Aydin, Suna; Polat, İsmail; Tural, Kevser; Duger, Nurullah; Ugur, Kader; Sahin, İbrahim; Aydin, Suleyman; Lee, Do-Youn

Background/Objectives: The underlying molecular mechanisms of deep vein thrombosis (DVT), which continues to be a major global public health concern, remain unclear. A key component of anticoagulant therapy, heparin (HP) interacts with heparin-binding growth factors including pleiotrophin (PTN) and midkine (MK), both of which have basic amino acid-rich domains that have a strong affinity for HP. The purpose of this study was to determine if changes in the levels of circulating HP, MK, and PTN are linked to the onset of acute DVT. Methods: Thirty patients diagnosed with acute DVT by venous Doppler ultrasonography (VDU) and 28 healthy controls with normal VDU findings were enrolled. Serum HP, MK, and PTN concentrations were measured using ELISA. In DVT patients, blood samples were obtained before and after routine subcutaneous low-molecular-weight heparin treatment; controls provided a single blood sample. ROC curve analysis was used to assess diagnostic performance. Results: Prior to treatment, patients with acute DVT exhibited significantly lower serum HP levels (p < 0.05) and significantly higher MK and PTN levels compared with healthy controls (both p < 0.05). Following heparin administration, serum HP levels increased significantly (p < 0.05), while MK and PTN levels showed a decreasing trend that did not reach statistical significance (p > 0.05). ROC curve analysis demonstrated limited diagnostic performance for HP (sensitivity 10.3%, specificity 68.8%), PTN (62.1%, 54.2%), and MK (82.8%, 35.4%). Conclusions: Decreased circulating HP and increased MK and PTN levels are characteristics of acute DVT that may indicate endogenous HP sequestration through binding to these growth factors. This imbalance could lead to less free HP being available, which would encourage the formation of thrombus. Therapeutic approaches that target MK- and PTN-mediated HP interactions may constitute a unique approach for the therapy of acute DVT, as evidenced by the partial normalization seen after exogenous heparin delivery.

Cerrah, Serkan; Baykan, Ahmed Ramiz; Sezgin, Esra Tuba; Huseynova, Gulbaniz; Karabacak, Elif; Tanas, Serdar; Baykan, Emine Kartal; Gunay, Murat; Gungor, Ali; Suleyman, Halis

Objective: Linezolid (LZD), an oxazolidinone antibiotic widely used against Gram-positive infections, has been associated with mitochondrial dysfunction and hepatotoxicity, particularly during prolonged use. This study aimed to investigate the protective effects of adenosine triphosphate (ATP) and Liv-52 against LZD-induced liver injury, with a focus on oxidative stress, inflammation, and necroptosis pathways. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: healthy control (HG), LZD-treated (LZDG), Liv-52 + LZD (LVLZ), and ATP + LZD (ATLZ). Liv-52 (50 mg/kg, orally) and ATP (5 mg/kg, intraperitoneally) were administered prior to LZD (125 mg/kg, orally) for 14 days. Results: Following LZD administration, malondialdehyde (MDA) levels markedly increased, indicating oxidative stress, while total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) activities significantly decreased. Histopathological examination revealed pronounced hepatocellular damage accompanied by increased NF-κB, NLRP3, RIPK3, and MLKL expression, indicating activation of inflammatory and necroptotic pathways. Treatment with ATP and Liv-52 significantly ameliorated these biochemical, histopathological, and molecular alterations. Conclusions: Treatment with ATP and Liv-52 significantly attenuated oxidative stress, improved histopathological alterations, and suppressed the expression of inflammatory and necroptotic markers. Notably, ATP exhibited a more pronounced protective effect compared to Liv-52. In conclusion, LZD induces hepatotoxicity through oxidative stress-mediated inflammatory and necroptotic mechanisms, while ATP and Liv-52 confer hepatoprotection, with ATP showing superior efficacy.

Cicek, Ibrahim; Esenulku, Cenap Mahmut; Somuncu, Ahmet Mehmet; Bulut, Seval; Yucel, Nurinisa; Bal Tastan, Tugba; Coban, Taha Abdulkadir; Suleyman, Halis

Background/objectives: Common carotid artery occlusion can cause oxidant and inflammatory damage to the optic nerve. In this study, the effect of sunitinib was investigated, the antioxidant and anti-inflammatory properties of which have been previously reported and shown to be protective in I/R injury and in preventing bilateral optic nerve ischemia–reperfusion (I/R) injuries after unilateral common carotid artery ligation in rats. Methods: In this study, 18 Albino Wistar male rats were divided into SG (sham-operated), CCU (clamping and unclamping), and SCCU (sunitinib + clamping and unclamping) groups. One hour before the surgical procedures, sunitinib (25 mg/kg, oral) was given to SCCU rats. Anesthesia was induced with ketamine (60 mg/kg, ip) and sevoflurane. The right common carotid arteries of all rats were accessed under anesthesia. While the skin opened in SG rats was closed with sutures, the right common carotid arteries of CCU and SCCU rats were clipped, and an ischemia period was created for 10 min. Then, reperfusion (6 h) was achieved by unclipping. After euthanasia with ketamine (120 mg/kg, intraperitoneally), the right and left optic nerves of the rats were removed and examined biochemically and histopathologically. Results: Malondialdehyde, tumor necrosis factor α, interleukin-1β, and interleukin-6 were increased, and total glutathione levels had decreased in both ipsilateral and contralateral optic nerves (p < 0.05). These changes were more prominent on the ipsilateral side. Similarly, histopathological damage was observed to be more on the ipsilateral side (p < 0.05). Biochemical and histopathological changes were significantly suppressed in rats receiving sunitinib treatment (p < 0.05). Conclusions: Sunitinib may protect optic nerve tissue against I/R injury by reducing oxidative stress and inflammation.

Ulusan, Mehmet; Erdogan, Mumin Alper; Simsek, Ozkan; Ustundag, Hilal; Dogan, Zafer; Ciftci, Bertug Bekir; Kocamuftuoglu, Mesih; Orhan, Imdat; Erbas, Oytun

Background and Objectives: Methotrexate (MTX) is a widely utilised pharmaceutical agent in the treatment of various malignancies and inflammatory diseases. However, its clinical utility is often constrained by its potential for hepatotoxicity. Although pyridostigmine is a well-established reversible acetylcholinesterase inhibitor, its potential therapeutic role in preventing hepatic injury remains incompletely defined. The present study aimed to investigate whether pyridostigmine provides protective effects against MTX-triggered liver damage in a rat model. Methods: Thirty-six female Wistar albino rats randomly assigned to three groups: control (n = 12), MTX + saline (n = 12), and MTX + pyridostigmine (n = 12). Hepatotoxicity was induced by a single-dose MTX injection (20 mg/kg), followed by daily oral administration of either pyridostigmine (5 mg/kg) or saline for ten consecutive days. Hepatic function markers, oxidative stress parameters, fibrosis-associated mediators, and histopathological changes were assessed. Results: Pyridostigmine significantly attenuated MTX-induced elevations in plasma alanine aminotransferase (p < 0.05) and cytokeratin-18 levels (p < 0.001), and reduced liver and plasma malondialdehyde (MDA) levels (p < 0.05). Additionally, pyridostigmine treatment resulted in reduced levels of transforming growth factor-beta (p < 0.05), bone morphogenetic protein-9 (p < 0.001), and endoglin levels (p < 0.05), as well as increased sirtuin 1 level (p < 0.05). Histopathological examination revealed that pyridostigmine treatment significantly reduced MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration. Conclusions: Pyridostigmine exerted hepatoprotective effects against MTX-induced liver injury by attenuating oxidative stress, restoring SIRT1 expression, and suppressing pro-fibrotic signaling. These findings indicate that pyridostigmine may hold therapeutic potential for the prevention of MTX-associated hepatotoxicity.

Karatas, Ezgi; Yavuzer, Bulent; Demir, Ozlem; Sezgin, Esra Tuba; Hendem, Engin; Cinici, Emine; Coban, Taha Abdulkadir; Suleyman, Halis

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib are widely used in non-small-cell lung cancer treatment, and accumulating evidence indicates they can markedly increase ocular toxicity. Nonetheless, whether erlotinib causes optic nerve injury has not been investigated before and remains a subject worth investigating. This study aimed to examine the impact of erlotinib on oxidative stress, inflammation, and histopathological changes in rat optic nerve tissue and evaluate the potential neuroprotective role of thiamine pyrophosphate (TPP). Methods: Twenty-four male Wistar rats were randomly assigned to four groups: healthy control, TPP alone, erlotinib alone, and erlotinib + TPP. Erlotinib (10 mg/kg, orally, on alternate days) and TPP (20 mg/kg, intraperitoneally, daily) were administered for two consecutive weeks. Optic nerve samples were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), followed by histopathological examination. Results: Erlotinib treatment significantly increased MDA, IL-1β, and TNF-α levels while reducing tGSH, SOD, and CAT activity, demonstrating oxidative stress and an inflammatory response. Co-administration of TPP ameliorated these changes by lowering reactive oxygen species, restoring antioxidant capacity, and attenuating inflammation. Histopathological alterations, including astrocyte degeneration, edema, and vascular congestion, were evident after erlotinib exposure but were significantly alleviated when TPP was administered concurrently. Conclusions: Erlotinib induces oxidative and inflammatory optic nerve injury, while TPP co-treatment offers significant neuroprotection. These findings support TPP as a potential adjunct to reduce EGFR-TKI-related ocular toxicity and highlight importance of redox modulation in limiting treatment-associated side effects.

Kahramanlar, Agah Abdullah; Ozgodek, Habip Burak; Ince, Ramazan; Yavuzer, Bulent; Admis, Ozlem; Mendil, Ali Sefa; Ekinci, Bilge; Suleyman, Halis

Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and modulate inflammation, including adenosine triphosphate (ATP), melatonin, and thiamine pyrophosphate (TPP), may counteract these mechanisms; however, their relative neuroprotective potential in amiodarone-induced neuropathy remains unclear. This study aimed to comparatively evaluate the effects of ATP, melatonin, and TPP on amiodarone-induced peripheral neuropathy and neuropathic pain in rats. Methods: Thirty male albino Wistar rats were assigned to five groups: healthy; amiodarone (50 mg/kg/orally); amiodarone + ATP (5 mg/kg/intraperitoneally); amiodarone + melatonin (10 mg/kg/orally); or amiodarone + TPP (20 mg/kg/intraperitoneally). Treatments were given once daily for 14 days. Oxidative stress indices (malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT)) and proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 Beta (IL-1β), interleukin-6 (IL-6)) were quantified in sciatic nerve by Enzyme-Linked Immunosorbent Assay (ELISA). Paw withdrawal thresholds were measured with the Randall-Selitto test before and after treatment. Histopathology was performed using Hematoxylin-eosin staining. Results: Amiodarone exposure resulted in pronounced elevations in MDA and proinflammatory cytokine levels, accompanied by significant reductions in tGSH, SOD, CAT activities, and paw withdrawal thresholds. ATP, melatonin and TPP ameliorated these alterations to varying degrees. Among them, TPP provided the most robust antioxidant and anti-inflammatory effects, followed by ATP and melatonin. Histopathological examination confirmed most severe axonal degeneration, interstitial edema and Schwann cell proliferation in the amiodarone group, with substantial amelioration in the TPP-treated rats. Conclusions: Amiodarone induces neuropathic pain through oxidative and inflammatory injury to peripheral nerves. TPP exhibited superior neuroprotective efficacy compared with ATP and melatonin, highlighting its potential as a candidate therapeutic agent for amiodarone-related neuropathy. Further clinical research is warranted to support translational application of these findings.

Ates, Irem; Isik, Bahar; Gozen, Fusun; Yazici, Gulce Naz; Gulaboglu, Mine; Mammadov, Renad; Huseynova, Gulbeniz; Altuner, Durdu; Suleyman, Halis

Background: Tramadol binds to opioid receptors and inhibits norepinephrine and serotonin reuptake, causing serotonin syndrome. Tianeptine stimulates serotonin reuptake and reduces serotonin levels. The aim of this study was to investigate whether tianeptine is effective against serotonin syndrome that may occur with serotoninergic drugs such as tramadol and citalopram. Methods: Rats were divided into eight groups (n = 6) that received tramadol (50 mg/kg), citalopram (10 mg/kg), or tianeptine (5 mg/kg) alone or a combination of tramadol + citalopram, tramadol + tianeptine, citalopram + tianeptine or tramadol + citalopram + tianeptine at the same doses administered to the stomach by oral gavage for 3 weeks. The healthy control group was given saline. Malondialdehyde, total glutathione, superoxide dismutase, and catalase levels were measured in removed brain tissues. The tissues were also examined histopathologically. Results: In the tramadol, tramadol + citalopram, and tramadol + citalopram + tianeptine groups, malondialdehyde levels were found to be higher compared to the control group, while glutathione, superoxide dismutase, and catalase levels were found to be lower. In other groups, values close to the control group were measured. Morphological degeneration was observed in neurons in the tramadol + citalopram group. The swelling of astrocytes and pericellular edema in oligodendrocytes were also observed. A significant population increase was noted in microglial cells. Blood vessels belonging to the tissue were observed to be severely dilated and congested. Histopathological damage was partially resolved in the group given tramadol + citalopram + tianeptine. Conclusions: The tramadol + citalopram combination caused severe oxidative stress in brain tissue. Tramadol alone caused mild damage in brain tissue, whereas tianeptine prevented the brain damage caused by tramadol.

Danisman, Betul; Cicek, Betul; Yildirim, Serkan; Bolat, Ismail; Kantar, Deniz; Golokhvast, Kirill S.; Nikitovic, Dragana; Tsatsakis, Aristidis; Taghizadehghalehjoughi, Ali

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin (IND) are the most commonly prescribed for inflammation or pain. However, widespread use causes several adverse effects, such as gastric ulcers, upper gastric system bleeding, and erosions. Carnosic acid (CA) is an important natural antioxidant found in rosemary (Rosmarinus essentials) and exhibits a protective effect by suppressing oxidative stress and inflammation. This study aimed to investigate the impact of CA on IND-induced gastric ulceration. Wistar male rats received CA (100 mg/kg) or esomeprazole (ESP) (20 mg/kg, standard drug) by oral gavage for 14 days, after that gastric ulceration was induced by oral administration of 100 mg/kg IND. CA pretreatment attenuated both gross morphological lesions and histopathological alterations. CA strongly reduced IND-induced oxidative stress, verified by a decrease in MDA (p < 0.001) and TOS levels (p < 0.05). Furthermore, an IND-dependent increase in CAT (p < 0.001) and GPx (p < 0.01) activities, as well as a reduction in GSH levels (p < 0.01), were ameliorated by CA pretreatment. CA also attenuated inflammatory damage by suppressing IL-1β (p < 0.01), IL-6 (p < 0.01), and TNFα (p < 0.001) production and increasing Nrf2/HO-1 (p < 0.05) expressions. In conclusion, CA shows a gastroprotective effect by reducing oxidative stress and attenuating inflammation.