Uslu, Gözde Atila; Uslu, Hamit; Çoban, Taha Abdulkadir; Toraman, Emine; Özkaraca, Mustafa

Although chemotherapy is still a widely used primary treatment modality for many cancers, it is an accepted fact that it causes many undesirable side effects and toxicity. Until a new, side-effect-free treatment modality is developed, new resources will continue to be sought to prevent and reduce the adverse effects of chemotherapy. In this study, we investigated the potential of apigenin, selenium, and their combination to prevent cardiovascular toxicity induced by 5-fluorouracil (5FU), an important chemotherapeutic agent. The study consisted of control (C), 5FU, apigenin + 5FU (Api + 5FU), selenium + 5FU (Se + 5FU), and apigenin + selenium + 5FU (Api + Se + 5FU) groups. Api (50 mg/kg) and Se (0.5 mg/kg) were administered orally to rats for 7 days. On Day 5, 5FU was administered i.p. at a dose of 150 mg/kg. Administration of 5FU significantly reduced GSH levels and CAT and TrxR activities in both cardiac and thoracic aortic tissues. It also decreased Bcl-2 expression and increased Bax and Caspase-3 expression in cardiac tissue, while reducing Bcl-2 and increasing Bax expression in the thoracic aorta. Thoracic aortic MDA levels were also significantly elevated. On the contrary, oxidative stress and apoptosis were significantly decreased, and cardiovascular damage was attenuated in apigenin and selenium treated groups. In this study, it was determined that 5FU caused a higher level of toxicity to the heart compared to the thoracic aorta. In addition, both apigenin and selenium were shown to have significant protective effects on the cardiovascular system against 5FU toxicity. However, the cardiovascular protection against 5FU toxicity was found to be higher when apigenin and selenium were used together.

Ayna, Adnan; Caglayan, Cuneyt; Türkeş, Cüneyt; Temel, Yusuf; Tahiroğlu, Veysel; Izol, Ebubekir; Inci, Hakan

Apilarnil, a relatively understudied bee-derived product from drone larvae, has recently gained attention due to its diverse chemical content and biological activities. Imatinib, a selective tyrosine kinase inhibitor widely used in cancer treatment, is recognized for its effectiveness but is also associated with off-target toxicities including disturbances in redox homeostasis. While previous studies have mainly focused on the roles of the key antioxidant enzymes glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S transferase (GST) and thioredoxin reductase (TrxR1) in tumor resistance mechanisms, their inhibition in non-cancerous cells may contribute systemic toxicity. This study investigated whether co-administration of apilarnil could alleviate the inhibitory effects of imatinib on these enzymes in vivo. The secondary metabolite profile of apilarnil was characterized using liquid chromatography–high resolution mass spectrometry (LC-HRMS) revealing a richness in phenolic compounds, notably isorhamnetin, phenolidzin, ascorbic acid, liquiritigenin, leucoside, 3-(4-hydroxyphenyl) propionic acid and caffeic acid. Enzyme activity assays showed that imatinib significantly suppressed the activities of G6PD, 6PGD, GR, GST and TrxR1 compared to the control group. However, co-treatment with apilarnil particularly at a dose of 400 mg/kg, markedly restored activities of these enzymes. Furthermore, molecular docking analysis was performed to assess the binding affinities and interaction profiles of imatinib with target enzymes, confirming its potent inhibitory potential and revealing distinct but comparable binding interactions. These findings suggest that apilarnil may exert a protective effect against imatinib-induced toxicity by modulating disruptions in metabolic enzyme activities.

Aktas Senocak, Esra; Alat, Omercan; Bolat, Ismail; Lacin, Burak Batuhan; Tekin, Samet; Atasever, Aslıhan; Bolat, Merve; Halici, Mesut Bunyami

Glyphosate (GLY) is a widely used herbicide active ingredient applied in agricultural, residential, and public areas. Although the European Chemicals Agency has stated that current evidence is insufficient to classify GLY as an endocrine disruptor, increasing experimental data indicate that GLY may induce organ toxicity. This study aimed to investigate glyphosate-induced liver toxicity and to evaluate the potential protective effects of eugenol in a rat model. Eugenol is a phenolic compound predominantly found in clove oil (Syzygium aromaticum L.) and is known for its antioxidant, anti-inflammatory, antimicrobial, and analgesic properties. It is classified as generally recognized as safe (GRAS) and non-mutagenic by the World Health Organization. Thirty-five male rats were randomly assigned to five groups: Control, EU-100, GLY, GLY + EU-50, and GLY + EU-100. All treatments were administered orally by gavage. Oxidative stress markers (lipid peroxidation, reduced glutathione, and superoxide dismutase), liver enzyme activities (ALT, AST, and ALP), and the expression of genes involved in antioxidant defense, apoptosis, and inflammation (HO-1, Nrf2, CAT, GPx, Bax, Caspase-3, Bcl-2, COX-2, NF-κB, IL-6, TNF-α, and IL-1β) were analyzed. Short-term GLY exposure resulted in oxidative imbalance, inflammatory activation, and apoptosis in hepatic tissue. Eugenol administration significantly alleviated these alterations by enhancing antioxidant defenses, activating the Nrf2/HO-1 signaling pathway, and suppressing pro-inflammatory responses. These findings suggest that eugenol may represent a promising natural hepatoprotective agent against glyphosate-induced liver toxicity.

Aygörmez, Serpil; Makav, Mustafa; Kuru, Mushap; Eliş Yıldız, Sevda; Atila Uslu, Gözde; Küçükler, Sefa; Maraşlı, Şaban

The objective of this study was to conduct a biochemical and immunohistochemical assessment of the potential effects of zingerone (ZNG) on colistin (COL)-induced pulmonary injury in rats. To achieve this, a total of 35 female rats were utilized, of which 28 underwent ovariectomy (OV). The experimental groups were as follows: Control group received only saline intramuscularly without OV; OV group underwent OV and received saline intramuscularly; OV + ZNG group received 50 mg/kg ZNG via oral gavage; OV + COL group received a total of 73 mg/kg COL intramuscularly; OV + COL + ZNG group received a COL intramuscularly administration. Subsequently, ZNG was administered by oral gavage for a duration of 7 days. The results obtained at the conclusion of the study indicated that COL administration led to a suppression of antioxidant markers, including glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), while it elevated malondialdehyde (MDA) levels in the lung tissue of rats. Furthermore, COL administration induced inflammation by increasing the levels of interleukin 1β (IL-1β), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α). Immunohistochemical analysis of Beclin-1, and Caspase-3 were found to be more pronounced in the OV + COL group compared to the other groups. ZNG treatment resulted in an increase in both nonenzymatic and enzymatic antioxidant levels and a reduction in MDA levels in rats. Furthermore, ZNG mitigated COL-induced inflammation, oxidative stress, autophagy, and apoptosis in lung tissue. No significant differences were observed in oxidative stress, inflammation, apoptosis, and autophagy parameters among the control, OV, and OV + ZNG groups. In conclusion, it was determined that COL administration in rats led to lung tissue damage and compromised tissue integrity, while ZNG treatment ameliorated the damage induced by COL.

Köroğlu, Zeynep; Kizir, Duygu; Karaman, Melike; Demir, Yeliz; Türkeş, Cüneyt; Beydemir, Şükrü

Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.

Korkmaz, Işıl Nihan; Türkeş, Cüneyt; Demir, Yeliz; Özdemir, Hasan; Beydemir, Şükrü

Paraoxonase 1 (PON1) can metabolize some compounds such as aromatic carboxylic acid and unsaturated aliphatic esters, arylesters, cyclic carbonate, plucuronide drugs, some carbamate insecticide classes, nerve gases, and lactone compounds. Methyl benzoate has recently been shown to display potent toxicity against several insect species. In the current study, we aimed to investigate the effect of the methyl benzoate compounds (1–17) on PON1 activity. Methyl benzoate compounds inhibited PON1 with KI values ranging from 25.10 ± 4.73 to 502.10 ± 64.72 μM. Compound 10 (methyl 4-amino-2-bromo benzoate) showed the best inhibition (KI = 25.10 ± 4.73 μM). Furthermore, using the ADME-Tox, Glide XP, and MM-GBSA tools of the Schrödinger Suite 2021-4, a complete ligand–receptor interaction prediction was performed to characterize the methyl benzoates (1–17), probable binding modalities versus the PON1.

Korkmaz, Işıl Nihan; Türkeş, Cüneyt; Demir, Yeliz; Öztekin, Aykut; Özdemir, Hasan; Beydemir, Şükrü

Serum paraoxonase 1 (PON1) is found in all mammalian species and is a calcium-dependent hydrolytic enzyme. PON1 hydrolyze several substrates, including carbonates, esters, and organophosphates. In the current study, we aimed to investigate the effect of the presynthesized benzohydrazide derivatives (1–9) on PON1 activity. Benzohydrazide compounds moderate inhibited PON1 with the half-maximal inhibitory concentration values ranging from 76.04 ± 13.51 to 221.70 ± 13.59 μM and KI values ranging from 38.75 ± 12.21 to 543.50 ± 69.76 μM. Compound 4 (2-amino-4-chlorobenzohydrazide) showed the best inhibition (KI = 38.75 ± 12.21 μM). Molecular docking and ADME-Tox studies of benzohydrazide derivatives were also carried out. In this context, we hope that the results obtained in this study contribute to the determination of the side effects of current and new benzohydrazide-based pharmacological compounds to be developed.

Maharramova, Gunel; Taslimi, Parham; Sujayev, Afsun; Farzaliyev, Vagif; Durmaz, Lokman; Gulçin, İlhami

In the presence of trifluoroacetic acid, on the basis of three-component condensation of phenylthiourea with its salicylaldehyde and methyl-3-oxobutanoate, an efficient method for the synthesis of 1-(4-(2-hydroxyphenyl)-6-methyl-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (I) has been worked out. These novel N-substituted tetrahydropyrimidines based on phenylthiourea showed good inhibitory action against acetylcholinesterase (AChE), α-glycosidase, and human carbonic anhydrase (hCA) isoforms I and II. K i values of AChE enzyme were in the range of 0.48 to 7.46 nM. The hCA I and II were effectively inhibited by the compounds, with K i values in the range of 502.44 to 923.11 nM for hCA I and 400.32 to 801.57 nM for hCA II, respectively. The antioxidant activity of the novel N-substituted tetrahydropyrimidines based on phenylthiourea was investigated by using different in vitro antioxidant assays; including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu 2+ and Fe 3+ reducing activities.

Dilek, Esra; Caglar, Sema; Erdogan, Kübra; Caglar, Bülent; Sahin, Onur

In this study, the effects of four novel mononuclear palladium(II) and platinum(II) complexes on the activity of human serum paraoxanase1 were examined. First, four novel mononuclear palladium(II) and platinum(II) complexes were synthesized with a nitrogen donor ligand 1-(2-aminoethyl)pyrrolidine and nonsteroidal anti-inflammatory drugs diclofenac, mefenamic acid. These complexes were characterized by spectroscopic, thermal, and elemental analyses. The crystal structures of complex [Pd(2-amepyr)2](dicl)2 1 and [Pd(2-amepyr)2](mef)2 3 were determined by X-ray crystallography. Then, paraoxonase1 enzyme was purified from human serum. The effects of these complexes on enzyme were evaluated in vitro. The complexes consist of the cationic unit and the counterions. The diclofenac and mefenamic acid acted as a counterion in the complexes. It was observed that all the complexes were stable up to high temperatures. These complexes, even at low doses, inhibited the activity of the enzyme with different inhibition mechanisms.

Altundas, Aliye; Gül, Berna; Çankaya, Murat; Atasever, Ali; Gülçin, İlhami

The conversion of carbon dioxide (CO2) and bicarbonate (HCO3 −) to each other is very important for living metabolism. Carbonic anhydrase (CA, E.C.4.2.1.1), a metalloenzyme familly, catalyzes the interconversion of these ions (CO2 and HCO3 −) and are very common in living organisms. In this study, a series of novel 2-amino-3-cyanopyridines supported with some functional groups was synthesized and tested as potential inhibition effects against both cytosolic human CA I and II isoenzymes (hCA I and II) using by Sepharose-4B-l-tyrosine-sulfanilamide affinity chromatography. The structural elucidations of novel 2-amino-3-cyanopyridines were achieved by NMR, IR, and elemental analyses. Ki values of the novel synthesized compounds were found in range of 2.84–112.44 μM against hCA I and 2.56–31.17 μM against hCA II isoenzyme. While compound 7d showed the best inhibition activity against hCA I (Ki: 2.84 μM), the compound 7b demonstrated the best inhibition profile against hCA II isoenzyme (Ki: 2.56 μM).