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Background: A pentacyclic lupenane-type natural triterpenoid, betulin, has attracted attention in the field of medicinal chemistry since it exhibited a variety of biological activities, including anticancer activity. Objective: The aim of this present work was to obtain derivatives of betulin through bacterial biotransformation and investigate its anticancer activity against A549, HepG2 and 5RP7 cancer cell lines. Methods: Bacterial biotransformation studies were continued in an MBH broth medium for 7 days at 35oC. Anticancer activities of betulin against A549, HepG2 and 5RP7 cell lines were carried out using XTT assay, and their selectivity was determined using a healthy cell line of NIH/3T3. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measuring proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used for measuring apoptotic cell percentages, caspase 3 activation and mitochondrial membrane potential. Results: Bacterial biotransformation studies with 7 bacteria of Staphylococcus aureus ATCC 6538, Proteus vulgaris NRRL B-123, Bacillus subtilis NRRL B-4378, Streptomyces griseolus NRRL B-1062, Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 43300 and Bacillus velezensis NRRL B-14580 produced no metabolite. In in vitro anticancer activity studies, betulin was found to exert anticancer activity against A549, HepG2 and 5RP7 cell lines with IC50 values of 207.7, 125.0 and 28.3 μg/mL, whereas SI values were found to be 30, 50 and 223, respectively. Early and late apoptotic percentages of betulin were found as 9.6, 12.1 and 85.4% on A549, HepG2 and 5RP7, respectively, while caspase 3 positive cell percentages were 2.3, 28.7 and 13.3% for IC50 concentrations. In addition, betulin caused G1 cell cycle arrest (49.5%) on 5RP7 cell line. Conclusion: The results have been shown that betulin activities against A549 and HepG2 cell lines were nonselective and limited its cytotoxic activity against healthy cells, but it is possible to say that it exerted selective activity against 5RP7 cell (28.33±1.53 μg/mL). Betulin effects on apoptosis were found to be dosedependent, while its effect on caspase 3 activation, mitochondrial membrane potential, and cell cycle arrest on G0/G1 phase was not dependent on doses. Therefore, betulin could be a good candidate for the treatment of H-ras active cancer types.

Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.

Sever, Belgin/0000-0003-4847-9711, WOS: 000522436400007, Background: Hydrazones, frequently occurring motifs in many bioactive molecules, have attracted a great deal of interest as potent antimicrobial agents. Objective: the aim of this work was to design and synthesize new hydrazone-based antimicrobial agents. Methods: 4-[2-((5-Arylfuran-2-yl)methylene) hydrazinyl]benzonitrile derivatives (1-10) were obtained via the reaction of 4-cyanophenylhydrazine hydrochloride with 5-arylfurfurals. Compounds 1-10 were evaluated for their antimicrobial effects using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cell line were determined using XTT assay. the most effective antimicrobial agents were investigated for their genotoxic effects using Ames MPF assay. in silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrodinger's Maestro molecular modeling package. Results: the antifungal effects of the compounds were more significant than their antibacterial effects. Compound 5 bearing 3-nitrophenyl moiety was the most potent antifungal agent against Candida albicans, Trichoderma harzianum and Fusarium species, whereas compound 10 bearing 4-chloro-2-nitrophenyl moiety was the most effective antifungal agent on Aspergillus ochraceus. According to XTT and Ames MPF assays, these compounds were neither cytotoxic nor genotoxic at the concentrations tested. Docking studies suggested that these compounds showed good affinity to the active site of lanosterol 14 alpha-demethylase (CYP51) (PDB code: 5V5Z) and interacted with the key residues such as Hem601 and Cys470. Based on in silico ADME studies, the compounds are expected to have high oral bioavailability. Conclusion: According to the in vitro and in silico studies, compounds 5 and 10 stand out as potential orally bioavailable antifungal agents for further studies., Anadolu University Scientific Research Projects CommissionAnadolu University [1805S185], This study was supported by Anadolu University Scientific Research Projects Commission under the Grant No: 1805S185.

The HPG axis is critical in the maintenance of spermatogenesis and sexual function in males. The GnRH-releasing neurons of the hypothalamus are the axis's main hierarchical element. These neurons make connections with different areas of the brain to regulate the release of GnRH. Neurotransmitters have a critical in the connections between these neurons. So, neurotransmitters can inhibit or stimulate the release of GnRH by affecting GnRH-releasing neurons. In neurological disorders, neurotransmitter's activities inevitably change; therefore, these changes can affect the HPG axis via affecting GnRH-releasing neurons, just like in epilepsy. Many investigations have attracted attention to be decreased fertility potential in males with epilepsy. It has been stated that changes in the HPG axis hormone levels have been found in these patients. Moreover, it has also been observed that sperm quality decreased in patients. It has been emphasized that a decrease in sperm quality may be related to both epilepsy and AEDs. It has been shown that AEDs caused decreased sperm quality by impairing the HPG axis, so they act like endocrine-disrupting chemicals. AEDs can affect fertility and cause additive adverse effects in terms of sperm quality together with epilepsy. Therefore, it is crucial to investigate the adverse reproductive effects of AEDs, which are frequently used during reproductive ages, and determine the role of the HPG axis on potential reproductive pathologies.

Quetiapine is one of the most commonly prescribed antipsychotics to treat schizophrenia in adults, in particular. In this study, quetiapine's effects were assessed on healthy sperm production in rats at repeated-pharmacological doses. Additionally, the effects of quetiapine on oxidative status and hormonal balance were also evaluated in rats. Quetiapine was administered to rats orally at 10, 20, and 40 mg/kg body weight doses for 28 days. At the end of this period, body and organ weights were measured, sperm concentration, motility, and morphology were determined, sperm damage was assessed, and histopathological analysis of testicular tissue was performed. Additionally, serum FSH, LH, and testosterone levels as male reproductive hormones were measured. Catalase, superoxide dismutase, glutathione, and malondialdehyde levels were determined for evaluating the oxidative status of testicular tissue. The findings obtained in this study showed that relative epididymis weights and sperm concentration decreased and abnormal sperm morphology increased in quetiapine-administered rats. Irregularity of typical architecture of the seminiferous tubules and germinal cell disorganization was observed in testicular sections of 20 and 40 mg/kg quetiapine-administered rats. Further, serum LH and testosterone levels decreased in 20 and 40 mg/kg quetiapine-administered rats. Additionally, decreased catalase and superoxide dismutase activities in testicular tissue of quetiapine-administered rats and increased malondialdehyde levels in testicular tissue of 40 mg/kg quetiapine-administered rats were measured. In conclusion, quetiapine treatment decreased sperm quality, altered hormone levels, and induced oxidative stress may be considered potential contributors to this adverse effect.

Introduction Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with both genetic and environmental dynamics contributing to disease progression that characterized by unbalanced proliferation and apoptosis of pulmonary arterial smooth muscle cells (PASMCs) (Nasim et al., 2012). Mutations in the bone morphogenetic protein receptor type II (BMPRII) gene have been associated with development of familial pulmonary artery hypertension (PAH). The function of SMAD signal transduction during the pulmonary vasculature and the role BMPRII mutations in the development of PAH are not fully understood. However, drug or toxin-induced PAH has been characterized by raised pulmonary arterial resistance leading to right heart failure. Aim and Methods in this study, the monocrotaline (MCT) model of PAH was used to examine alterations in SMADs (SMAD3 and SMAD1/5) signal transduction pathways in vivo. The SMAD signalling pathways were investigated in lungs harvested from rats treated with a single 50-mg/kg of MCT and an established drug at concentrations of 0.5 and 1 mg/Kg. The level of phosphorylation of SMAD3 and SMAD1/5 were detected by Western blot and the expression BMPR2, Id1, Pai1 transcripts was measured using quantitative real time PCR (qPCR). Results MCT-treated rats decreased the level of SMAD 3 phosphorylation, which was restored following the treatment with the established drug. The drug also modulated the expression of SMAD target genes. Conclusion Our study suggests that loss of SMAD3 could possibly present a key event in the pathophysiology in PAH and restoring this pathway may provide therapeutic intervention. Conflict of Interest The authors declare that there is no conflict of interest

Neonicotinoids, which are widely used worldwide, including in Turkey, are an insecticide group that are synthetic derivatives of nicotine. Recently, they have attracted attention due to their toxic effects on non-target organisms, especially bees. Numerous studies have shown that neonicotinoids have been found in detectable levels in the environment and cause various undesirable effects on living organisms, including humans and other mammals. In this study, the possible toxic effects of imidacloprid and acetamiprid, commonly used neonicotinoids, are investigated by their pure forms and commercial formulations on HT-29 cells with individual and combined exposures. According to our results, imidacloprid and acetamiprid induced cytotoxicity by caspase-mediated apoptosis, mitochondrial membrane depolarization, DNA damage, and oxidative stress under these experimental conditions. It is worth mentioning low doses of DNA damage, mixture exposure causes toxic effects at lower concentrations than individual exposure, and formulation groups are at the forefront of toxicity formation, though this varies depending on the parameters.

Risperidone (RIS), a commonly used drug during a lifetime for the treatment of schizophrenia, causes some adverse effects in the male reproductive system; however, there is no comprehensive reproductive toxicity study of RIS. For this purpose, male rats were administered orally for 1.25, 2.5 and 3 mg/kg RIS for 28 days and the sperm count, motility, morphology, DNA damage and the histological changes in testicular tissue were evaluated. Follicle-stimulating hormone (FSH), luteinising hormone (LH) and serum levels of testosterone, which are the main hormonal regulators of reproduction, and testicular glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA) levels as the indicators of oxidative stress were determined. Normal sperm morphology was decreased in RIS groups and histopathological degeneration occurred in testis tissue dose-dependently. Serum LH levels were not altered; however, FSH and testosterone levels decreased in the high-dose group. Histopathologic examination showed RIS toxicity targeted Leydig cells, which might be associated with impairment of the hypothalamic-pituitary-gonadal (HPG) axis. GSH levels were decreased and MDA levels were increased in the high-dose group which was evaluated as indicators of oxidative stress. In conclusion, RIS caused reproductive toxicity in male rats by inducing oxidative stress and disrupting hormonal regulation.

Many studies have been conducted on the selective inhibition of human monoamine oxidase B (hMAO-B) enzyme using benzylamine-sulphonamide derivatives. Using various chemical modifications on BB-4h, which was reported previously by our team and showed a significant level of MAO-B inhibition, novel benzylamine-sulphonamide derivatives were designed, synthesised, and their MAO inhibition potentials were evaluated. Among the tested derivatives, compounds 4i and 4t achieved IC50 values of 0.041 ± 0.001 µM and 0.065 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition by compounds 4i and 4t was studied using Lineweaver–Burk plot. The nature of inhibition was also determined to be non-competitive. Cytotoxicity tests were conducted and compounds 4i and 4t were found to be non-toxic. Molecular docking studies were also carried out for compound 4i, which was found as the most potent agent, within hMAO-B catalytic site.

WOS: 000441517900001, PubMed ID: 30151072, Depression and anxiety are recognized as public health problems. Epidemiological studies have shown that depression and anxiety often occur during reproductive ages between 20 and 60 years of age in males. Trazodone is one of the most frequently prescribed drugs in the treatment of depression and anxiety. Drugs used in repeated doses also play a role in the etiology of infertility. In our study, it was aimed to identify the possible toxic effects of trazodone on male rats and elucidate the underlying mechanisms. Vehicle or trazodone (5, 10, and 20 mg/kg/day) was administered to rats for 28 consecutive days (n = 8 per group). At the end of that period, sperm concentration, motility, morphology, and DNA damage were determined and testicular morphology was assessed histopathologically in rats. Additionally, we investigated hormonal status by determining serum testosterone, FSH, and LH levels and oxidative stress by determining glutathione and malondialdehyde levels in testicular tissue to elucidate mechanisms of possible reproductive toxicity. According to our results, sperm concentration, sperm motility, and normal sperm morphology were decreased; sperm DNA damage was increased in trazodone-administered groups. Degenerative findings on the testicular structure were observed after trazodone administration in rats. Additionally, serum FSH, LH, and testosterone levels were elevated in the trazodone-administered groups. Increased MDA levels were the signs of enhanced oxidative stress after trazodone administration in testis tissues. Thus, we concluded that trazodone induced reproductive toxicity in male rats; this reproductive toxicity was accompanied by oxidative stress and hormonal changes, which are considered as important causes of reproductive disorders.

WOS: 000433998700006, Background: Pyrazolines have played a pivotal role in antimicrobial and anticancer drug discovery. Moreover, thiazoles have attracted a great deal of interest due to their crucial roles in the lead identification and optimization. Objectives: The purpose of the current work was to design and synthesize new antimicrobial and anticancer agents. Methods: New thiazolyl-pyrazoline derivatives (2a-d) were synthesized via the ring closure reaction of 3-(2-thienyl)-5-(2,6-dichlorophenyl)-1-thiocarbamoyl-2-pyrazoline (1) with phenacyl bromides. The compounds were evaluated for their in vitro antimicrobial effects on pathogenic bacteria and Candida species using Microdilution assay, BacTiter-Glo (TM) microbial cell viability assay and Fluorescence microscopy. The possible binding interactions of compound 1 in the active site of CYP51 were confirmed by molecular docking studies, whereas its genotoxicity was investigated using Ames MPF test. Furthermore, MTT assay was performed to determine the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, C6 rat glioma, and NIH/3T3 mouse embryonic fibroblast cell lines. A computational study for the prediction of ADME properties of all compounds was also performed. Results: Compound 1 was found to be the most potent anticandidal agent against Candida species. MTT and Ames MPF assays indicated that compound 1 was neither cytotoxic nor genotoxic at the concentrations tested. Docking studies showed that compound 1 interacted with Heme group in the active site of CYP51. This compound also exhibited selective anticancer activity against HepG2 and C6 cell lines. According to in silico studies, this compound did not violate Lipinski's rule, making it a potential orally bioavailable chemotherapeutic agent. Conclusion: Compound 1 was identified as a promising candidate for further mechanistic studies., Anadolu University Scientific Research Projects Commission [1604S158], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1604S158.

There is an error in Table 2 in the published article, Journal of Food Bioactives, 2021;13:93–101, doi: 10.31665/JFB.2021.13263. The correct value in column “mg/100 g” under “D-glucose” is “59.50 ± 7.80”, not “9.50 ± 7.80”. The authors have included a corrected version of the table below.

WOS: 000426940800009, Sixteen new 2-(benzothiazol-2-ylthio)-N-(3-substituted-4-(3,4-substitutedphenyl)thiazol-2(3H)-ylidene)acetohydrazide derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were elucidated using FT-IR, H-1-NMR, C-13-NMR, and HRMS spectral data. Anticancer activity of the compounds 4a-4p against C6 (rat brain glioma) and A549 (human lung adenocarcinoma) cell lines was evaluated by using MTT, inhibition of DNA synthesis, and flow cytometric analysis assays. According to MTT assay, 4a and 4d were found to be the most active compounds against C6 cell line with an IC50 value of 0.03mM. Moreover, IC50 values of 4a (0.2 mM) and 4d (0.1 mM) against NIH3T3 (mouse embryo fibroblast cell line) were higher than their IC50 values (0.03 mM) against C6 cell line. Accordingly, selectivity of compound 4a against C6 cell line was two-fold higher than that of compound 4d. Flow cytometry analysis showed that these compounds display anticancer activity by inducing apoptosis. As a result, compound 4a has a remarkable anticancer activity and a good selectivity towards C6 cell lines. [GRAPHICS] ., Anadolu University Scientific Projects Fund [1601S019], This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1601S019.

Background Citalopram hydrobromide (CTL) has been shown to cause sexual dysfunction; however, its reproductive toxicity potential has not been sufficiently elucidated in men. Therefore, we aimed to clarify the toxic effects of CTL on the reproductive system of male rats. Methods For this purpose, CTL was administered at 5, 10, and 20 mg/kg/day to rats orally for 28 days. Sperm concentration, motility, and morphology were investigated using a computer-assisted sperm analysis system, and sperm DNA damage was detected using a Comet assay. The testes were histopathologically examined. Serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels were measured and the oxidative status of testes was investigated. Results Our results showed that sperm concentration was reduced, and abnormal sperm morphology and sperm DNA damage were increased in CTL-administered groups. Additionally, histopathological changes were observed in the testes of CTL-administered rats. Luteinizing hormone levels were increased in CTL-administered groups, while testosterone levels were increased in the 5 and 10 mg/kg CTL-administered groups. Decreased glutathione signaled enhanced oxidative stress in the 10 and 20 mg/kg CTL-administered groups. Conclusion Thus, we concluded that CT induced testicular damage in male rats; this testicular damage was accompanied by oxidative stress and hormonal changes, which are considered as the important causes of reproductive disorders. Birth Defects Research 109:475-485, 2017. © 2017 Wiley Periodicals, Inc.

Background and Aims: Citalopram is a selective serotonin reuptake inhibitor with a high potency which is occasionally prescribed and used to treat major depression associated with mood disorders as a first-line drug. According to the results of previous studies, evidence of hepatotoxicity related to citalopram treatment were limited and conflicting. Therefore, we aimed to evaluate the hepatotoxicity potential of sub-chronic citalopram administration. Methods: Citalopram was administered to female rats orally in 5 and 10 mg/kg for 30 days. After the exposure period, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin levels as biomarkers of hepatotoxicity were measured and histopathological examination of liver tissues was performed. Additionally, GSH levels of liver tissues were determined. Results: The risk of hepatotoxicity related to citalopram was shown by significant increases of serum hepatic biomarkers, AST, ALT, and total bilirubin in citalopram-administered groups. According to the histopathological findings, hepatocellular necrosis, hepatic nuclear asymmetry, and disarrangement of hepatic cord cells (hepatocytes) were prominent in the 10 mg/kg citalopram- administered group. On the other hand, there was no significant difference among the groups in terms of GSH levels. Conclusion: The results suggested that the administration of citalopram might cause hepatotoxic effects, depending on the dose.

In this study, some benzimidazole-oxadiazole derivatives were synthesised and tested for their in vitro anticancer activities on five cancer cell lines, including HeLa, MCF7, A549, HepG2 and C6. Their structures were elucidated by IR, 1H-NMR, 13C-NMR, 2 D-NMR and HRMS spectroscopic methods. Among all screened compounds; 5a, 5b, 5d, 5e, 5k, 5l, 5n and 5o exhibited potent selective cytotoxic activities against various tested cancer cell lines. Especially, compounds 5l and 5n exhibited the most antiproliferative activity than Hoechst 33342 and doxorubicin against HeLa cell line, with IC50 of 0.224 ± 0.011 µM and 0.205 ± 0.010 µM, respectively. Furthermore, these potent lead cytotoxic agents were evaluated in terms of their inhibition potency against Topoisomerase I and it was determined that selected compounds inhibited the Topoisomerase I. Docking studies were performed and probable interactions in the DNA-Topo I enzyme complex was determined.

Many studies have been conducted on the selective inhibition of human monoamine oxidase B (hMAO-B) enzyme using benzylamine-sulphonamide derivatives. Using various chemical modifications on BB-4h, which was reported previously by our team and showed a significant level of MAO-B inhibition, novel benzylamine-sulphonamide derivatives were designed, synthesised, and their MAO inhibition potentials were evaluated. Among the tested derivatives, compounds 4i and 4t achieved IC50 values of 0.041 ± 0.001 µM and 0.065 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition by compounds 4i and 4t was studied using Lineweaver–Burk plot. The nature of inhibition was also determined to be non-competitive. Cytotoxicity tests were conducted and compounds 4i and 4t were found to be non-toxic. Molecular docking studies were also carried out for compound 4i, which was found as the most potent agent, within hMAO-B catalytic site.

PubMed: 31476894, Zonisamide (ZNS) is an anticonvulsant which is used to treat the symptoms of epilepsy. Although it is frequently used during reproductive ages, studies that investigated the effects of ZNS on reproductive system are limited. Therefore, we aimed to assess the effects of ZNS on male reproductive system by oral administration to rats in 25, 50, and 100 mg/kg doses for 28 days. After the exposure period, sperm concentration, motility, morphology, and DNA damage, as biomarkers of reproductive toxic effects, were determined, and histopathological examination of testis was performed. In addition, levels of the hormones that play a role in the regulation of reproductive functions, such as follicle-stimulating hormone, luteinizing hormone (LH), and testosterone were measured and the levels of oxidative stress biomarkers that take part in the reproductive pathologies such as catalase, superoxide dismutase, glutathione, and malondialdehyde, were determined. Reproductive toxic effects related to ZNS administration were shown by the significant decrease of sperm concentration and normal sperm morphology in ZNS groups. Additionally, pathological findings were observed in the testicular tissues of ZNS-administered groups dose dependently. In addition, serum LH and testosterone levels were significantly decreased in the ZNS groups. Decreased catalase activities and increased malondialdehyde levels in ZNS groups were evaluated as oxidative stress findings in the testis tissue. It could be expressed that ZNS administration induced dose-dependent reproductive toxic effects in rats, and pathological findings associated with the reproductive system could be the result of that hormonal changes and testicular oxidative stress, which in turn might be considered as possible mechanisms of male reproductive toxicity

WOS: 000415108300007, A series of new thiazole-hydrazones (3a-3n) were synthesized, characterized, and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. Selectivity indexes (SIs) were expressed as IC50 (MAO-A) / IC50 (MAO-B). Compound 3f showed promising hMAO-A inhibition with an IC50 value of 1.20 mu M and displayed a very significant SI of 0.04 towards hMAO-A. The mechanism of hMAO-A inhibition was investigated by enzyme kinetics using Lineweaver-Burk graphics. Compound 3f was further screened for its cytotoxicity by using a healthy NIH/3T3 mouse embryonic fibroblast cell line (ATCC CRL1658) and was evaluated as nontoxic at its effective concentration against hMAO-A. The ADME prediction of the compounds revealed that they may have good pharmacokinetic profiles, which is necessary for drug candidates.

WOS: 000389464300007, In an effort to develop potent antimicrobial agents, new thiazolyl hydrazone derivatives were synthesized and investigated for their inhibitory effects on pathogenic bacteria and yeasts. MTT assay was carried out to determine the cytotoxic effects of the compounds on NIH/3T3 mouse embryonic fibroblast cell line. Among these compounds, 2-[2-[1-(4-(piperidin-1-yl)phenyl)ethylidene] hydrazinyl]-4-(4-fluorophenyl) thiazole (7) exhibited notable antimicrobial activity against Enterococcus faecalis (ATCC 51922), Pseudomonas aeruginosa, Escherichia coli (ATCC 35218), Candida krusei, Candida glabrata and Candida parapsilosis. Due to its promising antimicrobial activity, the mutagenic potential of compound 7 was also evaluated by means of Ames test. According to MTT and AMES assays, this compound was identified as non-toxic and non-mutagenic.

WOS: 000454945000005, PubMed ID: 29774748, Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.

WOS: 000456868000011, PubMed ID: 29745341, Background and Methods: In an attempt to develop potent antitumor agents, the synthesis of a series of N-(6-substituted benzothiazol-2-yl)-2-1(5-(arylamino)-1,3,4-thiadiazol-2-yl)thiolacetamides (1-14) was described and their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HepG2 human hepatocellular carcinoma and NIH/3T3 mouse embryonic fibroblast cell lines were investigated using Mil' assay. Results: Phenyl-substituted compounds (8-14) were found to be more effective than naphthyl-substituted compounds (1-7) on cancer cells. Compounds 8, 9, 10, 12, 13 and 14 were identified as the most potent anticancer agents on MCF-7 and HepG2 cell lines and therefore their effects on DNA synthesis and apoptosis/necrosis in MCF-7 cell line were evaluated. Among these compounds, N-(6-methoxybenzothiazol-2-yl)-2-[(5(phenylamino)-1,3,4-thiadiazol-2-yl)thiolacetamide (13) was the most selective anticancer agent against MCF-7 and HepG2 cell lines with a SI value of 100. On the other hand, compounds 8, 9, 10, 12, 13 and 14 inhibited DNA synthesis in MCF-7 cell line in a dose-dependent manner. Flow cytometric analyses clearly indicated that the compounds showed significant anticancer activity against MCF-7 cell line via the induction of apoptosis dose dependently. Conclusion: According to in vitro assays, compounds 8, 9, 10, 12, 13 and 14 stand out as promising candidates for further studies., Anadolu University Scientific Research Projects Commission [1406S315], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1406S315.

WOS: 000369191800035, PubMed ID: 26706351, New thiosemicarbazone derivatives (1-10) were obtained via the reaction of 4-(naphthalen-1-yl)thiosemicarbazide with fluoro-substituted aromatic aldehydes. The synthesized compounds were evaluated for their in vitro antifungal effects against pathogenic yeasts and molds using broth microdilution assay. Ames and umuC assays were carried out to determine the genotoxicity of the most effective antifungal derivatives. Furthermore, all compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using KIT test. Among these derivatives, 4-(naphthalen-1-yl)-1-(2,3-difluorobenzylidene)thiosemicarbazide (1) and 4-(naphthalen-1-yl)-1-(2,5-difluorobenzylidene)thiosemicarbazide (3) can be identified as the most promising anti fungal derivatives due to their notable inhibitory effects on Candida species and no cytotoxicity against NIH/3T3 mouse embryonic fibroblast cell line. According to Ames and umuC assays, compounds 1 and 3 were classified as non-mutagenic compounds. On the other hand, 4-(naphthalen-1-yI)-1-(2,4-difluorobenzylidene)thiosemicarbazide (2) can be considered as the most promising anticancer agent against A549 cell line owing to its notable inhibitory effect on A549 cells with an IC50 value of 31.25 mu g/mL when compared with cisplatin (IC50 = 16.28 mu g/mL) and no cytotoxicity against NIH/3T3 cells

WOS: 000380943600008, PubMed ID: 26429924, Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.

WOS: 000432533300007, Objectives: Cancer is one of the leading causes of death throughout the world. Current therapy options suffer from the major limitations of side effects and drug resistance. Thus, continuing search for newer and safer anticancer drugs remains critically important. From this point of view, in the present study benzimidazole-hydrazone derivatives were synthesized by aiming at the identification of new chemical entities as potent anticancer agents. Material and methods: A series of 12 new compounds of 4-(5(6)-substituted-1H-benzimidazol-2-yl)-N' thiophen/furan-2-yl-methylene) benzohydrazide derivatives were synthesized. The structures of the obtained compounds were elucidated using by IR, H-1 NMR, C-13 NMR, mass spectroscopy and elemental analyses. In vitro cytotoxic activity of the compounds against A549, MCF-7 and NIH/3T3 cell lines was evaluated by MTT assay. Results: Among the tested compounds, compound 3e showed higher cytotoxicity against MCF-7 human breast cancer cells when compared with cisplatin. Also, it has lower cytotoxicty against healthy cell line, NIH/3T3. Conclusions: It was determined that compound 3e showed inhibition towards MCF-7. Considering the substituent effect on cytotoxic activity, compound 3e bearing 2-methylthiophene has attracted attention with its higher anticancer activities.

WOS: 000453472300015, PubMed ID: 29308744, Background: The lack of selectivity and development of drug-resistance encourage researchers to search for novel, more efficient and multi-targeted agents with less toxicity. Objective: In this paper, a series of novel chalcone derivatives bearing diverse heterocycles have been synthesized and evaluated for their antiproliferative activity against A549 (Human Lung Adenocarcinoma) and C6 (Rat Brain Glioma) cells. Method: Structures of the title compounds (3-18) were verified by FT-IR, H-1 NMR, C-13 NMR, HRMS spectral data and elemental analyses. Antiproliferative activities of the compounds were evaluated using MTT assay, BrdU method, and flow cytometric analysis. Results: Compounds 9 and 15 were revealed as the most promising cytotoxic agents due to their selectivity towards A549 cells with lower IC50 values (IC50=0.05 mu M and IC50=0.0316 mu M) than cisplatin (IC50=0.06 mu M). Flow cytometric analysis of compounds 9 and 15 showed that they affected lung cancer cells by the apoptotic pathway. Conclusion: It is concluded that this study will contribute to the research of novel antiproliferative agents.

WOS: 000444248700007, PubMed ID: 30310659, Sertraline is an antidepressant that is frequently prescribed to treat depression, obsessive-compulsive disorder, panic disorder, and anxiety. This drug had a safe cardiotoxicity profile, until the reporting of cases of sertraline-associated cardiotoxicities in the early 2000s. Since then, there have been conflicting results on the cardiotoxicity of this drug. In the study reported here we aimed to identify the cardiotoxic effects of sertraline by evaluating serum cardiac biomarkers, such as serum aspartate aminotransferase (AST), creatinine phosphokinase-myoglobin band (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin T (cTn-T) levels as well as electrocardiographic parameters, DNA damage in cardiomyocytes, and histological findings of heart tissue in rats that were administered oral doses of 5, 10, or 20 mg kg(-1) of sertraline for 28 days. Additionally, to investigate the possible mechanisms underlying cardiotoxicity, glutathione and malondialdehyde levels in cardiac tissue were determined to evaluate oxidative stress. According to our results, AST, LDH, and cTn-T levels were significantly increased in the 10 and 20 mg kg(-1) sertraline groups when compared to the control group. Heart rates were increased, PR intervals prolonged, a short QTc value was observed, and T-wave amplitudes were decreased significantly in the 20 mg kg(-1) sertraline group when compared to the control group. Significant DNA damage was observed in the high-dose groups. Histopathological investigations also revealed some degenerative changes in the 10 and 20 mg kg(-1) sertraline groups. Glutathione levels were significantly decreased in the 10 and 20 mg kg(-1) sertraline groups when compared with the control group. In conclusion, our findings support the cardiotoxic potential of sertraline and also suggest that oxidative stress may play a role in the toxicity of sertraline.

WOS: 000423791300010, Background: In medicinal chemistry, thiazoles have gained great importance in anti-fungal and anticancer drug design and development. Objectives: The aim of this study was to synthesize new quinoline-based thiazolyl hydrazone derivatives and evaluate their anticandidal and anticancer effects. Methods: New thiazolyl hydrazone derivatives were evaluated for their anticandidal effects using disc diffusion method. Ames MPF assay was carried out to determine the genotoxicity of the most effective antifungal derivative. MTT assay was also performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, MCF7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines. Results: 4-(4-Fluorophenyl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (4) showed antifungal activity against Candida albicans and Candida krusei in the concentration of 1 mg/mL. In MTT and Ames MPF tests, it was determined that compound 4 did not show cytotoxic and genotoxic effects. MTT assay indicated that 4-(naphthalen-2-yl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (10) showed more selective anticancer activity than cisplatin against A549 and MCF-7 cell lines. Besides, 4-(4-chlorophenyl)-2-(2-((quinolin-4-yl) methylene) hydrazinyl) thiazole (5) exhibited more selective anticancer activity than cisplatin against HepG2 cell line. Conclusion: Due to their high selectivity index, these compounds are considered as candidate compounds to participate in further research.

WOS: 000425198100005, PubMed ID: 29248751, In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 mu M and 0.011 mu M and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound

WOS: 000406621300084, PubMed ID: 28677624, Matrix metalloproteinases (MMPs) are important proteases involved in tumor progression including angiogenesis, tissue invasion, and migration. Therefore, MMPs have been reported as potential diagnostic and prognostic biomarkers in many types of cancer. New oxadiazole, thiadiazole, and triazole derivatives were synthesized and evaluated for their anticancer effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines. In order to examine the relationship between their anticancer activity and MMP-9, the compounds were evaluated for their inhibitory effects on MMPs. N-(1,3-Benzodioxol-5-ylmethyl)-2-{[5-(((5,6,7,8-tetrahydronaphthalen-2- yl)oxy)methyl)-1,3,4-oxadiazol-2-yl]thio}acetamide (8) and N-(1,3-benzodioxol-5-ylmethyl)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl) thio] acetamide (9) revealed promising cytotoxic effects on A549 and C6 cell lines similar to cisplatin without causing any toxicity towards NIH/3T3 mouse embryonic fibroblast cell line. Compounds 8 and 9 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 8 and 9 had good affinity to the active site of the MMP-9 enzyme. The molecular docking and in vitro studies suggest that the MMP-9 inhibitory effects of compounds 8 and 9 may play an important role in lung adenocarcinoma and glioma treatment., Anadolu University Scientific Research Projects Commission [1505S371, 1604S158], This study was supported by the Anadolu University Scientific Research Projects Commission under the grant No.: 1505S371 and 1604S158.

WOS: 000338775200002, New pyrazole-based thiazolyl hydrazone derivatives were obtained via the ring closure reaction of 3,5-dimethyl-1H-1-phenylpyrazole-4-carboxaldehyde thiosemicarbazone with 2-bromoacetophenone derivatives. The compounds were investigated for their cytotoxic effects on A549 and NIH3T3 cell lines. Among these compounds, compound 2i bearing a trifluoromethyl substituent can be identified as the most promising anticancer agent against A549 cancer cell lines. Compound 2i exhibited its inhibitory effect on A549 cells with an IC50 value of 0.0316 mM, whereas cisplatin showed its anticancer activity with an IC50 value of 0.01 mM. According to the IC50 values, the inhibitory effect of compound 2i on A549 cells can be considered to be selective when compared with its effect on NIH3T3 cells., Anadolu University Scientific Research Projects Commission [1001S41], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1001S41.

Monocrotaline (MCT) is a pyrrolizidine alkaloid which induces cardio-pulmonary toxicity and hepatotoxicity in animals and humans. MCT is frequently ingested because of food grain contamination accidentally or in the form of herbal medicine preparations. The aim of this study was to observe the protective effect of N-acetyl cysteine (NAC) on MCT-induced pulmonary toxicity and hepatotoxicity. According to our results (right ventricular pressures [RVPs], ratios of right ventricle (RV)/heart weight (HW), plasma AST levels, liver glutathione levels, liver MDA levels and liver histopathological examinations of groups), protective effects were observed with NAC treatment in both MCT-induced pulmonary toxicity and hepatotoxicity.

WOS: 000321211800009, PubMed ID: 23821593, The present study aimed to compare the effect of gender difference on hemodynamic consequences in the development of monocrotaline (MCT)-induced pulmonary hypertension in rat. The effect of antioxidant enzyme systems on the development of pulmonary hypertension mediated by the phytotoxin MCT and the effect of gender on these antioxidant systems were also investigated. For this purpose, the right ventricular pressures (RVPs) and right ventricular/heart weight (HW) ratios were compared between groups and the glutathione (GSH) level and superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in lung and liver tissue samples of rats. RVP and right ventricular/HW ratios significantly increased in the MCT group compared to the control group. In the MCT group, RVP was significantly higher in males than females. MCT-induced pulmonary hypertension resulted in decreased GSH level, decreased GST and SOD activities and increased CAT activity in lung and liver tissues of both male and female rats. In addition, the lung and liver GSH level and GST and SOD levels were higher in female control rats compared to male control rats. The results of the present study, that antioxidant enzyme activities were different between the groups, highlight the possible role of oxidative stress in the pathogenesis of MCT-induced pulmonary hypertension in rats. Moreover, the lower antioxidant defense capacity of male rats than female rats may be considered as a cause of more aggressive course of MCT-induced pulmonary hypertension in males compared to females.