The effect of sulbutiamine, thiamine, riboflavin and their combinations on apoptotic biomarkers (CASP-3, CASP-9) and neutrophil gelatinase-associated lipocalin in vancomycin-induced acute renal failure in male rats
DOI:
https://doi.org/10.32947/ajps.v25i2.1142Keywords:
Vancomycin, ARF, Sulbutiamine, Apoptosis, NGALAbstract
Vancomycin is a glycopeptide antibiotic used to treat anaerobic and aerobic gram-positive bacteria, for example, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis. Vancomycin had some side effects, such as nephrotoxicity, ototoxicity, hypersensitivity reactions, and more. The present study aimed to evaluate the potential apoptotic effect of vancomycin on renal tissue and also evaluate the reno-protective effects of sulbutiamine, thiamine, riboflavin, and their combinations through inhibiting apoptosis.
Forty-two male rats were employed in this study, divided randomly into seven groups: the first group was the control group, the second group (the vancomycin group received 200 mg/ml twice daily) from the 15th-21st day of the study, and the other three groups were pretreated with sulbutiamine (50 mg/kg, orally once daily), thiamine (100 mg/kg, orally once daily), and riboflavin (100 mg/kg, orally once daily), respectively, for 21 days of the study. The sixth group was a combination group that received a mix of sulbutiamine and riboflavin, and the seventh group received a mix of thiamine and riboflavin for 21 days. The last five groups received vancomycin 200 mg/ml twice daily from the 15th-21st day of the study. The result of this study showed a significant increase p<0.05 in caspase-3, caspase-9, and NGAL in the induction group, while in the other group that was pretreated with sulbutiamine, thiamine, riboflavin, and their combinations, the mean tissue CASP-3, CASP-9, and concentration were significantly decreased. We concluded that the sulbutiamine, thiamine, and riboflavin-treated groups showed a significant decrease in caspase 3, caspase 9, and NGAL levels compared to the vancomycin-treated group. The combination group (sulbutiamine and riboflavin) showed the most significant decrease in mean tissue concentrations of CASP3, CASP9, and NGAL due to the additive effects of both treatments.
References
1- Saxena A, Meshram SV. Predictors of Mortality in Acute Kidney Injury Patients Admitted to Medicine Intensive Care Unit in a Rural Tertiary Care Hospital. Indian J Crit Care Med. 2018 Apr 22; (4):231-237.
2- Shang W, Wang Z. The Update of NGAL in Acute Kidney Injury. Curr Protein Pept Sci. 2017;18(12):1211-1217.
3- Vaara ST, Lakkisto P, Immonen K, Tikkanen I, Ala-Kokko T, Pettilä V; FINNAKI Study Group. Urinary Biomarkers Indicative of Apoptosis and Acute Kidney Injury in the Critically Ill. PLoS One. 2016 Feb 26;11(2):e0149956.
4- Umstätter F, Domhan C, Hertlein T, Ohlsen K, Mühlberg E, Kleist C, Zimmermann S, Beijer B, Klika KD, Haberkorn U, Mier W, Uhl P. Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides. Angew Chem Int Ed Engl. 2020 Jun 2;59(23):8823-8827.
5- Elyasi S, Khalili H, Dashti-Khavidaki S, Mohammadpour A. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review. Eur J Clin Pharmacol. 2012 Sep;68(9):1243-55.
6- Yu P, Luo J, Song H, Qian T, He X, Fang J, Dong W, Bian X. N-acetylcysteine Ameliorates Vancomycin-induced Nephrotoxicity by Inhibiting Oxidative Stress and Apoptosis in the in vivo and in vitro Models. Int J Med Sci. 2022 Apr 11;19(4):740-752.
7- Abd, Abdulkareem & Qasim, Ban & Sahib, Hayder & Raheem, Hanaa. Nephroprotective Effect of Vitamin E and Origanum vulgare Extracts against Vancomycin Induced Nephrotoxicity in Rats. International Journal of Pharmaceutical Sciences Review and Research. 2016 Aug 17; 36. 89-96.
8- Gupta A, Biyani M, Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med. 2011 Sep;69(9):379-83.
9- Arimura Y, Yano T, Hirano M, Sakamoto Y, Egashira N, Oishi R. Mitochondrial superoxide production contributes to vancomycin-induced renal tubular cell apoptosis. Free Radic Biol Med. 2012 May 1;52(9):1865-73.
10- Mergenhagen KA, Borton AR. Vancomycin nephrotoxicity: a review. J Pharm Pract. 2014 Dec;27(6):545-53.
11- Kan WC, Chen YC, Wu VC, Shiao CC. Vancomycin-Associated Acute Kidney Injury: A Narrative Review from Pathophysiology to Clinical Application. Int J Mol Sci. 2022 Feb 12;23(4):2052.
12- Han SJ, Lee HT. Mechanisms and therapeutic targets of ischemic acute kidney injury. Kidney Res Clin Pract. 2019 Dec 31;38(4):427-440.
13- Xu W, Mao Z, Zhao B, Ni T, Deng S, Yu P, He J, Mao E. Vitamin C attenuates vancomycin induced nephrotoxicity through the reduction of oxidative stress and inflammation in HK-2 cells. Ann Palliat Med. 2021 Feb;10(2):1748-1754.
14- Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB. Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother. 2018 Sep;105:981-991
15- Starling-Soares B, Carrera-Bastos P, Bettendorff L. Role of the Synthetic B1 Vitamin Sulbutiamine on Health. J Nutr Metab. 2020 Apr 20;2020:9349063.
16- Sevim S, Kaleağası H, Taşdelen B. Sulbutiamine shows promising results in reducing fatigue in patients with multiple sclerosis. Mult Scler Relat Disord. 2017 Aug;16:40-43.
17- Kang KD, et al. Sulbutiamine counteracts trophic factor deprivation induced apoptotic cell death in transformed retinal ganglion cells. Neurochem Res. 2010 Nov;35(11):1828-39.
18- Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults. Front Psychiatry. 2019 Apr 4;10:207.
19- Tallaksen CM, Taubøll E. Excitatory effect of thiamin on CA1 pyramidal neurones in rat hippocampal slices in vitro. Eur J Neurol. 2000 Nov;7(6):693-8.
20- Mrowicka M, Mrowicki J, Dragan G, Majsterek I. The importance of thiamine (vitamin B1) in humans. Biosci Rep. 2023 Oct 31;43(10):BSR20230374.
21- Gibson GE, Zhang H. Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Neurochem Int. 2002 May;40(6):493-504.
22- Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ. Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism. Int J Mol Sci. 2020 May 28;21(11):3847.
23- Bodiga VL, Bodiga S, Surampudi S, Boindala S, Putcha U, Nagalla B, Subramaniam K, Manchala R. Effect of vitamin supplementation on cisplatin-induced intestinal epithelial cell apoptosis in Wistar/NIN rats. Nutrition. 2012 May;28(5):572-80.
24- Al-Harbi NO, Imam F, Nadeem A, Al-Harbi MM, Korashy HM, SayedAhmed MM, et al. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats. Toxicol Mech Methods 2015 Sep;25: 417-23.
25- Suwannasom N, Kao I, Pruß A, Georgieva R, Bäumler H. Riboflavin: The Health Benefits of a Forgotten Natural Vitamin. Int J Mol Sci. 2020 Jan 31;21(3):950.
26- Zhang B, Cao JT, Wu YB, Gao KX, Xie M, Zhou ZK, Tang J, Hou SS. Riboflavin (Vitamin B2) Deficiency Induces Apoptosis Mediated by Endoplasmic Reticulum Stress and the CHOP Pathway in HepG2 Cells. Nutrients. 2022 Aug 16;14(16):3356.
27- Lina Bahjat Qasim, Ghaith A. Jasim, & Ihsan S. Rabeea. Histopathological study of diclofenac induced acute renal failure under lipoic acid and bosentan therapy in male albino rats. Al Mustansiriyah Journal of Pharmaceutical Sciences, 2022 Jul 22; (1), 49–58.
28- De Luca JF, Holmes NE, Trubiano JA. Adverse reactions to vancomycin and cross-reactivity with other antibiotics. Curr Opin Allergy Clin Immunol. 2020 Aug;20(4):352-361.
29- Peng Y, Li CY, Yang ZL, Shi W. Adverse reactions of vancomycin in humans: A protocol for meta-analysis. Medicine (Baltimore). 2020 Sep 18;99(38):e22376.
30- Pais GM, Liu J, Zepcan S, Avedissian SN, Rhodes NJ, Downes KJ, Moorthy GS, Scheetz MH. Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention. Pharmacotherapy. 2020 May;40(5):438-454.
31- Humanes B., Jado J.C., Camano S., Lopez-Parra V., Torres A.M., Alvarez-Sala L.A., Cercenado E., Tejedor A., Lazaro A. Protective effects of cilastatin against vancomycin-induced nephrotoxicity. Biomed Res. 2015 Oct 4;704382.
32- Yamanaka G, Suzuki S, Morishita N, Takeshita M, Kanou K, Takamatsu T, Morichi S, Ishida Y, Watanabe Y, Go S, Oana S, Kawashima H. Experimental and Clinical Evidence of the Effectiveness of Riboflavin on Migraines. Nutrients. 2021 Jul 29;13(8):2612.
33- Ghaiad HR, Ali SO, Al-Mokaddem AK, Abdelmonem M. Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats. Chem Biol Interact. 2023 Aug 25; 381:110544.
34- Maitham Abd Ali Mnati, Bahir Abdul Razzaq Mshimesh, & Nadia Hamid Mohammed. The Testicular Protection Effect of Thiamine Pyrophosphate Against Cisplatin-treated Male Rats . Al Mustansiriyah Journal of Pharmaceutical Sciences, 2022 Apr 20; (4) 147–155.
35- Abd, Maitham & Ibraheem, Mustafa & Yousif, Suzan & Razzaq, Bahir. Ameliorative Effect Of Thiamine Pyrophosphate Against Cisplatin-Induced Reproductive System Damage Within Male Rats. Systematic Reviews in Pharmacy. 2020 Nov 11; 396-403.
36- Sakarcan, Sinem & Ersahin, Mehmet & Eminoglu, Mehmet & Cevik, Ozge & Caliskan-Ak, Esin & Ercan, Feriha & Sener, Göksel. Riboflavin Treatment Reduces Apoptosis and Oxidative DNA Damage in a Rat Spinal Cord Injury Model. Clinical and Experimental Health Sciences. 2017 Feb 7;10.5152.
37- Singer E, Markó L, Paragas N, Barasch J, Dragun D, Müller DN, Budde K, Schmidt-Ott KM. Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta Physiol (Oxf). 2013 Apr;207(4):663-72.
38- Romejko, K.; Markowska, M.; Niemczyk, S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). Int. J. Mol. Sci. 2023, 24, 10470.
39- Han M, Pan Y, Gao M, Zhang J, Wang F. JNK Signaling Pathway Suppresses LPS-Mediated Apoptosis of HK-2 Cells by Upregulating NGAL. Int J Inflam. 2020 Apr 24;2020:3980507.
40- Pang HM, Qin XL, Liu TT, Wei WX, Cheng DH, Lu H, Guo Q, Jing L. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as early biomarkers for predicting vancomycin-associated acute kidney injury: a prospective study. Eur Rev Med Pharmacol Sci. 2017 Sep;21(18):4203-4213.
41- Pais GM, Avedissian SN, O'Donnell JN, Rhodes NJ, Lodise TP, Prozialeck WC, Lamar PC, Cluff C, Gulati A, Fitzgerald JC, Downes KJ, Zuppa AF, Scheetz MH. Comparative Performance of Urinary Biomarkers for Vancomycin-Induced Kidney Injury According to Timeline of Injury. Antimicrob Agents Chemother. 2019 Jun 24;63(7):e00079-19
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