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Öğe Alpha-lipoic acid prevents doxorubicin-induced acute hepatorenal toxicity in rats by reducing oxidative and inflammatory stress to suppress autophagy(Oxford Univ Press, 2025) Yeni, Yesim; Cicek, Betul; Hacimuftuoglu, Ahmet; Ozkaraca, Mustafa; Mokhtare, BehzadDoxorubicin (DOX) is a commonly used medicine in cancer therapy. This drug accumulation in healthy tissues causes harmful clinical outcomes. Strategies that reduce oxidative damage, including alpha-lipoic acid (ALA) treatment, have been proposed to diminish toxic effects on healthy cells by raising the therapeutical effect of DOX on cancer cells. In this study, the preventive effects of ALA, against DOX-induced hepatorenal harm in rats were researched biochemically, molecularly, histopathological, and immunohistochemical. The experiment was designed for 10 days and 4 groups of 8 rats were created. ALA was administered orally to rats at a dosage of 200 mg/kg for 10 days and DOX was administered intraperitoneally at an only dosage of 30 mg/kg on day 8. To define oxidative stress, SOD, GSH, MPO, MDA, GPx, and CAT levels were evaluated. Hepatorenal harm was detected both histopathologically and by serum creatinine, ALT, ALP, AST, and urea analyses To detect the effect of inflammation, NF-kappa B, IL-1 beta, TNF-alpha levels, were defined in the liver, and AQP-2 and NPHS1 levels in the kidney. In addition, APG5L, Beclin 1, and LC3B expressions were determined immunohistochemically. It was determined that DOX-induced oxidative harm reduced and hepatorenal function markers improved in ALA-applied groups. It was also determined that ALA pretreatment had a regulative effect on NF-kappa B, AQP-2, TNF-alpha, NPHS1, and IL-1 beta levels and prevented the rise in DOX-induced LC3B, Beclin 1, and APG5L expression. Histopathological analysis showed that it prevented hepatorenal harm. As a result, ALA demonstrated its protective potential against DOX-induced hepatorenal toxicity.Öğe Ameliorating effect of S-Allyl cysteine (Black Garlic) on 6-OHDA mediated neurotoxicity in SH-SY5Y cell line(Elsevier Inc., 2024) Yeni, Yesim; Cicek, Betul; Yildirim, Serkan; Bolat, İsmail; Hacimuftuoglu, AhmetTherapeutic approaches based on isolated compounds derived from natural products are more common in preventing diseases involving inflammation and oxidative stress at present. S-allyl cysteine (SAC) is a promising garlic-derived organosulfur compound with many positive effects in cell models and living systems. SAC has biological activity in various fields, enclosing healing in learning and memory disorders, neurotrophic effects, and antioxidant activity. In this study, we purposed to identify the neuroprotective activity of SAC toward 6-OHDA-induced cell demise in the SH-SY5Ycell line. For this purpose, 6-OHDA-induced cytotoxicity, and biochemical, and gene expression changes were evaluated in SH-SY5Y cells. SH-SY5Y cells grown in cell culture were treated with SAC 24 h before and after 6-OHDA application. Then, cell viability, antioxidant parameters, and gene expressions were measured. Finally, immunofluorescence staining analysis was performed. Our results showed that SAC increased cell viability by 144 % at 80 µg/mL with pre-incubation (2 h). It was observed that antioxidant levels were significantly increased and oxidative stress marker levels were decreased in cells exposed to 6-OHDA after pre-treatment with SAC (p<0.05). SAC supplementation also suppressed the increase in pro-inflammation levels (TNF-α/IL1/IL8) caused by 6-OHDA (p < 0.05). While 8-OHdG and Nop10 expressions were observed at a mild level in SAC pretreatment depending on the dose, 8-OHdG, and Nop10 expressions were observed at a moderate level in SAC treatment after 6-OHDA application (p<0.05). Our findings demonstrate the positive effect of pretreatment with SAC on SH-SY5Y cells injured by 6-OHDA, suggesting that SAC may be beneficial for neuroprotection in regulating oxidative stress and neuronal survival in an in vitro model of Parkinson's disease. © 2024 The AuthorsÖğe AuNPs with Cynara scolymus leaf extracts rescue arsenic-induced neurobehavioral deficits and hippocampal tissue toxicity in Balb/c mice through D1R and D2R activation(Elsevier, 2024) Cicek, Betul; Hacimuftuoglu, Ahmet; Yeni, Yesim; Kuzucu, Mehmet; Genc, Sidika; Cetin, Ahmet; Taghizadehghalehjoughi, AliThe present study was designed to evaluate whether AuNPs (gold nanoparticles) synthesized with the Cynara scolymus (CS) leaf exert protective and/or alleviative effects on arsenic (As)-induced hippocampal neurotoxicity in mice. Neurotoxicity in mice was developed by orally treating 10 mg/kg/day sodium arsenite (NaAsO2) for 21 days. 10 mu g/g AuNPs, 1.6 g/kg CS, and 10 mu g/g CS-AuNPs were administered orally simultaneously with 10 mg/ kg As. CS and CS-AuNPs treatments showed down-regulation of TNF-alpha and IL-1 beta levels. CS and CS-AuNPs also ameliorated apoptosis and reduced the alterations in the expression levels of D1 and D2 dopamine receptors induced by As. Simultaneous treatment with CS and CS-AuNPs improved As-induced learning, memory deficits, and motor coordination in mice assessed by water maze and locomotor tests, respectively. The results of this study provide evidence that CS-AuNPs demonstrated neuroprotective roles with antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as improving D1 and D2 signaling, and eventually reversed neurobehavioral impairments.Öğe Chlorogenic Acid Attenuates Doxorubicin-Induced Oxidative Stress and Markers of Apoptosis in Cardiomyocytes via Nrf2/HO-1 and Dityrosine Signaling(Mdpi, 2023) Cicek, Betul; Hacimuftuoglu, Ahmet; Yeni, Yesim; Danisman, Betul; Ozkaraca, Mustafa; Mokhtare, Behzad; Taghizadehghalehjoughi, Ali(1) Background: Doxorubicin (DOX) is extensively used for cancer treatments; however, its clinical application is limited because of its cardiotoxic adverse effects. A combination of DOX and agents with cardioprotective properties is an effective strategy to ameliorate DOX-related cardiotoxicity. Polyphenolic compounds are ideal for the investigation of novel cardioprotective agents. Chlorogenic acid (CGA), an essential dietary polyphenol found in plants, has been previously reported to exert antioxidant, cardioprotective, and antiapoptotic properties. The current research evaluated CGA's in vivo cardioprotective properties in DOX-induced cardiotoxicity and the probable mechanisms underlying this protection. (2) Methods: CGA's cardioprotective properties were investigated in rats that were treated with CGA (100 mg/kg, p.o.) for fourteen days. The experimental model of cardiotoxicity was induced with a single intraperitoneal (15 mg/kg i.p.) injection of DOX on the 10th day. (3) Results: Treatment with CGA significantly improved the DOX-caused altered cardiac damage markers (LDH, CK-MB, and cTn-T), and a marked improvement in cardiac histopathological features accompanied this. DOX downregulated the expression of Nrf2/HO-1 signaling pathways, and the CGA reversed this effect. Consistently, caspase-3, an apoptotic-related marker, and dityrosine expression were suppressed, while Nrf2 and HO-1 expressions were elevated in the cardiac tissues of DOX-treated rats after treatment with the CGA. Furthermore, the recovery was confirmed by the downregulation of 8-OHdG and dityrosine (DT) expressions in immunohistochemical findings. (4) Conclusions: CGA demonstrated a considerable cardioprotective effect against DOX-induced cardiotoxicity. One of the possible mechanisms for these protective properties was the upregulation of the Nrf2/HO-1-dependent pathway and the downregulation of DT, which may ameliorate oxidative stress and cardiomyocyte apoptosis. These findings suggest that CGA may be cardioprotective, particularly in patients receiving DOX-based chemotherapy.Öğe Morinda citrifolia protective effects on paclitaxel-induced testis parenchyma toxicity: An experimental study(Pergamon-Elsevier Science Ltd, 2024) Genc, Sidika; Cicek, Betul; Yeni, Yesim; Kuzucu, Mehmet; Hacimuftuoglu, Ahmet; Bolat, Ismail; Taghizadehghalehjoughi, AliThe current study aimed to investigate the sensitivity of male testis parenchyma cells to chemotherapy agents and the protective effects and mechanisms of Morinda citrifolia (Noni) administration against structural and functional changes before and after chemotherapy (Paclitaxel (PTX)). For this purpose, rats were randomly assigned into four groups (Control = G1, PTX 5 mg/kg = G2; PTX + Noni 10 mg/kg = G3, PTX + Noni 20 mg/kg = G4). PTX was injected intraperitoneally for 4 consecutive weeks, at a dose of 5 mg/kg to all groups except the control group. Then noni was administrated in 10 (G3) and 20 (G4) mg/kg groups orally (gavage) for 14 days. Biochemical analyses, Real-Time Polymerase Chain Reaction (PCR), and immunohistochemical analyses were performed. According to our results, Total Oxidative Stress (TOS) and Malondialdehyde (MDA) were significantly increased in the PTX group (P < 0.01). Superoxide Dismutase (SOD) enzyme activity and Total Antioxidant Capacity (TAC) levels were decreased (P < 0.01). The changes in the rats treated with PTX + Noni 20 mg/ kg were noteworthy. The increased levels of IL1-beta (Interleukin 1 beta) and TNF alpha (tumor necrosis factor-alpha) with PTX were down-regulated after treatment with PTX + Noni 20 mg/kg (P < 0.01) (9 % and 5 % respectively). In addition, Noni restored the testicular histopathological structure by reducing caspase-3 expression and significantly (61 %) suppressed oxidative DNA damage and apoptosis (by regulating the Bax (bcl-2-like protein 4)/Bcl-2 (B-cell lymphoma gene-2) ratio). In conclusion, Noni reduced cellular apoptosis and drastically changed Caspase 8 and Bax/Bcl-2 levels. Furthermore, it considerably decreases oxidative damage and can be used in testicular degeneration.Öğe Panax Ginseng Protects Against Doxorubicin-Induced Testicular Injury in Male Rats by Modulating NF-κB/COX-2 and AR Pathways(Springer, 2025) Yeni, Yesim; Cicek, Betul; Hacimuftuoglu, Ahmet; Ozkaraca, Mustafa; Mokhtare, BehzadPanax ginseng (PG) is a medicinal plant used for many years to treat many diseases. The current study aimed to investigate the possible prophylactic and therapeutic effects of PG extract on doxorubicin (DOX)-induced testicular toxicity in rats. 32 adult male Sprague-Dawley rats (200-250 g) were used in the experiment. The experimental groups were designed as control (normal saline, intraperitoneal), DOX (18 mg/kg, intraperitoneal), PG (200 mg/kg, gavage), and PG + DOX (200 mg/kg, gavage). After treatment, serum levels of testosterone, interleukin-1 beta (IL-1 beta), glutathione (GSH), luteinizing hormone (LH), superoxide dismutase (SOD), lactate dehydrogenase (LDH), catalase (CAT), follicle stimulating hormone (FSH), tumor necrosis factor-alpha (TNF-alpha), and malondialdehyde (MDA) were measured. Then, gene expression, histopathological, and immunohistochemical analyses were performed on testicular tissues. Compared to DOX, treatment with PG + DOX showed a significant improvement in serum levels of FSH, testosterone, LH, TNF-alpha, IL-1 beta, MDA, SOD, LDH, GSH, and CAT. It was also observed that PG + DOX decreased nuclear factor-kappa B and cyclooxygenase-2 expression levels, increased androgen receptor expression, restored testicular histopathological structure, and significantly improved spermatogenesis. The results of the present study showed that PG may have an ameliorative effect against DOX-induced male reproductive toxicity, as DOX causes male reproductive toxicity. It can be concluded that PG is one of the effects that protect against DOX-induced testicular toxicity in rats by reducing lipid peroxidation and activating the antioxidant system. In light of this information, PG may be a useful agent to prevent the testicular toxicity observed in men receiving DOX treatment.Öğe Protective Effect of HMG-CoA Reductase Inhibitor Rosuvastatin on Doxorubicin-Induced Cognitive Impairment, Oxidative Stress and Neuroinflammation: Possible Role of CREB, ERK1/2, and BDNF(Springer, 2025) Yeni, Yesim; Cicek, Betul; Hacimuftuoglu, Ahmet; Ozkaraca, Mustafa; Lacin, Burak BatuhanDuring or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosuvastatin (RVS), an HMG-CoA reductase inhibitor, in the context of neuroinflammation-related cognitive disruption. Here, we aimed to investigate the neuroprotective potential of RVS against doxorubicin (DOX)-induced cognitive impairments. Experimental groups were planned as control (normal saline, intraperitoneal), DOX (total cumulative dose 10 mg/kg, intraperitoneal), RVS (10 mg/kg, oral, 20 days), and RVS + DOX. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, genetic, histopathological, and immunohistochemical examinations. Results from Morris water maze (MWM), passive avoidance, locomotion activity, and elevated plus maze (EPM) tests showed that DOX administration caused behavioral disorders. Moreover, DOX increased the levels of inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-alpha), while decreasing the levels of interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase, catalase (SOD), endothelial nitric oxide (eNOS), and catalase (CAT). Co-treatment with RSV significantly attenuated DOX-induced behavioral changes and oxidative stress markers. In addition, similar to the immunohistochemical results, we determined that it increased the expression levels of extracellular signal-related kinases 1/2 (ERK1/2), cyclic adenosine monophosphate response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) and restored the histopathological structure of the brain. Therefore, these results indicated that RSV has a neuroprotective effect against DOX-induced cognitive impairment by reducing neurobehavioral impairments, exerting antioxidant and anti-inflammatory effects, and modulating brain growth factors.Graphical AbstractRSV ameliorated DOX-induced cognitive impairments by assessing oxidative stress, BDNF, CREB, and ERK1/2 expression. These beneficial effects induced by RSV provided strong protection against both cognitive dysfunction and anxiety-like behavior. RSV may help prevent or alleviate cognitive dysfunction in patients with various types of cancer undergoing chemotherapy and may have potential benefit in neurodegenerative diseasesÖğe Quinic Acid Protects Human SH-SY5Y Neuroblastoma Cells Against Amyloid-β Cytotoxicity(Atatürk Üniversitesi, 2024) Cicek, Betul; Yeni, Yeşim[Abstract Not Available]Öğe Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries(Mdpi, 2023) Cicek, Betul; Hacimuftuoglu, Ahmet; Kuzucu, Mehmet; Cetin, Ahmet; Yeni, Yesim; Genc, Sidika; Taghizadehghalehjoughi, AliAccording to population-based studies, lung cancer is the prominent reason for cancer-related mortality worldwide in males and is also rising in females at an alarming rate. Sorafenib (SOR), which is approved for the treatment of hepatocellular carcinoma and renal cell carcinoma, is a multitargeted protein kinase inhibitor. Additionally, SOR is the subject of interest for preclinical and clinical trials in lung cancer. This study was designed to assess in vivo the possible effects of sorafenib (SOR) in diethylnitrosamine (DEN)-induced lung carcinogenesis and examine its probable mechanisms of action. A total of 30 adult male rats were divided into three groups (1) control, (2) DEN, and (3) DEN + SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum and lung tissue samples were analyzed to determine SRY-box transcription factor 2 (SOX-2) levels. The tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) levels were measured in lung tissue supernatants. Lung sections were analyzed for cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) histopathologically. In addition, cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) were analyzed by immunohistochemistry and immunofluorescence methods, respectively. SOR reduced the level of SOX-2 that maintenance of cancer stemness and tumorigenicity, and TNF-alpha and IL-1 beta levels. Histopathological analysis demonstrated widespread inflammatory cell infiltration, disorganized alveolar structure, hyperemia in the vessels, and thickened alveolar walls in DEN-induced rats. The damage was markedly reduced upon SOR treatment. Further, immunohistochemical and immunofluorescence analysis also revealed increased expression of COX-2 and JNK expression in DEN-intoxicated rats. However, SOR treatment alleviated the expression of these inflammatory markers in DEN-induced lung carcinogenesis. These findings suggested that SOR inhibits DEN-induced lung precancerous lesions through decreased inflammation with concomitant in reduced SOX-2 levels, which enables the maintenance of cancer stem cell properties.
