Total flavonoids of Selaginella tamariscina (P. Beauv.) Spring ameliorates diabetes-induced acute lung injury via activating Nrf2/ HO-1

Document Type : Original Article

Authors

1 Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, China

2 Department of Clinical Medicine, Guizhou Medical University, Guiyang, 550001, Guizhou, China

3 Department of Tuberculosis, Guiyang Public Health Clinical Center, Guiyang, 550001, Guizhou, China

4 Department of Respiratory and Critical Care Medicine, The Fourth People’s Hospital of Guiyang, Guiyang, 550002, Guizhou, China

10.22038/ijbms.2024.79246.17166

Abstract

Objective(s): This investigation explored the mechanism by which the total flavonoids of Selaginella tamariscina (P.Beauv.) Spring (TFST) mitigate oxidative stress through the activation of the heme oxygenase-1 (HO-1) signaling pathway mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), thereby ameliorating acute lung injury (ALI) induced by diabetes. 
Materials and Methods: Male mice weighing 20–25 grams were divided into four groups: a control group, a diabetic group, a diabetic group treated with TFST, and a diabetic group treated with TFST and ML385. Various biological specimens were collected for analysis, including bronchoalveolar lavage fluid (BALF), blood, and tissue samples. These were subjected to a range of assessments covering hematological and BALF parameters tumor necrosis factor-alpha (TNF-α), interleukin-6 [IL-6]), biochemical markers (malondialdehyde [MDA], superoxide dismutase [SOD], glutathione peroxidase [GSH], Nrf2, and HO-1 levels), along with histopathological evaluations.
Results: Pre-treatment with TFST demonstrated a significant decrease in 
pulmonary tissue damage, evidenced by decreased wet-to-dry (W/D) lung ratios (P<0.001), reduced lung injury scores (P<0.0001), and lower levels of TNF-α, IL-6 (P<0.0001), as well as oxidative stress markers like MDA (P<0.05). Moreover, there was an elevation in the activity of anti-oxidative enzymes, specifically SOD and GSH (P<0.05), coupled with an enhanced expression of Nrf2 and HO-1 in the diabetic group (P<0.01). 
Conclusion: The study findings demonstrate that TFST can suppress oxidative stress by modulating the Nrf2 pathway and up-regulating HO-1 activity, thereby ameliorating diabetes-induced acute lung injury.

Keywords

Main Subjects


1. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138:271-281.
2. Hameed I, Masoodi SR, Mir SA, Nabi M, Ghazanfar K, Ganai BA. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J Diabetes 2015; 6:598-612.
3. Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BEK, et al. Diabetic microvascular disease: An endocrine society scientific statement. J Clin Endocrinol Metab 2017; 102:4343-4410.
4. Pitocco D, Fuso L, Conte EG, Zaccardi F, Condoluci C, Scavone G, et al. The diabetic lung--a new target organ? Rev Diabet Stud 2012; 9:23-35.
5. Wu J, Jin Z, Yan LJ. Redox imbalance and mitochondrial abnormalities in the diabetic lung. Redox Biol 2017; 11:51-59.
6. Talakatta G, Sarikhani M, Muhamed J, Dhanya K, Somashekar BS, Mahesh PA, et al. Diabetes induces fibrotic changes in the lung through the activation of TGF-β signaling pathways. Sci Rep 2018; 8:11920-11934.
7. Gläser S, Krüger S, Merkel M, Bramlage P, Herth FJ. Chronic obstructive pulmonary disease and diabetes mellitus: A systematic review of the literature. Respiration 2015; 89:253-264.
8. Albano GD, Gagliardo RP, Montalbano AM, Profita M. Overview of the mechanisms of oxidative stress: Impact in inflammation of the airway diseases. Antioxidants (Basel) 2022; 11:2237-2261.
9. Yadav R, Kailashiya V, Sharma HB, Pandey R, Bhagat P. Persistent hyperglycemia worsens the oleic acid induced acute lung injury in rat model of type II diabetes mellitus. J Pharm Bioallied Sci 2023; 15:197-204.
10. Wang D, Ma Y, Tong X, Zhang Y, Fan H. Diabetes mellitus contributes to idiopathic pulmonary fibrosis: A review from clinical appearance to possible pathogenesis. Front Public Health 2020; 8:196-202.
11. Johnson ER, Matthay MA. Acute lung injury: Epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv 2010; 23:243-252.
12. Fanelli V, Ranieri VM. Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc 2015; 12 Suppl 1:S3-S8.
13. Nieman GF, Gatto LA, Andrews P, Satalin J, Camporota L, Daxon B, et al. Prevention and treatment of acute lung injury with time-controlled adaptive ventilation: Physiologically informed modification of airway pressure release ventilation. Ann Intensive Care 2020; 10:3-18.
14. Ji M, Chen M, Hong X, Chen T, Zhang N. The effect of diabetes on the risk and mortality of acute lung injury/acute respiratory distress syndrome: A meta-analysis. Medicine (Baltimore) 2019; 98:e15095.
15. Boyle AJ, Madotto F, Laffey JG, Bellani G, Pham T, Pesenti A, et al. Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: An analysis of the LUNG SAFE database. Crit Care 2018; 22:268-281.
16. Moss M, Burnham EL. Chronic alcohol abuse, acute respiratory distress syndrome, and multiple organ dysfunction. Crit Care Med 2003; 31:S207-S212.
17. Esper A, Burnham EL, Moss M. The effect of alcohol abuse on ARDS and multiple organ dysfunction. Minerva Anestesiol 2006; 72:375-381.
18. Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, Christman BW, Dupont WD, et al. Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in sepsis study group. Crit Care Med 2000; 28:3137-3145.
19. Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191-1198.
20. Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, et al. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med 2000; 28:2187-2192.
21. Kong L, Deng J, Zhou X, Cai B, Zhang B, Chen X, et al. Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury. Cell Death Dis 2021; 12:928-938.
22. Uruno A, Yagishita Y, Yamamoto M. The Keap1-Nrf2 system and diabetes mellitus. Arch Biochem Biophys 2015; 566:76-84.
23. Liu C, Hua H, Zhu H, Cheng Y, Guo Y, Yao W, et al. Aloe polysaccharides ameliorate acute colitis in mice via Nrf2/HO-1 signaling pathway and short-chain fatty acids metabolism. Int J Biol Macromol 2021; 185:804-812.
24. Zhang Y, Han Z, Jiang A, Wu D, Li S, Liu Z, et al. Protective effects of pterostilbene on lipopolysaccharide-induced acute lung injury in mice by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways. Front Pharmacol 2020; 11:591836.
25. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016; 73:3221-3247.
26. Liu X, Wang X, Chang J, Zhang H, Cao P. Landscape analysis and overview of the literature on oxidative stress and pulmonary diseases. Front Pharmacol 2023; 14:1190817.
27. Zhang H, Zeng J, Li J, Gong H, Chen M, Li Q, et al. Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways. Biomol Biomed 2023; 23:457-470.
28. Bailly C. The traditional and modern uses of Selaginella tamariscina (P.Beauv.) Spring, in medicine and cosmetic: Applications and bioactive ingredients. J Ethnopharmacol 2021; 280:114444.
29. Long HP, Liu J, Xu PS, Xu KP, Li J, Tan GS. Hypoglycemic flavonoids from Selaginella tamariscina (P.Beauv.) Spring. Phytochemistry 2022; 195:113073.
30. Zheng XK, Wang WW, Zhang L, Su CF, Wu YY, Ke YY, et al. Antihyperlipidaemic and anti-oxidant effect of the total flavonoids in Selaginella tamariscina (Beauv.) Spring in diabetic mice. J Pharm Pharmacol 2013; 65:757-766.
31. Liu H, Peng H, Ji Z, Zhao S, Zhang Y, Wu J, et al. Reactive oxygen species-mediated mitochondrial dysfunction is involved in apoptosis in human nasopharyngeal carcinoma CNE cells induced by Selaginella doederleinii extract. J Ethnopharmacol 2011; 138:184-191.
32. Zheng XK, Liu CX, Zhai YY, Li LL, Wang XL, Feng WS. Protection effect of amentoflavone in Selaginella tamariscina against TNF-alpha-induced vascular injury of endothelial cells. Yao Xue Xue Bao 2013; 48:1503-1509.
33. Yang SF, Chu SC, Liu SJ, Chen YC, Chang YZ, Hsieh YS. Antimetastatic activities of Selaginella tamariscina (Beauv.) on lung cancer cells in vitro and in vivo. J Ethnopharmacol 2007; 110:483-489.
34. Shim SY, Lee SG, Lee M. Biflavonoids isolated from Selaginella tamariscina and their anti-inflammatory activities via ERK 1/2 signaling. Molecules 2018; 23:926-937.
35. Zhang J, Zhang M, Zhang WH, Zhu QM, Huo XK, Sun CP, et al. Total flavonoids of Inula japonica alleviated the inflammatory response and oxidative stress in LPS-induced acute lung injury via inhibiting the sEH activity: Insights from lipid metabolomics. Phytomedicine 2022; 107:154380.
36. Atta AH, Saad SA, Atta SA, Mouneir SM, Nasr SM, Desouky HM, et al. Cucumis sativus and Cucurbita maxima extract attenuate diabetes-induced hepatic and pancreatic injury in a rat model. J Physiol Pharmacol 2020; 71:507-518.
37. Zheng H, Wu J, Jin Z, Yan LJ. Potential biochemical mechanisms of lung injury in diabetes. Aging Dis 2017; 8:7-16.
38. Südy R, Schranc Á, Fodor GH, Tolnai J, Babik B, Peták F. Lung volume dependence of respiratory function in rodent models of diabetes mellitus. Respir Res 2020; 21:82-93.
39. Redmann M, Darley-Usmar V, Zhang J. The role of autophagy, mitophagy and lysosomal functions in modulating bioenergetics and survival in the context of redox and proteotoxic damage: Implications for neurodegenerative diseases. Aging Dis 2016; 7:150-162.
40. Yan LJ. Positive oxidative stress in aging and aging-related disease tolerance. Redox Biol 2014; 2:165-169.
41. Yan LJ. Protein redox modification as a cellular defense mechanism against tissue ischemic injury. Oxid Med Cell Longev 2014; 2014:343154.
42. Zheng H, Wu J, Jin Z, Yan LJ. Protein modifications as manifestations of hyperglycemic glucotoxicity in diabetes and its complications. Biochem Insights 2016; 9:1-9.
43. Williams JG, Morris AI, Hayter RC, Ogilvie CM. Respiratory responses of diabetics to hypoxia, hypercapnia, and exercise. Thorax 1984; 39:529-534.
44. Eren G, Cukurova Z, Hergunsel O, Demir G, Kucur M, Uslu E, et al. Protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in lung injury in rats with streptozotocin-induced diabetes. Respiration 2010; 79:402-410.
45. Zheng M, Zou C, Li M, Huang G, Gao Y, Liu H. Folic acid reduces tau phosphorylation by regulating PP2A methylation in streptozotocin-induced diabetic mice. Int J Mol Sci 2017; 18:861-873.
46. David JA, Rifkin WJ, Rabbani PS, Ceradini DJ. The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus. J Diabetes Res 2017; 2017:4826724.
47. Albert-Garay JS, Riesgo-Escovar JR, Salceda R. High glucose concentrations induce oxidative stress by inhibiting Nrf2 expression in rat Müller retinal cells in vitro. Sci Rep 2022; 12:1261-1272.
48. Motohashi H, Katsuoka F, Engel JD, Yamamoto M. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci U S A 2004; 101:6379-6384.
49. Yi M, Cruz Cisneros L, Cho EJ, Alexander M, Kimelman FA, Swentek L, et al. Nrf2 Pathway and oxidative stress as a common target for treatment of diabetes and its comorbidities. Int J Mol Sci 2024; 25:821-840.
50. Won AN, Kim SA, Ahn JY, Han JH, Kim CH, Lee JH, et al. HO-1 induction by Selaginella tamariscina extract inhibits inflammatory response in lipopolysaccharide-stimulated RAW 264.7 macrophages. Evid Based Complement Alternat Med 2018; 2018:7816923.
51. Torrente L, DeNicola GM. Targeting NRF2 and its downstream processes: Opportunities and challenges. Annu Rev Pharmacol Toxicol 2022; 62:279-300.
52. Xiong XQ, Wang WT, Wang LR, Jin LD, Lin LN. Diabetes increases inflammation and lung injury associated with protective ventilation strategy in mice. Int Immunopharmacol 2012; 13:280-283.
53. Dinkova-Kostova AT, Copple IM. Advances and challenges in therapeutic targeting of NRF2. Trends Pharmacol Sci 2023; 44:137-149.
54. Hu JF, Zhang GJ, Wang L, Kang PF, Li J, Wang HJ, et al. Ethanol at low concentration attenuates diabetes induced lung injury in rats model. J Diabetes Res 2014; 2014:107152.
55. Zheng XK, Zhang L, Wang WW, Wu YY, Zhang QB, Feng WS. Anti-diabetic activity and potential mechanism of total flavonoids of Selaginella tamariscina (Beauv.) Spring in rats induced by high fat diet and low dose STZ. J Ethnopharmacol 2011; 137:662-668.
56. Wang X, Feng A, Yuan P, Fu Y, Bai Z, Zhou N, et al. The total flavonoids from Selaginella tamariscina (Beauv.) Spring improve glucose and lipid metabolism in db/db mice. Iran J Basic Med Sci 2020; 23:1286-1292.
57. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.
58. Nathan DM. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: Overview. Diabetes Care 2014; 37:9-16.
59. Esper AM, Moss M, Martin GS. The effect of diabetes mellitus on organ dysfunction with sepsis: An epidemiological study. Crit Care 2009; 13:R18-R23.
60. Yu S, Christiani DC, Thompson BT, Bajwa EK, Gong MN. Role of diabetes in the development of acute respiratory distress syndrome. Crit Care Med 2013; 41: 2720–2732.