Özçelik, İbrahim; Çakir, Deniz Arca; Yildiztekin, Kübra Gizem; Erkekoğlu, Pınar

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical, whereas bisphenol F (BPF), a common BPA substitute, is less characterized, particularly regarding neuronal-derived cells and combined BPA + BPF exposure. Human SH-SY5Y neuroblastoma cells were exposed to BPA, BPF, or BPA + BPF for 24 h. Cell viability was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and oxidative stress and cytokine endpoints were evaluated at IC20 concentrations. SwissTargetPrediction and molecular docking were used to examine potential interactions with estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR). BPA was more cytotoxic than BPF, with IC50 values of 173.2 and 456.8 µM, respectively; the BPA + BPF combination IC50 was 196.9 µM. BPA and BPA + BPF significantly increased reactive oxygen species by 15.74% and 18.32% and protein carbonyl levels by 227.69% and 172.67%, respectively. BPA markedly increased interleukin-6, whereas BPF strongly increased tumor necrosis factor-alpha. In contrast, TNF-α decreased in the BPA and BPA + BPF groups, while malondialdehyde showed a non-significant downward trend. Docking predicted interactions of both compounds with AR, ERα, and ERβ, with binding energies of −7.3 to −8.5 kcal/mol. BPA and BPF produced distinct cytotoxic, oxidative, and cytokine-response profiles after acute exposure. BPA-containing treatments were associated with greater oxidative stress-related changes, whereas BPF elicited a distinct inflammatory response. Predicted receptor interactions require functional validation, and further studies should assess chronic, low-dose, and mixed exposures.

Uslu, Hamit; Atila Uslu, Gözde; Çoban, Taha Abdulkadir; Şahin, Mahmut; Güngör, Ali; Aygörmez, Serpil

5-Fluorouracil (5-FU) is an effective chemotherapeutic agent; however, its clinical use is frequently limited by toxicity in normal tissues, including the lungs. This study investigated the prophylactic protective effect of trigonelline (TRIG), a naturally occurring alkaloid, against 5-FU-induced pulmonary injury, with particular emphasis on oxidative stress, inflammation, and apoptosis. Twenty-eight male Sprague-Dawley rats were randomly assigned to four groups (n = 7): Control, TRIG, 5-FU, and TRIG + 5-FU. TRIG (50 mg/kg) was administered orally for seven consecutive days before a single intraperitoneal injection of 5-FU (100 mg/kg). Pulmonary injury was evaluated using biochemical, histopathological, and immunohistochemical analyses. Administration of 5-FU reduced body weight gain, increased relative lung weight, disrupted oxidant–antioxidant homeostasis, and induced histopathological alterations in lung tissue. These changes were accompanied by increased TNF-α, NFκB-p65, MAPK, and Bax expression together with decreased Bcl-2 expression, indicating activation of inflammatory and apoptotic pathways. Prophylactic TRIG administration restored oxidant–antioxidant balance, suppressed TNF-α, NFκB-p65, MAPK, and Bax expression, increased Bcl-2 expression, and markedly improved histopathological findings, demonstrating attenuation of oxidative stress, inflammation, and apoptosis. TRIG protects against 5-FU-induced pulmonary injury through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These findings provide experimental evidence supporting the prophylactic use of TRIG as a potential adjunctive strategy for reducing chemotherapy-associated pulmonary toxicity. Further experimental and preclinical studies are warranted to validate its efficacy, elucidate its molecular targets, and evaluate its translational potential.

Uslu, Hamit; Atila Uslu, Gözde; Çoban, Taha Abdulkadir; Özkaraca, Mustafa; Mendil, Ali Sefa; Can, Hasan

5-fluorouracil (5-FU) is an important chemotherapeutic agent that has been used alone or in combination with other chemotherapeutics for years in the treatment of various malignancies. However, as with other chemotherapeutic agents, the disadvantage of 5-FU is that it damages healthy cells as well as cancer cells. Natural compounds are the first option that comes to mind to reduce and/or prevent undesirable side effects of chemotherapeutics. In this study, we aimed to determine the effects of Juglans regia extract (JR), whose antioxidant, anti-inflammatory, anti-diabetic, and antimicrobial effects were previously determined, on 5-FU-induced autophagy, oxidative stress, and apoptosis after its constituents were determined by LC-MS/MS. Experimental groups were formed as Control (C), JR, 5-FU, and JR + 5-FU. Rats were pretreated with JR at a dose of 200 mg/kg for seven days, and on the eighth day, a single dose of 100 mg/kg 5-FU was administered intraperitoneally to the JR + 5-FU and 5-FU groups. 5-FU disturbed the oxidant-antioxidant balance by increasing Keap1, TOS, and 8-OHdG levels and decreasing TAS levels and triggered cellular autophagy and apoptosis by increasing LC3B, Bax, and Caspase-3 levels and decreasing Bcl-2. JR pretreatment was shown to have modulating effects on the Keap1/Nrf2 pathway in the reorganization of the oxidant-antioxidant balance, to show anti-apoptotic activity, and to partially alleviate autophagy. JR’s bioactive components were shown to alleviate oxidative stress and associated DNA damage via Keap1/Nrf2 and also attenuate fluorouracil-induced kidney damage by reducing autophagy and apoptosis, two important forms of programmed cell death, and have a promising potential against nephrotoxicity.

Yeter, Bahtinur; Suleyman, Zeynep; Bulut, Seval; Cicek, Betul; Coban, Taha Abdulkadir; Demir, Ozlem; Suleyman, Halis

The purpose of this trial was to assess the effects of methylphenidate on the kidney tissues and to investigate the protective effect of adenosine triphosphate (ATP) against possible methylphenidate nephrotoxicity in rats. The rats were separated into; healthy control (HG), methylphenidate (MPHG), ATP (ATPG), and ATP+ methylphenidate (AMPG). The ATPG and AMPG groups were administered ATP 4 mg/kg bw/d, and the HG and MPHG groups received distilled water intraperitoneally. One hour from, ATP and distilled water administration, methylphenidate 10 mg/kg bw/d was applied via oral gavage to the AMPG and MPHG groups once daily for 30 d (1 × 1). Animals were euthanized after 30 d and tissues were collected. The levels of certain oxidant/antioxidant parameters, pro-inflammatory cytokines, and Blood urea nitrogen (BUN) and creatinine levels were measured. Kidneys were also examined histopathologically. ATP inhibited the increase in oxidant and decrease antioxidant levels induced by methylphenidate. The amounts of pro-inflammatory cytokines were increased in methylphenidate-treated kidney tissue compared with the HG and AMPG groups. However, ATP increased oxidative damage markers and cytokines levels close to the healthy group. Serum BUN and creatinine levels increased with methylphenidate but ATP prevented BUN and creatinine from rising in the ATPG and MPHG groups. ATP also reduced the histopathological damage increased by methylphenidate. The potential efficacy of ATP in treating kidney damage induced by methylphenidate use.

Ölmeztürk Karakurt, Tülay Ceren; Emir, İzzet; Bedir, Zehra; Ozkaloglu Erdem, Kezban Tuna; Süleyman, Halis; Sarıgül, Cengiz; Mendil, Ali Sefa

Aim: We aimed to investigate the preventive effects of carvacrol against ketamine-induced cardiotoxicity biochemically and histopathologically in an experimental model. Material and method: The rats were divided into three groups; healthy control (HC), ketamine alone (KG), and ketamine + carvacrol (KCG) groups. Serum Creatine Kinase Myocardial Band (CK-MB) and Troponin I (TP I) levels were determined. Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Tumor Necrosis Factor α (TNF-α), Interleukin 1 beta (IL-1beta), and Interleukin 6 (IL-6) levels were measured in the heart tissues of the rats. Heart tissues were also evaluated histopathologically. Results: In the ketamine-treated group, tissue MDA, TNF-α, IL-1beta, and IL-6 levels increased while tissue GSH and SOD levels decreased significantly compared with the control group. However, in the ketamine plus carvacrol applied group, all those alterations were significantly less pronounced, close to the healthy controls. Severe mononuclear cell infiltrations, degenerated myocytes and hemorrhage were determined in the ketamine alone administered group, and these alterations were at a mild level in the carvacrol + ketamine administered group. Conclusion: Prolonged exposure to ketamine resulted in induced oxidative stress in rat heart tissue; concomitant carvacrol application could counteract the negative effects of ketamine by protecting tissues from lipid peroxidation and decreasing the inflammatory response.

Ölmeztürk Karakurt, Tülay Ceren; Eren, Nurhan; Subaşı, Faruk; Kuyrukluyıldız, Ufuk; Çoban, Taha Abdulkadir; Süleyman, Halis; Mokhtare, Behzad

In this experimental study we aimed to investigate the biochemical and histopathological effects of concomitantly administered taxifolin on tramadol-induced liver damage in rats. The rats were divided into three groups; control group (CG), tramadol alone (TRG), and taxifolin + tramadol given (TTRG) groups. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), nuclear factor-kappa beta (NF-kB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels were measured in liver tissues. Liver tissues were also examined histopathologically. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were determined in blood samples. In tissue analyses, determinants of oxidative stress and inflammation, all were significantly higher in the TRG group compared with the control and TTRG groups. In the TTRG group, all oxidative stress and inflammation markers were significantly lower than in the TRG group. In addition, there was not any significant difference between the control and TTRG groups regarding the TOS and TAS status. Serum liver enzymes were also significantly higher in the TRG group than in the other two groups. In histopathological examinations, the control group had a normal histological appearance. Degenerative-necrotic hepatocytes and hemorrhage, which were seen at a severe level in the TRG group, were found to be moderate in the treated TTRG group. In addition, mononuclear cell infiltrations were found to be severe in the TRG group and mild in the treated TTRG group. Finally it was concluded that Taxifolin alleviated the toxic effects of tramadol on the liver including the histopathological and biochemical changes as well as the oxidative damage.

Ozyurt, Busra; Ozkemahli, Gizem; Yirun, Anil; Ozyurt, Aylin Balci; Bacanli, Merve; Basaran, Nursen; Kocer-Gumusel, Belma; Erkekoglu, Pinar

Bisphenol A (BPA) BPA is an endocrine-disrupting chemical that has a wide range of uses. Exposure to BPA can be by oral, inhalation, and parenteral routes. Although its use in several products is limited, there is still concern on its adverse health effects, particularly for susceptible populations like children. Alternative bisphenols, such as bisphenol S (BPS) and bisphenol F (BPF), are now being used instead of BPA, although there is little information on the toxicity of these bisphenols. BPF is used as a plasticizer in the production of several industrial materials as well as in the coating of drinks and food cans. BPS is used in curing fast-drying epoxy glues, as a corrosion inhibitor and as a reactant in polymer reactions. In this study, the possible toxic effects of BPA, BPS, and BPF in HepG2 cells were evaluated comparatively. For this purpose, their effects on cytotoxicity, production of intracellular reactive oxygen species (ROS), oxidant/antioxidant parameters, and DNA damage have been examined. The cytotoxicity potentials of different bisphenols were found to be as BPS > BPF > BPA. All bisphenol derivatives caused increases in intracellular ROS production. We observed that all bisphenol derivatives cause an imbalance in some oxidant/antioxidant parameters. Bisphenols also caused significant DNA damage in order of BPF > BPA > BPS. We can suggest that both of the bisphenol derivatives used as alternatives to BPA also showed similar toxicities and may not be considered as safe alternatives. Mechanistic studies are needed to elucidate this issue.

Huyut, Zübeyir; Uçar, Bünyamin; Altındağ, Fikret; Yıldızhan, Kenan; Huyut, Mehmet Tahir

Abemaciclib (ABEM) is an important antitumor agent for breast cancer treatment. However, the side-effects of ABEM are unclear in the liver. This study investigated the protective effect of curcumin (CURC) on liver damage caused by ABEM. The rats were divided into five groups with eight animals in each group; Control, DMSO (150 µL for per rats), CURC, 30 mg/kg/day), ABE (26 mg/kg/day), and ABE + CURC (26 mg/kg/day ABE, 30 mg/kg/day) groups. Injections were administered daily for 28 days. The levels of AST, LDH, HDL, LDL, triglyceride, and total cholesterol in serum, and hepatic tissue fibrosis, caspase-3, Bax, and TNF-α expression were higher in the ABE group compared to the control group (p < 0.05). Also, these parameters in the ABEM + CURC group were lower than in the ABE group (p < 0.05). The results showed that ABE administration could cause liver damage and increase fibrosis in the liver. In addition, it was shown that co-administration of CURC with ABE could suppress the levels of AST, LDH, HDL, LDL, triglyceride, and total cholesterol in serum, and fibrosis, caspase-3, Bax, and TNF-α expressions in the liver. These data are the first in the literature. Therefore, the administration of CURC following ABE may be a therapeutic agent in preventing liver damage.

Ferah Okkay, Irmak; Okkay, Ufuk; Bayram, Cemil; Cicek, Betul; Sezen, Selma; Aydin, Ismail Cagri; Mendil, Ali Sefa; Hacimuftuoglu, Ahmet

The aim of this study was to investigate the molecular, biochemical, and histopathological effects of bromelain, which has antioxidant and anti-inflammatory properties, against cisplatin-induced ocular toxicity. The groups were designed as (1) Control, (2) Cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Bromelain (50 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Bromelain (100 mg/kg, orally for 14 consecutive days). The activity of total antioxidant capacity (TAC) and total oxidant status (TOS) and levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-1β (IL-1β), IL-10, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and 8-OHdG were measured in ocular tissue. The mRNA expression of NF-κB and Caspase-3 was also evaluated. Also, ocular sections were evaluated histopathologically. Bromelain demonstrated a dose-dependent protective effect in cisplatin-induced toxicity by regulating oxidative stress, inflammation, and tissue damage. Our results suggested that bromelain may be a potential adjuvant that can protect the eye from cisplatin-induced toxicity.

Beydemir, Şükrü; Türkeş, Cüneyt; Yalçın, Ahmet

Medications show their biological effects by interaction with enzymes, which have been known to play an essential role in the pathogenesis of many diseases. Inhibition or induction of drug metabolizing enzymes has an essential place in the drug design for many kinds of diseases including cardiovascular, neurological, metabolic, and cancer. The main goal of the current study is to contribute to this growing drug design field by observing PON1–drug interactions. In recent years, the safety of gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) has discussed. In the present study, paraoxonase 1 (PON1) enzyme was purified from human serum by simple chromatographic methods with 4095.24 EU mg−1 protein specific activity. The inhibitory activities of gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide were investigated on PON1 activity of the enzyme. IC50 values were found in the range of 51.28 ± 0.14 to 285.80 ± 0.96 mM. Ki constants were found as 67.95 ± 0.60 mM, 104.97 ± 0.96 mM, 202.33 ± 1.75 mM, and 299.43 ± 2.64 mM for gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide, respectively. While the inhibition types are determined as competitive of gadoxetate disodium and gadodiamide by the Lineweaver–Burk curves, it was noncompetitive for other compounds. In addition, the molecular docking analyses of gadoxetate disodium and gadodiamide were carried out to understand the binding interactions on the active site of the PON1 enzyme. The structure–activity relationship (SAR) of the drugs was established on the basis of different substituents and their positions in the compounds.