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Dual-targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR-2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4-thiazolidinones/2,4-thiazolidinediones carrying 2-methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR-2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. These compounds were also evaluated against MCF-7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, 3b (CAIX IC 50  = 0.035 µM, VEGFR-2 IC 50  = 0.093 µM) and 6i (CAIX IC 50  = 0.041 µM, VEGFR-2 IC 50  = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR-2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR-2 to comprehend the ligand-binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b., (© 2024 Wiley Periodicals LLC.)

Introduction: Bisphenols are widely used in the production of polycarbonate plastics and resin coatings. Bisphenol A (BPA) is suggested to cause a wide range of unwanted effects and "low dose toxicity". With the search for alternative substances to BPA, the use of other bisphenol derivatives namely bisphenol F (BPF) and bisphenol S (BPS) has increased., Methods: In the current study, we aimed to evaluate the in silico predicted inhibitory concentration 50s (pIC50s) of bisphenol derivatives on immune and apoptotic markers and DNA damage on HepG2 cells. Moreover, apoptotic, genotoxic and immunotoxic effects of BPA, BPF and BPS were determined comparatively. Effects of bisphenols on apoptosis were evaluated by detecting different caspase activities. The genotoxic effects of bisphenols were evaluated by measuring the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-oxoguanine glycosylase (OGG1). To determine the immunotoxic effect of bisphenol derivatives, the levels of interleukin 4 (IL-4) and interleukin 10 (IL-10), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), which are known to be expressed by HepG2 cells, were measured. Results: In silico data indicate that all of the bisphenols may cause alterations in immune and apoptotic markers as well as DNA damage at low doses. İn vitro data revealed that all bisphenol derivatives could affect immune markers at inhibitory concentration 30s (IC 30 s). In addition, BPF and BPS may also have apoptotic immunotoxic effects., Conclusion: Both in silico and in vivo research are needed further to examine the toxic effects of alternative bisphenol derivatives., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024. Published by Oxford University Press.)

This study aimed to estimate and compare dietary exposure to bisphenol A (BPA) in exclusively breastfed (EBF) and breastfed plus formula-fed (BF + FF) infants. A total of 70 mothers and their 0-6 month-old infants (40 in the EBF group and 30 in BF + FF group) were included in the study. After the questionnaire form was applied to the mothers, maternal breast milk, infant formula, and infant urine were collected from mother-infant dyads. Total BPA levels in breast milk, infant formula, and infant urine samples were analyzed by the high-pressure liquid chromatography (HPLC). While BPA was detected in 92.5% of the breast milk samples in the EBF group (mean ± SD = 0.59 ± 0.29 ng/mL), BPA was detected in all of the breast milk samples in the BF + FF group (mean ± SD= 0.72 ± 0.37 ng/mL) ( p  < 0.05). Similarly, 100% of the infant formula samples in the BF + FF group had detectable levels of BPA (mean ± SD = 7.54 ± 1.77 ng/g formula). The mean urinary BPA levels in the EBF infants (4.33 ± 1.89 µg/g creatinine) were not statistically different from the BF + FF infants (5.81 ± 0.11 µg/g creatinine) ( p  > 0.05). The average daily BPA intake in EBF infants (0.18 ± 0.13 µg/kg body weight (bw)/day) was found to be significantly higher than in BF + FF infants (0.12 ± 0.09 µg/kg bw/day) ( p  < 0.05). The estimated dietary intakes of BPA for infants in both groups were below the temporary tolerable daily intake (t-TDI) (4 µg/kg bw/day). Consequently, BPA intake of EBF and BF + FF infants were within safe daily limits during the first six months of life.

Aging is the most prominent risk factor for many diseases, which is considered to be a complicated biological process. The rate of aging depends on the effectiveness of important mechanisms such as the protection of DNA from free radicals, which protects the structural and functional integrity of cells and tissues. In any organism, not all organs may age at the same rate. Slowing down primary aging and reaching maximum lifespan is the most basic necessity. In this process, it may be possible to slow down or stabilise some diseases by using the compounds for both dietary and pharmacological purposes. Natural compounds with antioxidant and anti-inflammatory effects, mostly plant-based nutraceuticals, are preferred in the treatment of age-related chronic diseases and can also be used for other diseases. An increasing number of long-term studies on synthetic and natural compounds aim to elucidate preclinically and clinically the mechanisms underlying being healthy and prolongation of life. To delay age-related diseases and prolong the lifespan, it is necessary to take these compounds with diet or pharmaceuticals, along with detailed toxicological results. In this review, the most promising and utilised compounds will be highlighted and it will be discussed whether they have toxic effects in short/long-term use, although they are thought to be used safely.

This study was conducted to estimate the daily dietary intakes of melamine for human milk-fed (HMF) babies and mixed-fed (MF) babies. It was carried out in 70 mother-baby pairs (40 babies in the HMF group and 30 babies in the MF group). Human milk, formula milk, and baby urine samples were collected to assess the dietary exposure of babies. Melamine concentrations were analyzed by using a competitive enzyme-linked immunosorbent assay. Melamine was determined in 82.5 % of the human milk samples in the HMF group (median: 0.75 µg/L) while it was present in 96.7 % of human milk samples (median: 1.25 µg/L) and 96.7 % in formula milk samples (median: 0.95 µg/kg) in the MF group. The mean urinary melamine concentration of HMF babies (1.20 ± 0.21 µg/L) was not significantly different than MF babies (1.35 ± 0.49 µg/L). Melamine exposure was calculated as 0.12 µg/kg bw/day and 0.24 µg/kg bw/day in HMF and MF babies, respectively. Melamine exposure in both groups was below the tolerable daily intake. There were no significant associations between melamine exposure and various features of babies and mothers. As a result, it can be suggested that Turkish babies (aged 0-6 months) are not at risk for high melamine exposure through the diet., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

A series of isoxazolo[4,5-d]pyridazin-4(5H)-one hybrids with N-acylhydrazone structure was prepared and screened for their cytotoxic activities. The in vitro antiproliferative activity of the target molecules was evaluated against a panel of sixty cancer cell lines (NCI-60) by the National Cancer Institute. Seven of the target compounds showed prominent % inhibition against various cancer cell lines at the one-dose assay and were subsequently screened for five-dose assay. 4d, 4e and 4g (full panel mean graph midpoint GI 50 =9.33, 5.25 and 7.94 μM) emerged as the most promising derivatives against multiple cancer cell lines in comparison with 5-fluorouracil and gefitinib (full panel mean graph midpoint GI 50 =18.60 and 3.46 μM). They exhibited remarkable antiproliferative activity with GI 50 values submicromolar concentrations against some of the cell lines. The compounds were also found to display mild toxicity to the healthy cells compared to the cancer cell lines indicating safety. Druglikeness and high oral bioavailability were predicted for most of the compounds. As a result, a current study unveiled isoxazolo[4,5-d]pyridazin-4(5H)-ones bearing N-acylhydrazone as promising anticancer agents with antiproliferative effects., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

The present review aims to provide a complete and comprehensive summary of current literature relevant to oxysterols and related diseases. Oxidation of cholesterol leads to the formation of a large number of oxidized products, generally known as oxysterols. They are intermediates in the biosynthesis of bile acids, steroid hormones, and 1,25- dihydroxyvitamin D3. Although oxysterols are considered as metabolic intermediates, there is a growing body of evidence that many of them are bioactive, and their absence or excess may be part of the cause of a disease phenotype. These compounds derive from either enzymatic or non-enzymatic oxidation of cholesterol. This study provides comprehensive information about the structures, formation, and types of oxysterols even when involved in certain disease states, focusing on their effects on metabolism and linkages with these diseases. The role of specific oxysterols as mediators in various disorders, such as degenerative (age-related) and cancer-related disorders, has now become clearer. Oxysterol levels may be employed as suitable markers for the diagnosis of specific diseases or in predicting the incidence rate of diseases, such as diabetes mellitus, Alzheimer's disease, multiple sclerosis, osteoporosis, lung cancer, breast cancer, and infertility. However, further investigations may be required to confirm these mentioned possibilities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Sickle cell disease (SCD) causes anemia, oxidative stress, chronic inflammation, and lipid abnormalities. Oxysterols are oxidized derivatives of cholesterol and affect cholesterol metabolism and eryptosis. Our aim was to determine whether the plasma concentrations of 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (C-triol) were associated with hemolysis and lipid profile in patients with SCD. A total of 32 steady-state pediatric patients with SCD (22 HbSS and 10 HbSß + ) and 25 healthy controls were included in the study. Hemolysis parameters, ferritin, serum iron, lipids, 7-KC and C-triol concentrations of all subjects were measured. Oxysterols were quantified with N,N-dimethylglycine derivatization via LC-MS/MS. 7-KC and C-triol concentrations were found to be increased in SCD patients, while there was no difference between the HbSS and HbSß + subgroups. 7-KC concentrations s were correlated negatively with hemoglobin and positively with lactate dehydrogenase concentrations, while C-triol concentrations were negatively correlated with HDL cholesterol. Furthermore, while 7-KC and C-triol concentrations were highly correlated among controls, there was no correlation in patients. The findings of our study suggest that 7-KC and C-triol may have a role in SCD pathophysiology. The lack of correlation in patients' 7-KC and C-triol concentrations suggest alterations in oxysterol production in patients with SCD.

Objectives: Metabolic and endocrine adverse effects are among the most concerning unfavorable consequences of commonly used psychotropic drugs. The present research was planned to assess and determine the effects of haloperidol and clozapine on testosterone, cortisol, and corticosterone levels and also their influence on androgen-dependent organs in adult male Wistar rats., Materials and Methods: Animals were casually distributed into three groups ( n = 10 in each group). Drugs were administered intraperitoneally for 28 days. The control group received 2 mL of physiological saline, the second group received haloperidol (0.5 mg/kg), and the third group received clozapine (0.5 mg/kg). The subsequent testosterone, cortisol, and corticosterone plasma concentration levels were analyzed with chemiluminescent immunoassay., Results: Clozapine and haloperidol treatments altered testosterone hormone levels. Testosterone mean values in both the clozapine (1.00-0.58) and haloperidol (0.65-0.62) groups were found to be lower than compared to controls ( P = 0.003, P < 0.001). Histomorphometric analysis results also showed reduced testes size and reduced weight of androgen-dependent organs in drug-treated rats., Conclusion: It can be suggested that clozapine and haloperidol are effective in reducing the testosterone plasma concentration level and androgen-dependent organ sizes; therefore, clinicians should be aware of these effects when considering the use of antipsychotic drugs., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Indian Journal of Pharmacology.)

Human skin is a protective barrier against the toxic effects of cosmetics. Marketing of cosmetic products with ingredients tested on animals was prohibited in 2013. Since then, safety evaluation of cosmetic products is performed by using alternative in vitro toxicity tests. In vitro 3-D reconstructed human epidermis (RhE) tissue models are now used to define skin irritation/corrosion potentials of cosmetic ingredients and end-products. The main aim of this study was to evaluate skin irritation potentials of topically used cosmetic end-products which were marketed in Turkey during 2015-2017, by using the EpiDerm in vitro 3D-human skin model. Sixty widely used cosmetic products were collected from different markets/cosmetic shops. Among hair care products, only one shampoo was found to be strong/severe skin irritant/possible corrosive while 22 shampoos were moderate skin irritant and 11 shampoos were moderate to mild skin irritant. Among 6 skin care products, one was found to be moderate to mild skin irritant. We can suggest that alternative in vitro tests should continuously be used to test both the ingredients and the final cosmetic formulations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Myoglobinuric acute renal failure (MARF) may develop after severe muscle injury. Heme oxygenase-1 (HO-1), a stress-response protein, has been implicated as a protective agent against MARF. We hypothesized that hyperbaric oxygen therapy (HBOT) may alleviate MARF by inducing renal HO-1 expression. Wistar-Albino rats were randomly assigned into three groups: Control (n = 4), MARF (n = 8), MARF + HBO (n = 8). MARF was induced by intramuscular glycerol (50%, 8 mL/kg) injection. Saline (8 mL/kg) was injected into the hind limb of the animals in the control group. Animals in the MARF + HBO group received two sessions of HBO therapy (90 min at 2.5 atm) 2 and 18 h after glycerol injection. Serum and tissue samples were taken at 24 h. Serum urea and creatinine levels increased in the MARF and MARF + HBO groups confirming the development of MARF. But, serum urea and creatinine levels were similar in MARF and MARF + HBO groups. Oxidative stress parameters were similar among all groups. Histological renal injury score was similar in MARF and MARF + HBO groups. HO-1 level, determined by immunohistochemistry, was significantly higher in MARF and MARF + HBO groups, compared to the control group. Although HO-1 level in MARF + HBO group was higher than MARF group, it was not statistically significant. We found that HBOT did not reduce renal injury in experimental MARF model. HBOT is used to reduce the muscle damage after crush injury, which may be accompanied by MARF. Therefore, more studies are needed to understand the effects of HBO treatment on renal functions after MARF.

We explored the association between the activities of antioxidant enzymes and their metallic cofactors in rats treated with cisplatin. The antioxidant effects of aminoguanidine, and a combination of vitamins E and C were investigated. Plasma platin was significantly lower than liver and kidney. Cisplatin treatment caused significant increase in plasma Se-glutathione peroxidase activity. Activities of Se-glutathione peroxidase, glutathione S-transferase, catalase and Cu,Zn-superoxide dismutase have been found to be significantly decreased in liver and kidney compared to controls. Zn levels in these organs were diminished upon cisplatin treatment, while levels of Cu were unaffected. Interestingly, levels of iron, the cofactor of catalase, were found to be significantly increased in liver and kidney. Intervention with aminoguanidine or vitamins was generally prevented cisplatin-caused changes in the activity of enzymes and in the tissue levels of cofactor metals. These observations suggest that relation between activities of enzymes and levels of cofactor metals is multifactorial.

Purpose: This study was undertaken to determine the effects of season and gender on serum aflatoxin (AF) levels (AFG1, AFB1, AFG2 and AFB2) and ochratoxin A (OTA) concentrations of healthy adult population living in Central Anatolia Region of Turkey., Methods: AF levels were measured by high-performance liquid chromatography (HPLC) and OTA levels were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples of healthy adults (n = 233)., Results: In summer and winter, total AF levels in females were 0.98 ± 0.10 and 0.94 ± 0.12 ng/ml and in males 1.35 ± 0.17 and 0.93 ± 0.11 ng/ml, respectively. Male subjects had significantly higher serum total AF levels in summer compared with females (~38%). There was no marked seasonal change in AFG1, AFB1 and AFG2 concentrations in the whole population, except AFB2. Both of the genders had significantly higher OTA levels in winter compared with summer (~60%)., Conclusions: Overall results suggest that Central Anatolia residents are continuously exposed to AFs and OTA. Besides, season and gender can be effective in mycotoxin exposure.

Objective: The aim of this pilot clinical study was to determine the mercury release from amalgam fillings and antioxidant enzyme activities (Superoxide Dismutase [SOD] and Catalase[CAT] ) in body fluids after exposure to two different vital tooth bleaching systems., Material and Methods: Twenty eight subjects with an average age of 25.6 years (18-41) having at least two but not more than four Class II amalgam fillings on each quadrant arch in the mouth participated in the study. Baseline concentrations of mercury levels in whole blood, urine, and saliva were measured by a Vapor Generation Accessory connected to an Atomic Absorption Spectrometer. Erythrocyte enzymes, SOD, and CAT activities in blood were determined kinetically. Subjects were randomly assigned to two groups of 14 volunteers. Group 1 was treated with an at-home bleaching system (Opalescence PF 35% Carbamide Peroxide, Ultradent), and Group 2 was treated with a chemically activated office bleaching system (Opalescence Xtra Boost 38% Hydrogen Peroxide, Ultradent) according to the manufacturer's recommendations. Twenty-four hours after bleaching treatments, concentrations of mercury and enzymes were remeasured., Results: There were no significant differences on mercury levels in blood, urine, and saliva before and after bleaching treatments (p > 0.05). No differences were also found in the level of antioxidant enzyme activities (SOD and CAT) before and after treatments (p > 0.05). Mercury release did not affect the enzyme activities (p > 0.05)., Conclusion: Bleaching treatments either office or home did not affect the amount of mercury released from amalgam fillings in blood, urine, and saliva and the antioxidant-enzyme activities in blood., Clinical Significance: Bleaching treatments with the systems tested in this pilot study have no deleterious effect on the mercury release from amalgam fillings and antioxidant enzymes in body fluids., (© 2014 Wiley Periodicals, Inc.)

Objective: To determine the serum concentrations of aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2) in the healthy adult population living in both the Black Sea and Mediterranean regions of Turkey and to investigate the regional, seasonal and gender variability in aflatoxins (AF) exposure in these regions., Design: Serum AFB1, AFB2, AFG1 and AFG2 concentrations were analysed by HPLC. Settings In total, four hundred and eighty-four serum samples were analysed., Subjects: Four hundred and eighty-four healthy adult volunteers living in rural areas of the Black Sea and Mediterranean regions of Turkey were studied., Results: The mean serum concentration of total AF in the Black Sea region was 1·33 ppb (min-max 0·15-3·38 ppb) and 0·90 ppb (min-max 0·18-2·48 ppb) for summer and winter, respectively. In the Mediterranean region, the mean serum concentration of total AF was determined as 0·55 ppb (range 0·04-1·72 ppb) for summer and 0·45 ppb (range 0·12-1·43 ppb) for winter. The total AF concentrations in serum samples were statistically higher in summer compared with winter for the two regions. The differences between the regions were statistically significant concerning all samples, with higher total AF concentrations in the Black Sea region., Conclusions: The overall results suggest that the Turkish population living in these two regions is continuously exposed to AF, particularly in the summer, and that mycotoxin contamination in food should be monitored routinely for food safety and human health.

Doxorubicin (DOX) is a broad-spectrum anthracycline that has cardiotoxicity as a major side effect. Reactive oxygen species (ROS) and reactive nitrogen species generations have been proposed to be an important mechanism of DOX-induced cardiotoxicity and cardiomyocyte apoptosis, which may be mediated by p53 protein. Aminoguanidine (AG) is an effective antioxidant due to its free radical scavenger activity. A549 lung cell line was incubated with various concentrations of AG (100-1,000 μM) wit/without 0.25 μM DOX for 24 h. The expression of p53 and its transcriptional target p21 were analyzed by Western blot. Apoptosis was analyzed with Annexin V assay. JC1 and H2AX immunofluorescence were used to assess mitochondrial and nuclear DNA damage, respectively. This study demonstrated that AG has a dose-dependent antiapoptotic effect on DOX-induced apoptosis. Thus, these data further identify AG as a potential chemopreventive agent to reduce ROS and nitric oxide synthase damage generated by DOX.

The oxidative stress levels in plasma and hemolysate and cholesterol levels in plasma of sickle cell anemia patients, carriers and controls were evaluated. A total of 40 cases-17 patients, 13 carriers and 10 controls-were involved in the study. Plasma and hemolysate malondialdehyde (MDA) were detected via thiobarbituric acid reaction with a fluorimetric detector by high-performance liquid chromatography system. Plasma cholesterol was determined by enzymatic colorimetric method. Mean MDA levels of SCA patients were higher than those of the carriers' and healthy children's both in plasma and in hemolysate (P < 0.005). The mean plasma and hemolysate MDA levels were 25.3 ± 1.6 nmol/l and 86.7 ± 19.3 nmol/l in patients, 19.1 ± 0.8 nmol/l and 54.1 ± 10.8 nmol/l in carriers and 19.6 ± 0.8 nmol/l and 56.8 ± 9.3 nmol/l in healthy children. Mean plasma total cholesterol levels were 92.1 ± 19.1 mg/dl in patients, 116.2 ± 23.3 mg/dl in carriers and 126.6 ± 16.4 mg/dl in controls (P < 0.005). There was a significant negative correlation of -0.520 between hemolysate MDA and plasma cholesterol levels in patients (P < 0.05). The degree of correlation increased up to -0.782 (P = 0.008) in the patients with HbSS phenotype. This negative correlation between MDA and cholesterol may imply a potential association between oxidative stress and hypocholesterolemia in sickle cell anemia.