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    Cannabidiol mitigates methotrexate-induced hepatic injury via SIRT-1/p53 signaling and mitochondrial pathways: reduces oxidative stress and inflammation
    (Taylor & Francis Ltd, 2025) Ilhan, Ilter; Asci, Halil; Candan, Ibrahim Aydin; Savran, Mehtap; Imeci, Orhan Berk; Sevuk, Mehmet Abdulkadir
    Methotrexate (MTX), a widely used chemotherapeutic agent, often induces hepatotoxicity, limiting its clinical utility. Cannabidiol (CBD), derived from hemp, possesses antioxidant, anti-inflammatory, and antiapoptotic properties. This study aims to investigate CBD's protective effects against MTX-induced liver injury and elucidate the underlying mechanisms. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (20 mg/kg intraperitoneally [i.p.] once), MTX+CBD (20 mg/kg i.p. once + 5 mg/kg i.p. for seven days), and CBD (5 mg/kg, i.p. for seven days). Biochemical analyses of serum and liver tissues were performed to assess oxidative stress markers (total oxidant status, total antioxidant status, oxidative stress index), liver function tests (AST, ALT), and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase). Histopathological and immunohistochemical examinations were conducted to evaluate liver tissue damage and TNF-alpha expression. Genetic analyses were performed to measure the expression levels of SIRT-1, p53, Bcl-2, and Bax genes using RT-qPCR. MTX administration increased oxidative stress markers, liver enzymes, TNF-alpha, p53, and Bax levels while decreasing antioxidant defenses and SIRT-1 expression. CBD administration reversed these alterations effectively. CBD mitigated MTX-induced hepatotoxicity by reducing oxidative stress, inflammation, and apoptosis. It activates antioxidant defenses via SIRT-1 upregulation, suppresses inflammation by reducing TNF-alpha, and prevents apoptosis by modulating p53, Bcl-2, and Bax gene expressions. These findings suggest CBD could be a promising therapeutic agent for chemotherapy-induced liver damage. Further research is warranted to explore additional pathways and broader molecular mechanisms.
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    Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity
    (Springer, 2023) Karakuyu, Nasif Fatih; Savran, Mehtap; Candan, Ibrahim Aydin; Buyukbayram, Halil Ibrahim; Erzurumlu, Yalcin
    Although doxorubicin (DOX) is an effective anti-neoplastic drug for many types of cancer, particularly dose-related cardiotoxicity limits the use of the drug. In this study, it was aimed to investigate the protective effect of lercanidipine (LRD) against DOX-induced cardiotoxicity. In our study, 40 Wistar albino female rats were randomly divided into 5 groups as control, DOX, LRD 0.5 (DOX + 0.5 mg/kg LRD), LRD 1 (DOX + 1 mg/kg LRD), and LRD 2 (DOX + 2 mg/kg LRD). At the end of the experiment, the rats were sacrificed, and their blood, heart, and endothelial tissues were examined biochemically, histopathologically, immunohistochemically, and genetically. According to our findings, necrosis, tumor necrosis factor alpha activity, vascular endothelial growth factor activity, and oxidative stress were increased in the heart tissues of the DOX group. In addition, DOX treatment caused the deteriorations in biochemical parameters, and levels of autophagy-related proteins, Atg5, Beclin1, and LC3-I/II were detected. Significant dose-related improvements in these findings were observed with LRD treatment. Besides, Atg5, LC3-I/II, and Beclin1 levels evaluated by western blot revealed that LRD exerts a tissue protective effect by regulating autophagy in endothelial tissue. LRD treatment, which is a new-generation calcium channel blocker, showed antioxidant, anti-inflammatory, and anti-apoptotic properties in heart and endothelial tissue in a dose-dependent manner and also showed protective activity by regulating autophagy in endothelial tissue. With studies evaluating these mechanisms in more detail, the protective effects of LRD will be revealed more clearly.
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    Melatonin protects the heart and endothelium against high fructose corn syrup consumption-induced cardiovascular toxicity via SIRT-1 signaling
    (Sage Publications Ltd, 2019) Savran, Mehtap; Aşçı, Halil; Özmen, Özlem; Erzurumlu, Yalçın; Savaş, Hasan Basri; Sönmez, Yasin; Şahin, Yasemin
    High fructose corn syrup (HFCS) has been shown to cause cardiovascular toxicity via oxidative stress and inflammation. The aim of this study is to demonstrate the protective effects of melatonin (MLT) against HFCS-induced endothelial and cardiac dysfunction via oxidative stress and inflammation. Thirty-two Sprague Dawley male rats were distributed into three groups as control, HFCS, and HFCS + MLT. HFCS form F55 was prepared as 20% fructose syrup solution and given to the rats through drinking water for 10 weeks, and MLT administrated 10 mg/kg/day orally for last 6 weeks in addition to F55. After decapitation, blood and half of the heart samples were collected for biochemical analysis and other half of the tissues for histopathological and immunohistochemical analysis. Aspartate transaminase, creatine kinase MB, lactate dehydrogenase, total oxidant status and oxidative stress index, and caspase-3 levels increased and total antioxidant status levels decreased significantly in HFCS group. MLT treatment reversed all these parameters. Histopathologically, hyperemia, endothelial cell damage and increased levels of angiogenin, C-reactive protein, inducible nitric oxide synthase, myeloperoxidase and decreased sirtuin-1 (SIRT-1) expressions were observed in HFCS group. MLT ameliorated all these changes. MLT has an anti-inflammatory, antioxidant, antiapoptotic effects on HFCS-induced cardiovascular toxicity through enhancing the expression of SIRT-1.
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    Melatonin receptor agonist ramelteon alleviates experimental acute ocular inflammation via HIF-1?/VEGF/E-NOS signaling
    (Sage Publications Ltd, 2023) Sofu, Gulsah Usta; Erzurumlu, Yalcin; Karaca, Umut; Candan, Ibrahim Aydin; Savran, Mehtap; Asci, Halil; Hasseyid, Nursel
    Purpose: Ramelteon (RML) is a potent, selective agonist of the high-affinity melatonin receptor 1 and 2 receptors. In addition, RML is known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the effects of RML on HIF-1 alpha, VEGF and e-NOS signaling pathway in a rat model of endotoxin-induced uveitis (EIU). Methods: Twenty-eight Wistar albino rats were divided into 4 groups as controls, lypopolysaccharide (LPS) group (5 mg/kg i.p.), LPS + RML group (5 mg/kg i.p and 8 mg/kg orally, respectively) and RML group (8 mg/kg orally). EIU was induced by a single intraperitoneal LPS injection. Histopathological and genetical analyses were performed. Results: In histopathological analysis, LPS caused mild anterior uveitis characterized by increased surface area of iris leaflets and ciliary body due to edema, mild to moderate congestion, and inflammatory infiltrate 6 h following the injection. The pathological findings were reduced by RML. Higher inflammation levels seen in LPS group were significantly reduced in LPS + RML group. Also, HIF-1 alpha, eNOS and VEGF expressions increased in LPS and decreased in LPS + RML group. Conclusion: RML treatment reversed the changes in the HIF-1 alpha /eNOS/ VEGF signaling pathway in LPS-induced uveitis in rats, preventing the progression of the damage and showed positive effects.
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    The impact of prophylactic lacosamide on LPS-induced neuroinflammation in aged rats
    (Springer/Plenum Publishers, 2019) Savran, Mehtap; Özmen, Özlem; Erzurumlu, Yalçın; Savaş, Hasri Basri; Aşçı, S.; Kaynak, M.
    Sepsis-induced central nervous system damage is called sepsis-associated encephalopathy (SAE). In addition to neuroinflammation, oxidative stress and apoptosis act in the development of SAE. In the current study, we evaluated the protective effects of lacosamide (LCM) on neuroinflammation induced by lipopolysaccharide (LPS). Twenty-four Wistar albino rats were divided into 3 groups as controls, LPS group (5 mg/kg i.p.), and LPS plus LCM group (5 mg/kg i.p and 40 mg/kg i.p, respectively). In the rat brain, LPS-induced tissue damage was revealed histopathologically as hyperemia and microhemorrhages. LCM pretreatment ameliorated these histopathological changes. LPS decreased brain TAS levels and significantly increased MDA, CRP, HSP, IL-1 beta, and TNF-alpha expressions in the cortex, hippocampus, and cerebellum. Western analysis revealed increased brain tissue levels of TNF-alpha, NF-K beta, and caspase-3 following LPS. Prophylactic LCM treatment reversed these parameters including oxidative stress, inflammation, and apoptosis in the cortex, hippocampus, and cerebellum.