Therapeutic outcome of quercetin nanoparticles on Cerastes cerastes venom-induced hepatorenal toxicity: a preclinical study
Abstract
Aim: The objective of this study was to investigate the therapeutic potential of quercetin (QT) and QT-loaded poly(lactic-co-glycolic acid) nanoparticles (QT-NPs) on Cerastes cerastes venom-mediated inflammation, redox imbalance, hepatorenal tissue damage and local hemorrhage. Methods: The developed QT-NPs were first submitted to physicochemical characterization and then evaluated in the ‘challenge then treat’ and ‘preincubation’ models of envenoming. Results: QT-NPs efficiently alleviated hepatorenal toxicity, inflammation and redox imbalance and significantly attenuated venom-induced local hemorrhage. Interestingly, QT-NPs were significantly more efficient than free QT at 24 h postenvenoming, pointing to the efficacy of this drug-delivery system. Conclusion: These findings highlight the therapeutic potential of QT-NPs on venom-induced toxicity and open up the avenue for their use in the management of snakebite envenoming.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Snakebite envenoming. Nat. Rev. Dis. Primers 3, 17063 (2017).
- 2. . Snake envenoming: a disease of poverty. PLOS Negl. Trop. Dis. 3(12), e569 (2009).
- 3. . Snakebite envenomation turns again into a neglected tropical disease! J. Venom. Anim. Toxins Incl. Trop. Dis. 23, 38 (2017).
- 4. World Health Organization. Snakebite envenoming: a strategy for prevention and control. WHO Document Production Services, 1–50, Geneva, Switzerland (2019). https://apps.who.int/iris/handle/10665/312195 (Accessed 2 June 2020). • Describes the global strategy of the WHO to reduce the impact of snakebite envenoming.
- 5. Strategy for a globally coordinated response to a priority neglected tropical disease: snakebite envenoming. PLOS Negl. Trop. Dis. 13(2), e0007059 (2019).
- 6. . A fibrinogen-clotting serine proteinase from Cerastes cerastes (horned viper) venom with arginine-esterase and amidase activities. Purification, characterization and kinetic parameter determination. Toxicon 30(11), 1399–1410 (1992).
- 7. . Afaâcytin, αβ-fibrinogenase from Cerastes cerastes (horned viper) venom, activates purified factor X and induces serotonin release from human blood platelets. Eur. J. Biochem. 233(3), 756–765 (1995).
- 8. . Venomous and poisonous animals. II. Viper bites. Med. Trop. (Mars.) 66(5), 423–428 (2006).
- 9. . Isolation and characterization of an anti-leishmanial disintegrin from Cerastes cerastes venom. J. Biochem. Mol. Toxicol. 32(2), e22018 (2018).
- 10. . Biochemical and biological characterization of a dermonecrotic metalloproteinase isolated from Cerastes cerastes snake venom. J. Biochem. Mol. Toxicol. 31(2), 2 (2016).
- 11. . Beneficial effects of heparin and L arginine on dermonecrosis effect induced by Vipera lebetina venom: involvement of NO in skin regeneration. Acta Trop. 171, 226–232 (2017).
- 12. . Myotoxicity induced by Cerastes cerastes venom: beneficial effect of heparin in skeletal muscle tissue regeneration. Acta Trop. 202, 105274 (2020).
- 13. . Irradiated Cerastes cerastes venom as a novel tool for immunotherapy. Immunopharmacol. Immunotoxicol. 30(1), 37–52 (2008).
- 14. . Therapeutic outcome of anti-inflammatory and antioxidative medicines on the dermonecrotic activity of Cerastes cerastes venom. Inflammation 45(4), 1700–1719 (2022).
- 15. . Pathophysiological and pharmacological effects of snake venom components: molecular targets. Clin. Toxicol. 4(2), 1–9 (2014).
- 16. Inflammation and oxidative stress in viper bite: an insight within and beyond. Toxicon 98, 89–97 (2015). •• Describes the contributory role of inflammation and oxidative stress in envenoming pathogenesis.
- 17. Evaluation of the genotoxicity of Crotalus durissus terrificus snake venom and its isolated toxins on human lymphocytes. Mut. Res. 724(1–2), 59–63 (2011).
- 18. . Cytotoxicity of Cerastes cerastes snake venom: involvement of imbalanced redox status. Acta Trop. 173, 116–124 (2017).
- 19. . Guidelines for the production, control and regulation of snake antivenom immunoglobulins. Biol. Aujourdhui 204(1), 87–91 (2010).
- 20. A multicomponent strategy to improve the availability of antivenom for treating snakebite envenoming. Bull. World Health Organ. 92(7), 526–532 (2014).
- 21. . Snake antivenoms. J. Toxicol. Clin. Toxicol. 41(3), 277–290 (2003).
- 22. Preclinical antivenom – efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa. PLOS Negl. Trop. Dis. 11(10), e0005969 (2017).
- 23. . Adverse reactions to snake antivenom, and their prevention and treatment. Br. J. Clin. Pharmacol. 81(3), 446–452 (2016).
- 24. The Global Snake Bite Initiative: an antidote for snake bite. Lancet 375(9708), 89–91 (2010).
- 25. The urgent need to develop novel strategies for the diagnosis and treatment of snakebites. Toxins 11(6), 363 (2019).
- 26. . Pharmacokinetics of snake venom. Toxins 10(2), 73 (2018).
- 27. . Melatonin inhibits snake venom and antivenom induced oxidative stress and augments treatment efficacy. Acta Trop. 169, 14–25 (2017).
- 28. . Developing small molecule therapeutics for the initial and adjunctive treatment of snakebite. J. Trop. Med. 2018, 4320175 (2018).
- 29. . Research into the causes of venom-induced mortality and morbidity identifies new therapeutic opportunities. Am. J. Trop. Med. Hyg. 100(5), 1043–1048 (2019).
- 30. The search for natural and synthetic inhibitors that would complement antivenoms as therapeutics for snakebite envenoming. Toxins 13(7), 451 (2021). •• Discusses the key aspect in the search for novel venom inhibitory compounds and summarizes some of the most promising developments in this field.
- 31. . Small molecule drug discovery for neglected tropical snakebite. Trends Pharmacol. Sci. 42(5), 340–353 (2021).
- 32. . Viper venom-induced oxidative stress and activation of inflammatory cytokines: a therapeutic approach for overlooked issues of snakebite management. Inflamm. Res. 62(7), 721–731 (2013).
- 33. . Rutin (quercetin-3-rutinoside) modulates the hemostatic disturbances and redox imbalance induced by Bothrops jararaca snake venom in mice. PLOS Negl. Trop. Dis. 12(10), e0006774 (2018).
- 34. . Perspective on the therapeutics of anti-snake venom. Molecules (Basel) 24(18), 3276 (2019).
- 35. . Antioxidant activity of quercetin and its glucosides from propolis: a theoretical study. Sci. Rep. 7(1), 7543 (2017).
- 36. Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-beta1/Smads and PI3K/Akt pathways. Sci. Rep. 7(1), 9289 (2017).
- 37. Quercetin, a natural flavonoid interacts with DNA, arrests cell cycle and causes tumor regression by activating mitochondrial pathway of apoptosis. Sci. Rep. 6, 24049 (2016).
- 38. Rheumatoid arthritis induces enteric neurodegeneration and jejunal inflammation, and quercetin promotes neuroprotective and anti-inflammatory actions. Life Sci. 238, 116956 (2019).
- 39. . Combined effects of quercetin and curcumin on anti-inflammatory and antimicrobial parameters in vitro. Eur. J. Pharmacol. 859, 172486 (2019).
- 40. Quercetin as a Lyn kinase inhibitor inhibits IgE-mediated allergic conjunctivitis. Food Chem. Toxicol. 135, 110924 (2020).
- 41. . Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Antioxid. Redox Signal. 13(5), 691–719 (2010).
- 42. Flavonoids inhibit COX-1 and COX-2 enzymes and cytokine/chemokine production in human whole blood. Inflammation 38(2), 858–870 (2015).
- 43. . Dietary flavonoids as xanthine oxidase inhibitors: structure–affinity and structure–activity relationships. J. Agric. Food Chem. 63(35), 7784–7794 (2015).
- 44. Correlating in vitro target-oriented screening and docking: inhibition of matrix metalloproteinases activities by flavonoids. Planta Med. 83(11), 901–911 (2017).
- 45. Protective effect of quercetin on posttraumatic cardiac injury. Sci. Rep. 6(1), 30812 (2016).
- 46. . Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules 10(1), 59 (2019).
- 47. Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells. Cell Biosci. 10(1), 32 (2020).
- 48. . The antidiabetic potential of quercetin: underlying mechanisms. Curr. Med. Chem. 24(4), 355–364 (2017).
- 49. . Quercetin alleviates high-fat diet-induced inflammation in brown adipose tissue. J. Funct. Foods 85, 104614 (2021).
- 50. . Towards an understanding of the low bioavailability of quercetin: a study of its interaction with intestinal lipids. Nutrients 9(2), 111 (2017).
- 51. Therapeutic potential of quercetin based on nanotechnology: a review. Revista Virtual Química 11, 1405–1416 (2019).
- 52. . Nanotechnology innovations to enhance the therapeutic efficacy of quercetin. Nanomaterials 11(10), 2658 (2021). • Demonstrates the potential biomedical and healthcare applications of quercetin nanoparticles.
- 53. Polymeric nanoparticles for drug delivery: recent developments and future prospects. Nanomaterials 10(7), 1403 (2020).
- 54. . Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3(3), 1377–1397 (2011).
- 55. . Development and evaluation of polymeric nanoparticles as a delivery system for snake envenoming prevention. Biologicals 70, 44–52 (2021).
- 56. Improved therapeutic efficacy of quercetin-loaded polymeric nanoparticles on triple-negative breast cancer by inhibiting uPA. RSC Adv. 10(57), 34517–34526 (2020).
- 57. Quercetin-loaded PLGA nanoparticles: a highly effective antibacterial agent in vitro and anti-infection application in vivo. J. Nanopart. Res. 18(1), 3 (2015).
- 58. . PLGA–quercetin nano-formulation inhibits cancer progression via mitochondrial dependent caspase-3,7 and independent FOXO1 activation with concomitant PI3K/AKT suppression. Pharmaceutics 14(7), 1326 (2022).
- 59. . Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int. J. Pharm. 55(1), R1–R4 (1989).
- 60. . Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity: assessment of inflammation in rat and hamster models. Gastroenterology 87(6), 1344–1350 (1984).
- 61. . A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J. Immunol. Methods 38(1), 161–170 (1980).
- 62. . Oxidative stress and beta cell dysfunction. Methods Mol. Biol. 900, 347–362 (2012).
- 63. . Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95(2), 351–358 (1979).
- 64. . Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem. 47(3), 469–474 (1974).
- 65. . Studies on the quantitative method for determination of hemorrhagic activity of Habu snake venom. Jpn. J. Med. Sci. Biol. 13(1–2), 43–51 (1960).
- 66. . Development of simple standard assay procedures for the characterization of snake venom. Bull. World Health Organ. 61(6), 949–956 (1983).
- 67. Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology. Molecules 25(16), 3731 (2020).
- 68. . Shape dependent cytotoxicity of PLGA–PEG nanoparticles on human cells. Sci. Rep. 7(1), 7315 (2017).
- 69. . Control of polymeric nanoparticle size to improve therapeutic delivery. J. Control. Rel. 219, 536–547 (2015).
- 70. . Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307(1), 93–102 (2006).
- 71. . Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5(4), 505–515 (2008).
- 72. . Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers. Adv. Drug Deliv. Rev. 157, 142–160 (2020).
- 73. . Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors. Expert Opin. Drug Deliv. 19(2), 199–212 (2021).
- 74. . Nanoparticle ζ -potentials. Acc. Chem. Res. 45(3), 317–326 (2012).
- 75. The effects of quercetin-loaded PLGA–TPGS nanoparticles on ultraviolet B-induced skin damages in vivo. Nanomedicine 12(3), 623–632 (2016).
- 76. . Smart PLGA nanoparticles loaded with quercetin: cellular uptake and in-vitro anticancer study. Mater. Today Proc. 5(3), 9698–9705 (2018).
- 77. Nanoencapsulated quercetin improves cardioprotection during hypoxia–reoxygenation injury through preservation of mitochondrial function. Oxid. Med. Cell. Longev. 2019, 7683051 (2019).
- 78. . Neuroprotective role of nanoencapsulated quercetin in combating ischemia–reperfusion induced neuronal damage in young and aged rats. PLOS ONE 8(4), e57735 (2013).
- 79. . Quercetin-loaded nanoparticles enhance cytotoxicity and antioxidant activity on C6 glioma cells. Pharm. Dev. Technol. 25(6), 757–766 (2020).
- 80. . Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem. Rev. 116(4), 2602–2663 (2016).
- 81. . Pathophysiological effects of Cerastes cerastes and Vipera lebetina venoms: immunoneutralization using anti-native and anti-(60)Co irradiated venoms. Biologicals 44(1), 1–11 (2016).
- 82. . Hepatotoxicity and oxidative stress induced by Naja haje crude venom. J. Venom. Anim. Toxins Incl. Trop. Dis. 20(1), 42–42 (2014).
- 83. . Serum biomarkers for acute hepatotoxicity of Echis pyramidum snake venom in rats. Int. J. Clin. Exp. Med. 8(1), 1376–1380 (2015).
- 84. . Acute hepatotoxicity of Crotalus durissus terrificus (South American rattlesnake) venom in rats. J. Venom. Anim. Toxins Incl. Trop. Dis 15(1), 61–78 (2009).
- 85. Acute kidney injury following Eastern Russell’s viper (Daboia siamensis) snakebite in Myanmar. Kidney Int. Rep. 4(9), 1337–1341 (2019).
- 86. . Clinicopathological spectrum of snake bite-induced acute kidney injury from India. World J. Nephrol. 6(3), 150–161 (2017).
- 87. Evaluation of the geographical utility of Eastern Russell’s viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity. PLOS Negl. Trop. Dis. 13(10), e0007338 (2019).
- 88. . Allopurinol reduces the lethality associated with acute renal failure induced by Crotalus durissus terrificus snake venom: comparison with probenecid. PLOS Negl. Trop. Dis. 5(9), e1312 (2011).
- 89. Acute kidney injury induced by Bothrops venom: insights into the pathogenic mechanisms. Toxins 11(3), 148 (2019).
- 90. Oxidative stress-induced methemoglobinemia is the silent killer during snakebite: a novel and strategic neutralization by melatonin. J. Pineal Res. 59(2), 240–254 (2015).
- 91. . Polymorphonuclear neutrophil leukocytes in snakebite envenoming. Toxicon 187, 188–197 (2020).
- 92. . The role of neutrophils in host defense and disease. J. Allergy Clin. Immunol. 145(6), 1535–1544 (2020).
- 93. . Tumor necrosis factor signaling. Cell Death Differ. 10(1), 45–65 (2003).
- 94. Immune response to snake envenoming and treatment with antivenom; complement activation, cytokine production and mast cell degranulation. PLOS Negl. Trop. Dis. 7(7), e2326 (2013).
- 95. Melatonin alleviates Echis carinatus venom-induced toxicities by modulating inflammatory mediators and oxidative stress. J. Pineal Res. 56(3), 295–312 (2014).
- 96. . Human cytokine response to Texas crotaline envenomation before and after antivenom administration. Am. J. Emerg. Med. 28(8), 871–879 (2010).
- 97. . Polymorphonuclear neutrophil leukocytes in snakebite envenoming. Toxicon 187, 188–197 (2020).
- 98. Contribution of endothelial cell and macrophage activation in the alterations induced by the venom of Micrurus tener tener in C57BL/6 mice. Mol. Immunol. 116, 45–55 (2019).
- 99. . ROS function in redox signaling and oxidative stress. Curr. Biol. 24(10), 034 (2014).
- 100. . NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2(1), 17023 (2017).
- 101. . Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model. Drug Deliv. Transl. Res. 2(2), 112–123 (2012).
- 102. . Iron chelation by the powerful antioxidant flavonoid quercetin. J. Agric. Food Chem. 54(17), 6343–6351 (2006).
- 103. . Antioxidant activity of quercetin: a mechanistic review. Turk. J. Agric. For. 4(12), 1134–1138 (2016).
- 104. Quercetin, inflammation and immunity. Nutrients 8(3), 167 (2016). • Describes the pharmacological properties of quercetin.
- 105. . Antioxidant activities of quercetin and its complexes for medicinal application. Molecules 24(6), 1123 (2019).
- 106. . Quercetin protects against lipopolysaccharide-induced intestinal oxidative stress in broiler chickens through activation of Nrf2 pathway. Molecules 25(5), 1053 (2020).
- 107. . Quercetin inhibition of myocardial fibrosis through regulating MAPK signaling pathway via ROS. Pak. J. Pharm. Sci. 32(3 Special), 1355–1359 (2019).
- 108. Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice. Mol. Nutr. Food Res. 60(2), 300–312 (2016).
- 109. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int. J. Med. Sci. 11(3), 282–290 (2014).
- 110. Quercetin attenuates trauma-induced heterotopic ossification by tuning immune cell infiltration and related inflammatory insult. Front. Immunol. 12, 649285 (2021).
- 111. . Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. Redox Biol. 9, 104–113 (2016).
- 112. . Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium. Int. J. Nanomed. 12, 7799–7813 (2017).
- 113. Quercetin as an inhibitor of snake venom secretory phospholipase A2. Chem. Biol. Interact. 189(1–2), 9–16 (2011). •• Study demonstrating quercetin’s inhibitory potential against snake venom secretory phospholipase A2.
- 114. . Quercetin-3-O-rhamnoside from Euphorbia hirta protects against snake venom induced toxicity. Biochim. Biophys. Acta 1860(7), 1528–1540 (2016).
- 115. An evaluation of 3-rhamnosylquercetin, a glycosylated form of quercetin, against the myotoxic and edematogenic effects of sPLA 2 from Crotalus durissus terrificus. BioMed Res. Int. 341270(10), 18 (2014).
- 116. Novel apigenin based small molecule that targets snake venom metalloproteases. PLOS ONE 9(9), e106364 (2014).
- 117. . Inhibition of a snake venom metalloproteinase by the flavonoid myricetin. Molecules 23(10), 2662 (2018).
- 118. . Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper snake venom: insights from docking and molecular modeling. Toxicon 71, 41–48 (2013).
- 119. . Quercetin supplementation and upper respiratory tract infection: a randomized community clinical trial. Pharmacol. Res. 62(3), 237–242 (2010).
- 120. Isoquercetin as an adjunct therapy in patients with kidney cancer receiving first-line sunitinib (QUASAR): results of a phase I trial. Front. Pharmacol. 9, 189 (2018).
- 121. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight 4(4), e125851 (2019).
- 122. . The effect of quercetin supplementation on oxidative stress, glycemic control, lipid profile and insulin resistance in type 2 diabetes: a randomized clinical trial. J. Health Sci. Surveillance Syst. 2(1), 8–14 (2014).
- 123. . Quercetin dampens postprandial hyperglycemia in type 2 diabetic patients challenged with carbohydrates load. Int. J. Diabetes Res. 1(3), 32–35 (2012).
- 124. . Does quercetin improve cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes: a double-blind randomized controlled clinical trial. Int. J. Prev. Med. 4(7), 777 (2013).
- 125. A randomized placebo-controlled double blind clinical trial of quercetin in the prevention and treatment of chemotherapy-induced oral mucositis. J. Clin. Diagn. Res. 11(3), ZC46–ZC50 (2017).
- 126. . Effects of quercetin supplementation on hematological parameters in non-alcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Clin. Nutr. Res. 9(1), 11–19 (2020).