Gallic acid attenuates torsion/detorsion-induced testicular injury in rats through suppressing of HMGB1/NF-κB axis and endoplasmic reticulum stress

El ácido gálico atenúa la lesión testicular inducida por torsión/detorsión en ratas mediante la supresión del eje HMGB1/NF-κB y el estrés del retículo endoplásmico

It was aimed to evaluate whether gallic acid (GA) have a beneficial effect in the testicular ischemia/reperfusion injury (IRI) model in rats for the first time. Testicular malondialdehyde, 8-hydroxy-2′-deoxyguanosine, superoxide dismutase, catalase, high mobility group box 1 protein, nuclear factor kappa B, tumor necrosis factor-alpha, interleukin-6, myeloperoxidase, 78-kDa glucose-regulated protein, activating transcription factor 6, CCAAT-enhancer-binding protein homologous protein and caspase-3 levels were determined using colorimetric methods. The oxidative stress, inflammation, endoplasmic reticulum stress and apoptosis levels increased statistically significantly in the IRI group compared with the sham operated group (p < 0.05). GA application improved these damage significantly (p < 0.05). Moreover, it was found that the results of histological examinations supported the biochemical results to a statistically significant extent. Our findings suggested that GA may be evaluated as a protective agent against testicular IRI.

Resumen

El objetivo era evaluar si el ácido gálico (GA) tenía un efecto beneficioso en el modelo de lesión por isquemia/reperfusión testicular (IRI) en ratas por primera vez. Malondialdehído testicular, 8-hidroxi-2′-desoxiguanosina, superóxido dismutasa, catalasa, proteína del grupo de alta movilidad caja 1, factor nuclear kappa B, factor de necrosis tumoral alfa, interleucina-6, mieloperoxidasa, proteína regulada por glucosa de 78 kDa, activadora el factor de transcripción 6, la proteína homóloga de la proteína de unión al potenciador de CCAAT y los niveles de caspasa-3 se determinaron mediante métodos colorimétricos. El estrés oxidativo, la inflamación, el estrés del retículo endoplásmico y los niveles de apoptosis aumentaron de manera estadísticamente significativa en el grupo IRI en comparación con el grupo operado de forma simulada (p < 0.05). La aplicación de GA mejoró significativamente estos daños (p < 0.05). Además, se encontró que los resultados de los exámenes histológicos respaldaron los resultados bioquímicos en un grado estadísticamente significativo. Nuestros hallazgos sugieren que GA puede evaluarse como un agente protector contra IRI testicular.

Apoptosis; Endoplasmic reticulum stress; Gallic acid; Inflammation; Oxidative stress; Testicular torsion

Palabras Clave

Apoptosis; Estrés del retículo endoplásmico; Ácido gálico; Inflamación; Estrés oxidativo; Torsión testicular

[1] Shamsi-Gamchi N, Razi M, Behfar M. Cross-link between mitochondrial-dependent apoptosis and cell cycle checkpoint proteins after experimental torsion and detorsion in rats. Gene. 2021; 795: 145793.

[2] Arena S, Iacona R, Antonuccio P, Russo T, Salvo V, Gitto E, et al. Medical perspective in testicular ischemia-reperfusion injury. Experimental and Therapeutic Medicine. 2017; 13: 2115–2122.

[3] Vaos G, Zavras N. Antioxidants in experimental ischemia-reperfusion injury of the testis: where are we heading towards? World Journal of Methodology. 2017; 7: 37.

[4] Osumah TS, Jimbo M, Granberg CF, Gargollo PC. Frontiers in pediatric testicular torsion: an integrated review of prevailing trends and management outcomes. Journal of Pediatric Urology. 2018; 14: 394–401.

[5] Karaguzel E, Kadihasanoglu M, Kutlu O. Mechanisms of testicular torsion and potential protective agents. Nature Reviews Urology. 2014; 11: 391–399.

[6] Chong WC, Shastri MD, Eri R. Endoplasmic reticulum stress and oxidative stress: a vicious nexus implicated in bowel disease pathophysiology. International Journal of Molecular Sciences. 2017; 18: 771.

[7] Xin Q, Ji B, Cheng B, Wang C, Liu H, Chen X, et al. Endoplasmic reticulum stress in cerebral ischemia. Neurochemistry International. 2014; 68: 18–27.

[8] Su Y, Li F. Endoplasmic reticulum stress in brain ischemia. International Journal of Neuroscience. 2016; 126: 681–691.

[9] Lin C. Attenuation of endoplasmic reticulum stress as a treatment strategy against ischemia/reperfusion injury. Neural Regeneration Research. 2015; 10: 1930.

[10] Bayramoglu G, Kurt H, Bayramoglu A, Gunes HV, Degirmenci İ, Colak S. Preventive role of gallic acid on hepatic ischemia and reperfusion injury in rats. Cytotechnology. 2015; 67: 845–849.

[11] Asci H, Ozmen O, Ellidag HY, Aydin B, Bas E, Yilmaz N. The impact of gallic acid on the methotrexate-induced kidney damage in rats. Journal of Food and Drug Analysis. 2017; 25: 890–897.

[12] Gao J, Hu J, Hu D, Yang X. A role of gallic acid in oxidative damage diseases: a comprehensive review. Natural Product Communications. 2019; 14: 1934578X1987417.

[13] Abarikwu SO, Mgbudom-Okah CJ, Njoku RC, Okonkwo CJ, Onuoha CC, Wokoma AFS. Gallic acid ameliorates busulfan-induced testicular toxicity and damage in mature rats. Drug and Chemical Toxicology. 2022; 45: 1881–1890.

[14] Canbek M, Bayramoglu G, Senturk H, Oztopcu Vatan AP, Uyanoglu M, Ceyhan E, et al. The examination of protective effects of gallic acid against damage of oxidative stress during induced-experimental renal ischemia-reperfusion in experiment. Bratislava Medical Journal. 2014; 115: 557–562.

[15] Sun J, Li Y, Ding Y, Wang J, Geng J, Yang H, et al. Neuroprotective effects of gallic acid against hypoxia/reoxygenation-induced mitochondrial dysfunctions in vitro and cerebral ischemia/reperfusion injury in vivo. Brain Research. 2014; 1589: 126–139.

[16] Badavi M, Sadeghi N, Dianat M, Samarbafzadeh A. Effects of gallic acid and cyclosporine a on antioxidant capacity and cardiac markers of rat isolated heart after ischemia/reperfusion. Iranian Red Crescent Medical Journal. 2014; 16: e16424.

[17] Basuguy E, Okur MH, Arslan S, Zeytun H, Aydogdu G, Ekinci A. Effect of gallic acid on liver injury during obstructive cholestasis after bile duct ligation in rat. Experimental Biomedical Research. 2021; 4: 47–57.

[18] Turner TT, Tung KS, Tomomasa H, Wilson LW. Acute testicular ischemia results in germ cell-specific apoptosis in the rat. Biology of Reproduction. 1997; 57: 1267–1274.

[19] Kutlu O, Mentese A, Turkmen S, Turedi S, Gunduz A, Yulug E, et al. Investigation of the possibility of using ischemia-modified albumin in testicular torsion: an experimental study. Fertility and Sterility. 2011; 95: 1333–1337.

[20] Kazaz IO, Mentese A, Demir S, Kerimoglu G, Colak F, Bodur A, et al. Berberine inhibits the ischemia-reperfusion induced testicular injury through decreasing oxidative stress. The American Journal of Emergency Medicine. 2020; 38: 33–37.

[21] Demir S, Kazaz IO, Aliyazicioglu Y, Kerimoglu G, Teoman AS, Yaman SO, et al. Effect of ethyl pyruvate on oxidative state and endoplasmic reticulum stress in a rat model of testicular torsion. Biotechnic & Histochemistry. 2020; 95: 317–322.

[22] Praveen Kumar P, D. M, Siva Sankar Reddy L, Dastagiri Reddy Y, Somasekhar G, Sirisha NVL, et al. A new cerebral ischemic injury model in rats, preventive effect of gallic acid and in silico approaches. Saudi Journal of Biological Sciences. 2021; 28: 5204–5213.

[23] Obafemi TO, Jaiyesimi KF, Olomola AA, Olasehinde OR, Olaoye OA, Adewumi FD, et al. Combined effect of metformin and gallic acid on inflammation, antioxidant status, endoplasmic reticulum (ER) stress and glucose metabolism in fructose-fed streptozotocin-induced diabetic rats. Toxicology Reports. 2021; 8: 1419–1427.

[24] Kazaz IO, Demir S, Kerimoglu G, Colak F, Alemdar NT, Akman AU, et al. Effect of chrysin on endoplasmic reticulum stress in a rat model of testicular torsion. Journal of Investigative Surgery. 2022; 35: 1106–1111.

[25] Johnsen SG. Testicular biopsy score count—a method for registration of spermatogenesis in human testes: Normal values and results in 335 hypogonadal males. Hormones. 1970; 1: 2–25.

[26] Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Analytical Biochemistry. 1978; 86: 271–278.

[27] Demir EA, Mentese A, Kucuk H, Alemdar NT, Demir S. p-Coumaric acid alleviates cisplatin-induced ovarian toxicity in rats. Journal of Obstetrics and Gynaecology Research. 2022; 48: 411–419.

[28] Demir, S, Kazaz IO, Kerimoglu G, Ayazoglu Demir E, Colak F, Yilmaz S, et al. Astaxanthin protects testicular tissue against torsion/detorsion-induced injury via suppressing endoplasmic reticulum stress in rats. Journal of Investigative Surgery. 2022; 35: 1044–1049.

[29] Ayazoglu Demir E, Mentese A, Livaoglu A, Turkmen Alemdar N, Demir S. Ameliorative effect of gallic acid on cisplatin-induced ovarian toxicity in rats. Drug and Chemical Toxicology. 2023; 46: 97–103.

[30] Kazaz IO, Demir S, Kerimoglu G, Colak F, Turkmen Alemdar N, Yilmaz Dogan S, et al. Chlorogenic acid ameliorates torsion/detorsion-induced testicular injury via decreasing endoplasmic reticulum stress. Journal of Pediatric Urology. 2022; 18: 289.e1–289.e7.

[31] Mard SA, Azad SM, Ahangarpoor A. Protective effect of crocin on gastric mucosal lesions induced by ischemia-reperfusion injury in rats. Iranian Journal of Pharmaceutical Research. 2016; 15: 93–99.

[32] Zhou F, Wang M, Ju J, Wang Y, Liu Z, Zhao X, et al. Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation. American Journal of Translational Research. 2019; 11: 199–209.

[33] Arfian N, Wahyudi DAP, Zulfatina IB, Citta AN, Anggorowati N, Multazam A, et al. Chlorogenic acid attenuates kidney ischemic/reperfusion injury via reducing inflammation, tubular injury, and myofibroblast formation. BioMed Research International. 2019; 2019: 5423703.

[34] Almoiliqy M, Wen J, Xu B, Sun Y, Lian M, Li Y, et al. Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53. Acta Pharmacologica Sinica. 2020; 41: 1208–1222.

[35] Dong LY, Chen F, Xu M, Yao LP, Zhang YJ, Zhuang Y. Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-κB signaling pathway. American Journal of Translational Research. 2018; 10: 1273–1283.

[36] Zhang B, Zhong Q, Chen X, Wu X, Sha R, Song G, et al. Neuroprotective effects of celastrol on transient global cerebral ischemia rats via regulating HMGB1/NF-κB signaling pathway. Frontiers in Neuroscience. 2020; 14: 847.

[37] Yang C, Yang W, He Z, He H, Yang X, Lu Y, et al. Kaempferol improves lung ischemia-reperfusion injury via antiinflammation and antioxidative stress regulated by SIRT1/HMGB1/NF-κB axis. Frontiers in Pharmacology. 2020; 10: 1635.

[38] Lai HJ, Zhan YQ, Qiu YX, Ling YH, Zhang XY, Chang ZN, et al. HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage. Surgery. 2021; 170: 239–248.

[39] Singh JP, Singh AP, Bhatti R. Explicit role of peroxisome proliferator-activated receptor gamma in gallic acid-mediated protection against ischemia-reperfusion-induced acute kidney injury in rats. Journal of Surgical Research. 2014; 187: 631–639.

[40] Gao X, Xu Y. Therapeutic effects of natural compounds and small molecule inhibitors targeting endoplasmic reticulum stress in Alzheimer’s disease. Frontiers in Cell and Developmental Biology. 2021; 9: 745011.

[41] Blas-Valdivia V, Franco-Colín M, Rojas-Franco P, Chao-Vazquez A, Cano-Europa E. Gallic acid prevents the oxidative and endoplasmic reticulum stresses in the hippocampus of adult-onset hypothyroid rats. Frontiers in Pharmacology. 2021; 12: 671614.

[42] Kazaz IO, Demir S, Yulug E, Colak F, Bodur A, Yaman SO, et al. N-acetylcysteine protects testicular tissue against ischemia/reperfusion injury via inhibiting endoplasmic reticulum stress and apoptosis. Journal of Pediatric Urology. 2019; 15: 253.e1–253.e8.

[43] Oyagbemi AA, Omobowale TO, Saba AB, Adedara IA, Olowu ER, Akinrinde AS, et al. Gallic acid protects against cyclophosphamide-induced toxicity in testis and epididymis of rats. Andrologia. 2016; 48: 393–401.

[44] Owumi SE, Adedara IA, Akomolafe AP, Farombi EO, Oyelere AK. Gallic acid enhances reproductive function by modulating oxido-inflammatory and apoptosis mediators in rats exposed to aflatoxin-B1. Experimental Biology and Medicine. 2020; 245: 1016–1028.

[45] Altındağ F, Meydan İ. Evaluation of protective effects of gallic acid on cisplatin-induced testicular and epididymal damage. Andrologia. 2021; 53: e14189.

[46] Hosseinzadeh A, Mehrzadi S, Siahpoosh A, Basir Z, Bahrami N, Goudarzi M. Gallic acid ameliorates di-(2-ethylhexyl) phthalate-induced testicular injury in adult mice. Human & Experimental Toxicology. 2022; 41: 096032712210788.

[47] Owumi SE, Bello SA, Najophe SE, O Nwozo S, O Esan I. Coadministration of gallic acid abates zearalenone-mediated defects in male rat’s reproductive function. Journal of Biochemical and Molecular Toxicology. 2022; 36: e22940.