioglu S, Armagan G, Yalcin A, Atalayin C, Dagci T. 2013; Effects of resveratrol on hydrogen peroxide-induced oxidative stress in embryonic neural stem cells. Neural Regen Res. 8:485–95. DOI: 10.3969/j.issn.1673-5374.2013.06.001. PMID: 25206691. PMCID: PMC4146049.

63. Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, El May M, Gharbi N, Kamoun A, El-Fazaâ S. 2007; Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver. Life Sci. 80:1033–9. DOI: 10.1016/j.lfs.2006.11.044. PMID: 17258234.

64. Kolouchova-Hanzlikova I, Melzoch K, Filip V, Smidrkal J. 2004; Rapid method for resveratrol determination by HPLC with electrochemical and UV detections in wines. Food Chem. 87:151–8. DOI: 10.1016/j.foodchem.2004.01.028.

65. Kong F, Zhang R, Zhao X, Zheng G, Wang Z, Wang P. 2017; Resveratrol raises in vitro anticancer effects of paclitaxel in NSCLC cell line A549 through COX-2 expression. Korean J Physiol Pharmacol. 21:465–74. DOI: 10.4196/kjpp.2017.21.5.465. PMID: 28883751. PMCID: PMC5587597.

66. Zhou ZX, Mou SF, Chen XQ, Gong LL, Ge WS. 2018; Anti-inflammatory activity of resveratrol prevents inflammation by inhibiting NF-κB in animal models of acute pharyngitis. Mol Med Rep. 17:1269–74. DOI: 10.3892/mmr.2017.7933.

67. Duntas LH. 2011; Resveratrol and its impact on aging and thyroid function. J Endocrinol Invest. 34:788–92. DOI: 10.3275/7926. PMID: 21946130.

68. Chen TT, Peng S, Wang Y, Hu Y, Shen Y, Xu Y, Yin J, Liu C, Cao J. 2019; Improvement of mitochondrial activity and fibrosis by resveratrol treatment in mice with Schistosoma japonicum infection. Biomolecules. 9:658. DOI: 10.3390/biom9110658. PMID: 31717714. PMCID: PMC6920829.

69. Wang J, He F, Chen L, Li Q, Jin S, Zheng H, Lin J, Zhang H, Ma S, Mei J, Yu J. 2018; Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways. Biomed Pharmacother. 105:37–44. DOI: 10.1016/j.biopha.2018.05.104. PMID: 29843043.

70. Robb EL, Moradi F, Maddalena LA, Valente AJF, Fonseca J, Stuart JA. 2017; Resveratrol stimulates mitochondrial fusion by a mechanism requiring mitofusin-2. Biochem Biophys Res Commun. 485:249–54. DOI: 10.1016/j.bbrc.2017.02.102. PMID: 28235489.

71. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. 2006; Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 127:1109–22. DOI: 10.1016/j.cell.2006.11.013. PMID: 17112576.

72. Abolaji AO, Ajala VO, Adigun JO, Adedara IA, Kinyi HW, Farombi EO. 2019; Protective role of resveratrol, a natural polyphenol, in sodium fluoride-induced toxicity in Drosophila melanogaster. Exp Biol Med (Maywood). 244:1688–94. DOI: 10.1177/1535370219890334. PMID: 31766888. PMCID: PMC6963375.