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Article Effectiveness of Boric Acid in Sepsis in Rats With Cecal Perforation(Springer Nature, 2025) Kurtipek, Ali Can; Dursun, Ali Dogan; Yigman, Zeynep; Ozdemir, Cagri; Kucuk, Aysegul; Gonullu, Ugur; Arslan, MustafaIntroduction and AimSepsis is a systemic inflammatory response that develops in the host against microorganisms, which results in end-organ damage. Boric acid (BA) has been shown to have immune modulatory effects in vitro and in animal studies. The aim of the study is to investigate the effects of high dose BA on lung and kidney tissues in rats with sepsis induced by the CLP method.Method28 rats were randomly divided into four groups: Group C (control group), Group BA, Group CLP (cecal ligation and puncture), and Group CLP + BA. Cecum was ligated below the ileocecal valve and punctured. BA was administered to the treatment groups at an intraperitoneal dose of 200 mg/kg, and at the end of 24 h, lung and kidney tissue samples were collected and evaluated for biochemical and histopathological parameters.ResultsHistopathologically, in kidney tissue, CLP + BA group showed significantly less peritubular capillary dilatation and brush border loss in the proximal tubule epithelium compared to the CLP group. In lung tissue, CLP + BA group had significantly less alveolar wall thickening compared to the CLP group. Biochemical analyses indicated that BA administration reduced oxidative stress in both renal and lung tissues.ConclusionWe found that intraperitoneal administration of high dose boric acid partially ameliorated the tissue damage in rats subjected to CLP induced sepsis. Further studies are needed regarding the dosage and application at different time points.Article Organ-Protective Effects of Fullerenol and Desflurane in a Rat Model of Ischemia–Reperfusion Injury(Nature Portfolio, 2025) Kip, Gulay; Koksal, Zeynep; Yigman, Zeynep; Kucuk, Aysegul; Arslan, Mustafa; Akarca Dizakar, Saadet Ozen; Sivgin, VolkanTo investigate the protective effects of fullerenol applied before ischemia induction and desflurane anesthesia applied during ischemia-reperfusion (IR) induction in the lungs and kidneys of a lower-extremity IR injury rat model. After receiving ethical approval, we randomly divided 30 rats into five groups: sham (S), IR, IR with 100 mg/kg fullerenol (IR-FUL), IR with 6.7% desflurane (IR-DES), IR with 100 mg/kg fullerenol and 6.7% desflurane (IR-FUL-DES). Fullerenol was administered 30 min before the IR procedure in the IR-FUL and IR-FUL-DES groups, and desflurane was administered during the IR procedure in the IR-DES and IR-FUL-DES groups. During the procedure, an atraumatic microvascular clamp was placed in the aorta for 120 min. The clamp was then removed to achieve reperfusion for 120 min. Finally, at the end of reperfusion, we evaluated the extracted lung and kidney tissue samples and assessed them biochemically and histopathologically. The lung damage scores of the IR-FUL, IR-DES, and IR-FUL-DES groups were significantly lower than those of the IR group (p < .0001, p = .002, and p < .0001, respectively). The renal tubule injury scores of the IR, IR-FUL, IR-DES, and IR-FUL-DES groups were significantly higher than those of the S group (p < .0001). By contrast, the renal tubule injury scores of the IR-FUL and IR-FUL-DES groups were significantly lower than those of the IR group (p < .0001 and p = .001, respectively). Moreover, kidney intercellular adhesion molecule 1 (ICAM1) expression was significantly lower in all the treatment groups, particularly the IR-FUL group, than in the IR group, and lung ICAM1 expression was significantly lower in the IR-FUL and IR-FUL-DES groups than in the other treatment groups. In the lung and kidney tissues, thiobarbituric acid reactive substance levels, catalase activity, glutathione-S-transferase activity, and arylesterase activity were relatively high in the treatment groups. The application of fullerenol before and after desflurane anesthesia during IR has protective effects on rat lungs and kidneys. In particular, histopathology confirmed that the application of fullerenol 30 min before IR induction and desflurane anesthesia during IR induction reduced oxidative stress and alleviated IR-related damage in the lungs and kidneys. These findings may have important translational relevance, suggesting potential perioperative strategies for protecting organs from ischemia-reperfusion injury in clinical settings.Article Citation - WoS: 4Citation - Scopus: 7Protective Effects of Bosentan Via Endothelin Receptor Antagonism in Experimental Ischemia-Reperfusion Injury in the Lower Limb of Rats(Dove Medical Press Ltd, 2025) Demirtas, Hueseyin; Oezer, Abdullah; Guelcan, Mehmet Burak; Yigman, Zeynep; Kuecuek, Ayseguel; Tekin, Esra; Arslan, MustafaObjective: This study aimed to evaluate the protective effects of bosentan, a dual endothelin receptor antagonist, against skeletal muscle ischemia-reperfusion injury (IRI) in rats. Methods: A total of 24 male Wistar Albino rats were divided into four groups: control (C, n=6), bosentan-treated (B, n=6), ischemiareperfusion (IR, n=6), and bosentan plus ischemia-reperfusion (B+IR, n=6). Bosentan (10 mg/kg) was administered 30 minutes prior to reperfusion. In the IR and B+IR groups, ischemia was induced using vascular bulldog clamps for 45 minutes, followed by 120 minutes of reperfusion. Results: Histological and biochemical assessments revealed significant differences among the groups. The disorganization and degeneration scores of the muscle cells in the B+IR group were significantly lower than those in the IR group (P = 0.001). The degree of interstitial edema in the IR group was markedly more severe than in the C and B groups (all P < 0.001), while the interstitial edema score in the B+IR group was significantly lower than that in the IR group (P < 0.001). The total muscle injury scores were markedly reduced in the B+IR group compared to the IR group (P < 0.001). Biochemically, TAS levels were significantly higher in the B+IR group compared to the IR group (1.03 f 0.18 vs 0.59 f 0.10 mmol/L, P = 0.016). Conversely, TOS (1.97 f 0.39 vs 2.86 f 0.43 IU/mg, P < 0.001) and OSI levels (P < 0.001) were significantly lower in the B+IR group. Additionally, paraoxonase (PON-1) enzyme activity was significantly reduced in the B+IR group compared to the IR group (P < 0.001). These findings suggest that bosentan exerts its protective effects by antagonizing endothelin-1 receptors, thereby mitigating vasoconstriction, oxidative stress, and inflammation. The observed reductions in muscle cell disorganization, interstitial edema, hemorrhage, neutrophil infiltration and oxidative stress markers underscore bosentan's potential as a therapeutic agent for managing ischemia-reperfusion injury. Conclusion: Bosentan demonstrates significant protective effects against skeletal muscle IRI by reducing oxidative stress and inflammation through endothelin receptor antagonism. These findings underscore bosentan's potential as a therapeutic agent for mitigating ischemia-reperfusion injury in vascular surgeries and managing critical limb ischemia in clinical settings. Further research is warranted to explore the long-term effects of bosentan on muscle recovery and systemic health following ischemia-reperfusion injury.Article Citation - Scopus: 3Protective Effects of Metformin in Non-Diabetic Rats With Experimentally Induced Lower Extremity Ischemia-Reperfusion Injury(Turkish National Vascular and Endovascular Surgery Society, 2025) Küçük, Ayşegül; Dursun, Alı Dogan; Arslan, Mustafa; Sezen, Şaban Cem; Yıldırım, Alperen Kutay; Özer, Abdullah; Demirtas, HuseyinAim: Lower extremity ischemia-reperfusion (IR) injury can lead to substantial skeletal muscle damage and systemic complications, primarily driven by oxidative stress and inflammation. In addition to its well-known glucose-lowering effects, metformin possesses antioxidant and anti-inflammatory properties that may confer protection against tissue damage caused by IR. This study aims to evaluate the potential protective effects of metformin on skeletal muscle injury using a rat model of lower extremity IR.Material and Methods: A total of twenty-four male Wistar albino rats were randomly divided into four experimental groups: Control (C), Ischemia-Reperfusion (IR), IR with metformin at 4 mg/kg (IR+M4), and IR with metformin at 8 mg/kg (IR+M8). Ischemia was induced by clamping the infrarenal aorta for 45 minutes, followed by a reperfusion period of 120 minutes. In the treatment groups, metformin was administered intraperitoneally at the onset of ischemia. Gastrocnemius muscle tissues were harvested for subsequent histopathological and biochemical evaluations, including measurements of Total Antioxidant Status (TAS), Total Oxidant Status (TOS), and Oxidative Stress Index (OSI).Results: Histopathological analysis demonstrated a significant reduction in muscle atrophy, degeneration, leukocyte infiltration, and fiber fragmentation in the IR+M8 group compared to the IR group. Biochemical assessments showed that TAS levels were considerably elevated, whereas TOS and OSI levels were markedly reduced in the metformin-treated groups, with the most prominent effects observed at the higher dosage of 8 mg/kg.Conclusion: The findings indicate that metformin exerts a dose-dependent protective effect against skeletal muscle injury resulting from lower extremity ischemia-reperfusion in rats. These protective properties are likely due to metformin’s antioxidant and anti-inflammatory mechanisms, highlighting its potential therapeutic value in mitigating IR-induced tissue damage.Article Citation - WoS: 10Citation - Scopus: 13Protective Effects of Hydrogen Rich Saline Solution in Rats With Experimental Myocardial Ischemia Reperfusion Injury(Cell Press, 2023) Koksal, Zeynep; Kurtipek, Omer; Arslan, Mustafa; Dursun, Ali Dogan; Yigman, Zeynep; Ozer, AbdullahAim: The aim of our study is to show whether the administration of hydrogen-rich saline solution (HRSS) intraperitoneally before left main coronary artery (LAD) ischemia protects the myocardium against ischemia-reperfusion (IR) injury.Materials and methods: After ethics committee approval, 24 Wistar Albino rats were divided into 4 groups, 6 rats in each group. For experimental IR, myocardial ischemia was performed by LAD ligation. Left thoracotomy was performed without ischemia in the Control group (Group C). Left thoracotomy was performed without myocardial ischemia to the rats in the HRSS group, and HRSS was given intraperitoneally (ip) at a rate of 10 ml/kg throughout the procedure. In the MIRHRSS group, a single dose of 10 ml/kg HRSS was administered 5 min before reperfusion. Histopathological and biochemical parameters were compared in myocardial tissue samples taken at the end of the reperfusion period.Results: When the groups were compared among themselves in terms of TOS and TAS levels, there was a significant difference between the groups (p = 0.006, p = 0.002). The severity of cardiomyocyte degeneration was significantly greater in MIR group than that in the control and HRSS groups (p = 0.002 and p = 0.001, respectively), as well as severity score of cardiomyocyte degeneration was higher in MIR-HRSS group compared with HRSS group (p = 0.035).Conclusion: Our study shows that HRSS is protective in IR injury, with the application of HRSS 5 min before reperfusion, interstitial edema severity, subendocardial haemorrhage are reduced, and oxidant status parameters are increased, while antioxidant status parameters are decreased. We believe that when it is supported by other studies, the protective effects of HRSS on IR damage will be shown in detail and its indications will be expanded.Article Citation - WoS: 3Citation - Scopus: 4Effects of Cerium Oxide on Kidney and Liver Tissue Damage in an Experimental Myocardial Ischemia-Reperfusion Model of Distant Organ Damage(Mdpi, 2024) Gunes, Isin; Dursun, Ali Dogan; Ozdemir, Cagri; Kucuk, Aysegul; Sezen, Saban Cem; Arslan, Mustafa; Ozer, AbdullahBackground and Objectives: Ischemia-reperfusion (I/R) injury is a process in which impaired perfusion is restored by restoring blood flow and tissue recirculation. Nanomedicine uses cutting-edge technologies that emerge from interdisciplinary influences. In the literature, there are very few in vivo and in vitro studies on how cerium oxide (CeO2) affects systemic anti-inflammatory response and inflammation. Therefore, in our study, we aimed to investigate whether CeO2 administration has a protective effect against myocardial I/R injury in the liver and kidneys. Materials and Methods: Twenty-four rats were randomly divided into four groups after obtaining approval from an ethics committee. A control (group C), cerium oxide (group CO), IR (group IR), and Cerium oxide-IR (CO-IR group) groups were formed. Intraperitoneal CeO2 was administered at a dose of 0.5 mg/kg 30 min before left thoracotomy and left main coronary (LAD) ligation, and myocardial muscle ischemia was induced for 30 min. After LAD ligation was removed, reperfusion was performed for 120 min. All rats were euthanized using ketamine, and blood was collected. Liver and kidney tissue samples were evaluated histopathologically. Serum AST (aspartate aminotransferase), ALT (alanine aminotransaminase), GGT (gamma-glutamyl transferase), glucose, TOS (Total Oxidant Status), and TAS (Total Antioxidant Status) levels were also measured. Results: Necrotic cell and mononuclear cell infiltration in the liver parenchyma of rats in the IR group was observed to be significantly increased compared to the other groups. Hepatocyte degeneration was greater in the IR group compared to groups C and CO. Vascular vacuolization and hypertrophy, tubular degeneration, and necrosis were increased in the kidney tissue of the IR group compared to the other groups. Tubular dilatation was significantly higher in the IR group than in the C and CO groups. TOS was significantly higher in all groups than in the IR group (p < 0.0001, p < 0.0001, and p = 0.006, respectively). However, TAS level was lower in the IR group than in the other groups (p = 0.002, p = 0.020, and p = 0.031, respectively). Renal and liver histopathological findings decreased significantly in the CO-IR group compared to the IR group. A decrease in the TOS level and an increase in the TAS level were found compared to the IR group. The AST, ALT, GGT, and Glucose levels are shown. Conclusions: CeO2 administered before ischemia-reperfusion reduced oxidative stress and ameliorated IR-induced damage in distant organs. We suggest that CeO2 exerts protective effects in the myocardial IR model.Article Citation - WoS: 4Citation - Scopus: 4The Effect of Cerium Oxide (ceo2) on Ischemia-Reperfusion Injury in Skeletal Muscle in Mice With Streptozocin-Induced Diabetes(Mdpi, 2024) Ozer, Abdullah; Sengel, Necmiye; Kucuk, Ayseguel; Yigman, Zeynep; Ozdemir, Cagri; Kilic, Yigit; Arslan, MustafaObjective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, in temporary clamping of the aorta in aortic surgery, or following acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress such as DM. Cerium oxide (CeO2) nanoparticles mimic antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n = 6), diabetes group (group D, n = 8), diabetes-CeO2 (group DCO, n = 8), diabetes-ischemia/reperfusion (group DIR, n = 8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n = 8). The DCO and DIRCO groups were given doses of CeO2 of 0.5 mg/kg intraperitoneally 30 min before the IR procedure. A 120 min ischemia-120 min reperfusion period with 100% O-2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p = 0.047 and p = 0.022, respectively). In group DIRCO, total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p < 0.001). The oxidative stress index (OSI) was found to be significantly lower in group DIR compared with group DCO (p < 0.001). Paraoxanase (PON) enzyme activity was found to be significantly increased in group DIR compared with group DCO (p < 0.001). The disorganization and degeneration score for muscle cells, inflammatory cell infiltration score, and total injury score in group DIRCO were found to be significantly lower than in group DIR (p = 0.002, p = 0.034, and p = 0.001, respectively). Conclusions: Our results confirm that CeO2, with its antioxidative properties, reduces skeletal muscle damage in lower extremity IRI in diabetic mice.Article Citation - WoS: 9Citation - Scopus: 15Therapeutic Efficacy of Boric Acid Treatment on Brain Tissue and Cognitive Functions in Rats With Experimental Alzheimer's Disease(Dove Medical Press Ltd, 2023) Ozdemir, Cagri; Arslan, Mustafa; Kucuk, Aysegul; Yigman, Zeynep; Dursun, Ali DoganIntroduction: Oxidative stress has an important role in the pathophysiology of Alzheimer's disease (AD), the most common type of dementia. Boric acid (BA) contributes significantly to the protection of the brain by reducing lipid peroxidation and supporting antioxidant defense. We aimed to evaluate the therapeutic potential of BA treatment in AD rats. Materials and Methods: Four groups were formed as Control (C), Alzheimer's (A), Alzheimer's + Boric acid (ABA), Boric acid (BA). Intracerebroventricular injection of Streptozotocin (STZ) was preferred to create an AD. After 4 weeks, BA was applied 3 times every other day. The Radial Arm Maze Test (RAMT) was used to evaluate memory and learning abilities. Biochemical and histopathological evaluations were made in the hippocampus. Results: Initial RAMT inlet/outlet (I/O) numbers were similar. Two weeks after STZ injection, I/O numbers decreased in group A and ABA compared to group C and BA (p<0.05). After the second BA application, I/O numbers increased in the ABA group compared to the A group (p<0.05). In group A, PON-1, TOS and OSI levels were higher and TAS levels were lower than in groups BA and C. After BA treatment, PON-1 and OSI levels were lower in the ABA group than in the A group (p<0.05). Although there was an increase in TAS value and a decrease in TOS, this did not make a statistical difference. The thickness of the pyramidal cell in CA1 and the granular cell layers in the dentate gyrus, and the number of intact and degenerated neurons in the pyramidal cell layer were similar between the groups. Discussion: Significant improvement in learning and memory abilities after BA application is promising for AD. Conclusion: These results show that BA application positively affects learning and memory abilities, and reduces oxidative stress. More extensive studies are required to evaluate histopathological efficacy.Article Effects of Pomegranate Seed Oil on Lower Extremity Ischemia-Reperfusion Damage: Insights into Oxidative Stress, Inflammation, and Cell Death(MDPI, 2025) Bozok, Ummu Gulsen; Ergorun, Aydan Iremnur; Kucuk, Aysegul; Yigman, Zeynep; Dursun, Ali Dogan; Arslan, MustafaAim: This study sought to clarify the therapeutic benefits and mechanisms of action of pomegranate seed oil (PSO) in instances of ischemia–reperfusion (IR) damage in the lower extremities. Materials and Methods: The sample size was determined, then 32 rats were randomly allocated to four groups: Control (C), ischemia–reperfusion (IR), low-dose PSO (IR + LD, 0.15 mL/kg), and high-dose PSO (IR + HD, 0.30 mL/kg). The ischemia model in the IR group was established by occluding the infrarenal aorta for 120 min. Prior to reperfusion, PSO was delivered to the IR + LD and IR + HD groups at doses of 0.15 mL/kg and 0.30 mL/kg, respectively, followed by a 120 min reperfusion period. Subsequently, blood and tissue specimens were obtained. Statistical investigation was executed utilizing Statistical Package for the Social Sciences version 20.0 (SPSS, IBM Corp., Armonk, NY, USA). Results: Biochemical tests revealed significant variations in total antioxidant level (TAS), total oxidant level (TOS), and the oxidative stress index (OSI) across the groups (p < 0.0001). The IR group had elevated TOS and OSI levels, whereas PSO therapy resulted in a reduction in these values (p < 0.05). As opposed to the IR group, TASs were higher in the PSO-treated groups. Histopathological analysis demonstrated muscle fiber degeneration, interstitial edema, and the infiltration of cells associated with inflammation in the IR group, with analogous results noted in the PSO treatment groups. Immunohistochemical analysis revealed that the expressions of Tumor Necrosis Factor-alpha (TNF-α), Nuclear Factor kappa B (NF-κB), cytochrome C (CYT C), and caspase 3 (CASP3) were elevated in the IR group, while PSO treatment diminished these markers and attenuated inflammation and apoptosis (p < 0.05). The findings demonstrate that PSO has a dose-dependent impact on IR injury. Discussion: This research indicates that PSO has significant protective benefits against IR injury in the lower extremities. PSO mitigated tissue damage and maintained mitochondrial integrity by addressing oxidative stress, inflammation, and apoptotic pathways. Particularly, high-dose PSO yielded more substantial enhancements in these processes and exhibited outcomes most comparable to the control group in biochemical, histological, and immunohistochemical investigations. These findings underscore the potential of PSO as an efficacious natural treatment agent for IR injury. Nevertheless, additional research is required to articulate this definitively.Article Citation - WoS: 8Citation - Scopus: 12Protective Effects of BPC 157 on Liver, Kidney, and Lung Distant Organ Damagein Rats with Experimental Lower-Extremity Ischemia–Reperfusion Injury(MDPI, 2025) Demirtas, Hueseyin; Ozer, Abdullah; Yildirim, Alperen Kutay; Dursun, Ali Dogan; Sezen, Saban Cem; Arslan, MustafaBackground and Objectives: Ischemia–reperfusion (I/R) injury can affect multiple distant organs following I/R in the lower extremities. BPC-157’s anti-inflammatory and free radical-neutralizing properties suggest its potential in mitigating ischemia–reperfusion damage. This study evaluates the protective effects of BPC-157 on remote organ damage, including the kidneys, liver, and lungs, in a rat model of skeletal muscle I/R injury. Materials and Methods: A total of 24 male Wistar albino rats were randomly divided into four groups: sham (S), BPC-157(B), lower extremity I/R(IR) and lower extremity I/R+BPC-157(I/RB). Some 45 min of ischemia of lower extremity was followed by 2 h of reperfusion of limbs. BPC-157 was applied to groups B and I/RB at the beginning of the procedure. After 2 h of reperfusion, liver, kidney and lung tissues were harvested for biochemical and histopathological analyses. Results: In the histopathological examination, vascular and glomerular vacuolization, tubular dilation, hyaline casts, and tubular cell shedding in renal tissue were significantly lower in the I/RB group compared to other groups. Lung tissue showed reduced interstitial edema, alveolar congestion, and total damage scores in the I/RB group. Similarly, in liver tissue, sinusoidal dilation, necrotic cells, and mononuclear cell infiltration were significantly lower in the I/RB group. Additionally, the evaluation of TAS, TOS, OSI, and PON-1 revealed a statistically significant increase in antioxidant activity in the liver, lung, and kidney tissues of the I/RB group. Conclusions: The findings of this study demonstrate that BPC-157 exerts a significant protective effect against distant organ damage in the liver, kidneys, and lungs following lower extremity ischemia–reperfusion injury in rats.
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