Cumaali Demirtas

Objective: Hepatic ischemia-reperfusion (I/R) injury leads not only to localized liver dysfunction but also to remote organ injury involving the kidneys and spleen, substantially contributing to high clinical morbidity and mortality. This study aimed to investigate the protective effects of non-invasive transauricular vagus nerve stimulation (tVNS) against secondary kidney and spleen injury in a standardized rat model of hepatic I/R.Methods: Twenty-one male Sprague-Dawley rats were randomly assigned to three experimental groups (n=7 each): Sham Control (laparotomy with inactive tVNS electrodes), I/R (1-hour partial hepatic ischemia followed by 3-hour reperfusion), and I/R + tVNS (1-hour ischemia + 3-hour reperfusion with simultaneous active tVNS at 1 mA, 20 Hz). Following the reperfusion period, kidney and spleen tissues were harvested. Objective, blinded histopathological evaluations and quantitative image analysis were paired with biochemical assays for oxidative stress and inflammatory markers.Results: Blinded histological analysis demonstrated that tVNS significantly attenuated I/R-induced pathological damage, including glomerular matrix expansion and tissue congestion. In renal tissues, active tVNS significantly increased total antioxidant status (TAS) (p<0.05), while significantly reducing total oxidant status (TOS) and the oxidative stress index (OSI) (p<0.05 and p<0.01, respectively) compared to the untreated I/R group. Furthermore, renal downstream inflammatory markers IL-1β and hypoxia-inducible factor-1α (HIF-1α) were markedly suppressed by tVNS (p<0.01 and p<0.001, respectively). In splenic tissues, tVNS treatment similarly led to a significant decrease in TOS and OSI levels (p<0.05 and p<0.01, respectively), which was accompanied by a robust reduction in IL-1β expression (p<0.01).Conclusions: Our findings demonstrate that tVNS exerts systemic protective effects by mitigating hepatic I/R-induced remote tissue injury in both the kidneys and spleen. This neuro-modulatory approach significantly improved antioxidant capacity suppressed tissue hypoxia signaling via HIF-1α, and modulated local inflammatory cytokine cascades. These results suggest that non-invasive tVNS serves as a promising therapeutic strategy to alleviate I/R-related secondary organ damage through the activation of anti-inflammatory pathways.

Chronic alcohol consumption causes serious damage to the liver and cardiovascular system and leads to neoplastic lesions in various organs such as the esophagus, liver, and breast. In our study, we evaluated the protective effects of standard and high doses of dapagliflozin against alcohol-related cardiac damage by using its anti-inflammatory, antifibrotic, and anticardiac remodeling effects with biochemical and pathological parameters. Twenty male and 20 female Sprague–Dawley rats were used in the experiments. The animals were randomly divided into 5 groups, with 4 male rats and 4 female rats in each group. The experimental groups (ALCOHOL, ALCOHOL + DAP, and ALCOHOL+hDAP groups) were given 20% ethyl alcohol intraperitoneally (i.p.) once daily for 28 days. Dapagliflozin (DAP, ALCOHOL + DAP, and ALCOHOL+hDAP groups) and saline solution (CONT and ALCOHOL groups) were administered orally via gavage (o.g.). In the hearts of animals exposed to alcohol, cardiomyocyte hypertrophy, irregular myofiber arrangement, widespread or focal infiltration of inflammatory cells such as neutrophils and lymphocytes, and marked cytoplasmic vacuolization were observed. Treatment with high-dose dapagliflozin alleviated these structural changes. Alcohol caused significant proximal tubular damage. High-dose dapagliflozin resulted in a greater reduction in alcohol-induced renal damage. Although standard dose of dapagliflozin improved alcohol-induced impaired caspase-3, cytokeratin 18-M30, cytokeratin 18-M65, TAS, TOS, OSI, MDA, IL-1β, TNF-α, HsCRP, endothelin-1, IMA, total thiol, native thiol, and disulfide levels, high-dose dapagliflozin provided significant improvements ( P < 0.001). This study suggests that high-dose dapagliflozin (3 mg/kg) may have the potential to regulate mitochondrial function and thiol/disulfide balance in alcohol-related heart damage by inhibiting fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress through various mechanisms.

The original article can be accessed at https://doi.org/10.55730/1300-0144.6192. Background/aim: Subarachnoid haemorrhage (SAH) is a severe cerebrovascular condition with high morbidity and mortality. Inflammation and oxidative stress are key factors in its pathophysiology, particularly in secondary vascular injury. This study aimed to evaluate the effects of colchicine on vascular integrity and biochemical markers following SAH in an experimental rat model. Materials and methods: Eighteen female Sprague-Dawley rats were divided into three groups: Control (no SAH), SAH (induced without treatment), and SAH + Colchicine (1 mg/kg intraperitoneally at 1 h and 24 h). SAH was induced by autologous blood injection into the cisterna magna. Rats were sacrificed 48 h post-induction. Serum and tissue samples were analyzed for oxidative stress indices and inflammatory cytokines, and histopathological evaluations were performed to assess vascular injury. Results: SAH caused significant increases in oxidative stress and pro-inflammatory cytokines compared to the Control group. Tissue TOS and OSI levels were higher, while TAS was lower in both SAH and colchicine groups (p < 0.05). Serum cytokines (IL-1β, IL-6, TNF-α) and OSI were highest in the colchicine group, intermediate in SAH, and lowest in Control, whereas TAS showed the opposite pattern (p < 0.05). Thiol-disulfide homeostasis shifted toward oxidation, with reduced total/native thiols and elevated disulfide ratios. Histologically, colchicine partially reduced endothelial damage and inflammation, but basilar artery diameter and wall thickness remained unchanged. Conclusion: At the administered dose and 48-hour time point, colchicine produced partial histological improvement without reducing systemic oxidative or inflammatory markers. Some serum indices were higher than in untreated SAH, suggesting a limited short-term protective effect. Further studies are required to explore optimal dosing and timing for colchicine as a potential neuroprotective agent

Excessive alcohol consumption causes significant cardio‐hepatic damage. This study investigated the effects of standard (10 mg/kg) and high (40 mg/kg) doses of atorvastatin on fibrosis, hypertrophy, apoptosis, inflammation, oxidative stress, mitochondrial‐mediated apoptotic pathways, and thiol/disulfide balance in alcohol‐induced heart and liver injury. Forty Sprague‐Dawley rats were divided into five groups ( n = 8; 4 male/4 female): Control (CONT), ALCOHOL (2.5 g/kg 20% ethanol i.p./28 days), ATOR (10 mg/kg o.g./28 days), ALCOHOL + ATOR (10 mg/kg o.g./28 days) and ALCOHOL+ hATOR (40 mg/kg o.g./28 days). Histopathologically, alcohol caused cardiac myocyte dilation, vacuolization, inflammation, and hepatic cord disruption. While standard ATOR partially improved tissue architecture ( p < 0.001), the ALCOHOL+ hATOR group showed the lowest severity. Alcohol exposure significantly increased apoptosis (Caspase‐3, M30, M65), oxidative stress (TOS, OSI, MDA), ischemia (IMA), and inflammatory cytokines (IL‐1β, TNF‐α, HsCRP, Endothelin‐1) across serum, heart, and liver samples, while decreasing TAS, total thiol, and native thiol levels ( p < 0.001 for all vs. CONT). Conversely, high‐dose atorvastatin (ALCOHOL + hATOR) significantly reversed alcohol‐induced toxicity by decreasing Caspase‐3, M30, M65, TOS, OSI, MDA, TNF‐α, HsCRP, Endothelin‐1, and disulfide levels, while significantly restoring TAS, total thiol, and native thiol levels ( p < 0.001 vs. ALCOHOL). TAS was significantly higher in the ALCOHOL+hATOR group than the ALCOHOL + ATOR group ( p < 0.001). Despite marked improvements by hATOR, OSI, TOS, IL‐1β, and HsCRP levels remained higher than CONT ( p < 0.001). High‐dose atorvastatin (40 mg/kg) exerts robust pleiotropic, anti‐apoptotic, and antioxidant cytoprotection. By preserving thiol‐disulfide homeostasis and limiting inflammation, high‐dose atorvastatin effectively mitigates alcohol‐induced subchronic cardiac and hepatic injury.

Purpose: Lower extremity ischemia‐reperfusion injury (IRI) triggers systemic inflammation and oxidative stress, causing myocardial remote ischemia‐reperfusion injury (MIRI). Current treatments are limited. Methods: Male Sprague‐Dawley rats ( n = 6 per group) were assigned to Sham, I/R, I/R + colchicine (C), I/R + HBOT, and I/R + HBOT + C. IRI was induced by 60‐min infrarenal aortic clamping and 120‐h reperfusion. Treatment: Once daily colchicine (0.3 mg/kg) and HBOT (2.5 ATA, 100% O ₂ ) twice daily were administered for 5 days post‐reperfusion. Cardiac damage, oxidative stress, inflammation, and NRF‐2/HO‐1 signaling were measured, and electrocardiography (ECG) was performed. Results: I/R caused severe MIRI (Hs‐Troponin T: 568.54 pg/mL; heart OSI: 20.98; TNF‐α: 582.89 pg/mL). Both monotherapies reduced damage, but HBOT + C was superior: Hs‐Troponin T 342.07 pg/mL, OSI 2.26, TNF‐α 278.82 pg/mL, and IL‐6 12.25 pg/mL, with the upper end of the interquartile range for NRF‐2 (41.03) and HO‐1 (14.45) activation and restored redox balance (%DIS/NT: 26.31). No differences were observed between groups on the ECG. Conclusions: Colchicine suppresses inflammation, relieving inhibition of antioxidant defenses, enabling HBOT to fully activate NRF‐2/HO‐1. This synergistic HBOT + C strategy effectively mitigates MIRI, offering a promising multimodal therapy for remote organ protection after major ischemia.

Objective: Sodium–glucose cotransporter 2 (SGLT2) inhibitors, particularly empagliflozin, have attracted considerable attention because of their cardiovascular benefits beyond glycemic control. However, the interaction between empagliflozin and exercise-induced physiological cardiac remodeling in healthy individuals remains insufficiently understood. This study investigated the effects of different swimming exercise protocols (anaerobic, aerobic, and endurance), administered alone or in combination with empagliflozin, on cardiac structure and electrophysiology. Methods: Thirty-six male Sprague–Dawley rats were randomly assigned to six groups (n = 6 per group): anaerobic (An), aerobic (Ae), endurance (En), and the corresponding exercise groups combined with empagliflozin (An + Empa, Ae + Empa, and En + Empa). Empagliflozin was administered by oral gavage at a dose of 15 mg/kg/day for 30 days. Transthoracic echocardiography, electrocardiography (ECG), and gastrocnemius electromyography were performed at baseline and at the end of the study to assess cardiac remodeling, heart rate, and neuromuscular function. The study was carried out over a 30-day intervention period following ethics committee approval on 24 July 2024. Results: No significant between-group differences were observed in echocardiographic parameters before the intervention. On day 30, significant differences were identified among the groups in interventricular septal thickness at end-diastole (IVSd) (p = 0.027), left ventricular internal diameter at end-diastole (LVIDd) (p = 0.009), and end-diastolic volume (EDV) (p = 0.014). Bonferroni-corrected post hoc analysis showed that the aerobic exercise plus empagliflozin group differed from several exercise-only groups, particularly in parameters related to ventricular size and filling volume, including LVIDd and EDV (p < 0.008). On day 30, electrocardiographic repolarization-related parameters, including QT, QTc, JT, and Tpeak–Tend intervals, also differed significantly among the groups (all p < 0.05). In post hoc analysis, the anaerobic exercise group showed significant differences in QT and JT intervals compared with the aerobic and endurance groups (p < 0.008). In the anaerobic protocol, empagliflozin was associated with a reduction in heart rate compared with the corresponding control group (p = 0.019). No significant between-group differences were observed in EMG findings. Conclusions: Different exercise protocols induce distinct patterns of adaptation in cardiac structure and electrophysiology in healthy rats. Empagliflozin (15 mg/kg/day) may modulate exercise-induced cardiac responses in a modality-dependent manner; the most pronounced echocardiographic effects were observed in the aerobic protocol, whereas the effect on heart rate was observed in the anaerobic protocol. These findings highlight the need for longer-term and mechanistic studies to further clarify the effects of SGLT2 inhibitors on physiological cardiac remodeling.

The effects of alpha-tocopherol on seizure parameters, locomotor-cognitive functions, inflammatory response, oxidative stress response, histopathological changes, immunohistochemical parameters, and miRNA fold changes were investigated in rats with traumatic brain injury (TBI) and pentylenetetrazol (PTZ)-induced seizures. Sprague–Dawley male rats were randomly divided into three groups: Control ( n = 8), TBI + PTZ ( n = 10), and TBI + PTZ + tocopherol ( n = 10). After inducing TBI in animals using the weight-drop method, increased post-injury seizure susceptibility was achieved by administering subconvulsive doses of PTZ. Saline was administered intraperitoneally to the control and TBI + PTZ groups for 6 days, while 500 mg/kg alpha-tocopherol was administered intraperitoneally to the TBI + PTZ + tocopherol group. Seizure intensity, seizure frequency, and total seizure duration were significantly reduced in the TBI + PTZ + tocopherol group compared to the TBI + PTZ group ( p < 0.05). No significant adverse effects related to TBI and PTZ were observed in the animals’ locomotor activity, anxiety-like behaviors, or learning and memory test outcomes. In the TBI + PTZ + tocopherol group, significant reductions were observed in inflammatory cytokine response, oxidative stress, and SUR1-TRPM4 channel activity compared to the TBI + PTZ group ( p < 0.001). While degenerative and apoptotic neurons and the number of 8-OHdG-positive cells in the CA1 and dentate gyrus regions were limited in the TBI + PTZ + tocopherol group, downregulated miR-324-5p increased ( p < 0.05). Alpha-tocopherol reduced the severity and duration of seizures, reduced oxidative stress and inflammation, and stabilized the thiol-disulfide balance. It also reduced degenerative cell structures and DNA damage in the cortex, hippocampus, and dentate gyrus. In conclusion, the findings of this study suggest that alpha-tocopherol is a potential neuroprotective agent that modulates early epileptogenic network instability in TBI and seizure susceptibility through multiple pathways, including oxidative stress, inflammation, and ion channel regulation.