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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.

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.

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.

Although it is reported that olanzapine (OLZ), which is an atypical antipsychotic drug, causes sexual dysfunction in men, it is noteworthy that there is not any study evaluating the toxic effects of OLZ on the male reproductive system. In the scope of this research, it was aimed to assess the reproductive toxic effects of OLZ by oral administration of 2.5, 5, or 10 mg/kg of it to male rats for 28 days. For this purpose, sperm concentration, motility and morphology, and DNA damage were determined, and histopathological examination of testis tissue was carried out in rats. Also, the levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, which play roles in the regulation of reproductive functions, and the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA) which play roles in reproductive pathologies as oxidative stress biomarkers, were determined. According to the results, normal sperm morphology was decreased in 5 ve 10 mg/kg OLZ-administered groups, and pathological findings were evident in the testicular structure of the OLZ-administered group when compared with the control group. It was determined that serum LH, FSH, and testosterone levels were decreased in the OLZ-administered group. Also, decreases of GSH levels in testis tissue were determined and evaluated as the markers of the oxidative stress induced by OLZ in the testis. In conclusion, it was determined that reproductive toxic effects were induced in rats by OLZ administration. This pathology was accompanied by alterations of the hormone levels and testicular oxidative stress.

Breast cancer is the most common cancer type amoung post-menopausal women. Aromatase inhibitors were used in the treatment of patients. However, drug resistance may develop in long-term drug use, especially in 3rd and 4th stage (advanced) cancer cases. Therefore, there is a constant need for new agents. In this study, new triazolothiadiazine derivatives were synthesized and their anticancer activities were investigated. Compounds 2k, 2s, and 2w showed inhibitor activity against MCF-7 cell line with IC

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.

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.

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.

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.

WOS: 000404248000004, PubMed ID: 28561221, Looking for new cytotoxic and antimicrobial agents with improved antitumor activity, a series of hydrazide and oxadiazole derivatives were designed and synthesized using 3-methoxyphenol as starting substance. Novel N'-(arylidene)-2-(3-methoxyphenoxy) acetohydrazide derivatives (4a-f) / 1-(4-substitutedphenyl)-2-[(5-[(3-methoxyphenoxy) methyl]1,3,4- oxadiazol-2-yl) thio] ethan-1-one derivatives (6a-f)/N-(6-substitutedbenzothiazol-2-yl)-2-[(5-[(3-methoxyphenoxy) methyl]-1,3,4-oxadiazol-2-yl) thio] acetamide derivatives (7a-e) were obtained and evaluated for their in vitro antimicrobial activity against various gram-positive, gram-negative bacteria and fungi. The antimicrobial activity potential of the compounds against gram-negative bacteria was found to have higher compared to the potential against gram-positive bacteria. Also, compounds were screened for their antiproliferative activity against 2 selected human tumor cell lines, A549 lung, MCF7 breast cancer cell line and mouse embryo fibroblast cell line, NIH/3T3 as healthy cell line. Among the compounds evaluated, compound 7c bearing 1,3,4-oxadiazole ring and 6-methoxy benzothiazole moiety exhibited the highest inhibitory activity against A549 and MCF-7 tumor cell lines in contrary to NIH/3T3 cell line, as desired.

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: 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: 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: 000388251200005, PubMed ID: 30475497, The synthesis of nine new quinazoline derivatives (2a-21) and evaluation of their antimicrobial and cytotoxic activities were aims of the present work. For the synthesis of the compounds, 2-chloro-6,7-dimethoxyquinazolin-4-amine was used as the initial starting material. The intermediate product, 2-hydrazinyl-6,7-dimethoxyquinazolin-4-amine, was reacted with appropriate aromatic aldehydes to obtain 2-(2-benzylidenehydrazinyl)-6,7-dimethoxyquinazolin-4-amine derivatives as final compounds. The structures of the compounds were elucidated by and C-13-NMR, IR, and MS analyses. The new pure compounds were evaluated for their potential antimicrobial and cytotoxic activities using in vitro microdilution and cell culture techniques, respectively. The compounds 2e and 2f may be promising candidates for the treatment of fungal infections with their activity and cytotoxicity.

WOS: 000427476800009, Background: Alzheimer's Disease (AD) is a complicated neurodegenerative disorder with a multifaceted pathogenesis. AD, characterized by gradual memory loss, falling in language ability and other cognitive deterioration, and has been a prominent risk to ageing population. This means that there is an urgent need to find new lead compounds for controlling and fighting against (AD). In this way, a new thiophene-2-pyrazoline derivatives (A1-A5) and benzothiazole derivatives (A6-A13) have been synthesized to give beneficial compounds to controlling and battling against (AD). Results: Compounds A5 and A13 showed the most remarkable activity with an 18.53 mu M and 15.26 mu M IC50 values against AChE enzyme. In like manner, compound A4 was active with a 20.34 mu M IC50 value against MAO-A. These active compounds are in fact non-toxic making them very attractive for additional future studies. Enzyme kinetic was analyzed and the Lineweaver-Burk plot reveals that compound A13 was typically mixed AChE inhibitors, which showed significant similarity to donepezil. In addition, the best docking pose was done by analyzing the docking pattern of the most active compound A13 which was very compatible with the gorge and in interaction with both CAS and PAS. Conclusion: The synthesis of new thiophene-2-pyrazoline and benzothiazole derivatives targeting AChE/(MAO-A)/(MAO-B) enzymes was described. The selection of enzyme-kinetic analysis, molecular docking and toxicity test was led to good understanding to the therapeutic potential for the active derivatives. Therefore, these compounds may be accepted as promising leads for future research efforts in fighting against AD.

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: 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.

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.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.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.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.

WOS: 000399875200060, PubMed ID: 28419133, Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are potential contributors to reproductive toxicity., Anadolu University Scientific Research Projects Commission [1505S412], This study was supported by the Anadolu University Scientific Research Projects Commission under grant no 1505S412.

WOS: 000419242400081, PubMed ID: 29189730, In an effort to develop new potent antimicrobial and anticancer agents, new pyrrole-based chalcones were designed and synthesized via the base-catalyzed Claisen-Schmidt condensation of 2-acetyl-1-methylpyrrole with 5-(aryl)furfural derivatives. The compounds were evaluated for their in vitro antimicrobial effects on pathogenic bacteria and Candida species using microdilution and ATP luminescence microbial cell viability assays. 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. 1-(1-Methyl-1H-pyrrol-2-yl)-3-(5-(4-chlorophenyl)furan-2-yl)prop-2-en-1-one (7) and 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2,5-dichlorophenyl)furan-2-yl)prop-2-en-1-one (9) were found to be the most potent antifungal agents against Candida krusei and therefore these compounds were chosen for flow cytometry analysis and Ames MPF assay. ATP bioluminescence assay indicated that the antifungal activity of compounds 7 and 9 against C. krusei was significantly higher than that of other compounds and the reference drug (ketoconazole), whereas flow cytometry analysis revealed that the percentage of dead cells treated with compound 7 was more than that treated with compound 9 and ketoconazole. According to Ames MPF assay, compounds 7 and 9 were found to be non-genotoxic against TA98 and TA100 with/without metabolic activation. MTT assay indicated that 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2-nitrophenyl)furan-2-yl)prop-2-en-1-one (3) showed more selective anticancer activity than cisplatin against the HepG2 cell line. On the other hand, 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(4-nitrophenyl)furan-2-yl)prop-2-en-1-one (1) was found to be more effective and selective on the A549 cell line than cisplatin., Anadolu University Scientific Research Projects Commission [1605S488, 1705S166], This study was supported by the Anadolu University Scientific Research Projects Commission under the grant numbers: 1605S488 and 1705S166.

WOS: 000414231000054, PubMed ID: 29089569, Peroxisome proliferator-activated receptor gamma (PPAR gamma) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPAR. and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPAR gamma. Furthermore, docking experiments revealed that BTZDs interact with PPAR gamma through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPAR. for further development in the clinical treatment of type 2 diabetes mellitus., UGC-MANF [MUS-JH-12-13-11472], First author acknowledge UGC-MANF (MUS-JH-12-13-11472) for award of JRF fellowship. We are also thankful to DST-FIST (SR/FST/CSI-242/2012) for NMR facility at Birla Institute of Technology, Mesra and Institute of Life Sciences, Hyderabad, AP, India for providing spectral data.

WOS: 000404984700004, Background: In recent years, thiazole derivatives incorporated with hydrazone moiety have attracted a great deal of interest due to their pivotal role in the field of current cancer research. Methods: In the present study, new thiazolyl hydrazone derivatives were synthesized via the reaction of 1-(4-phenylcyclohexylidene) thiosemicarbazide with 2-bromoacetophenone derivatives. MTT assay was performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human liver hepatocellular carcinoma and C6 rat glioma cell lines. The selectivity of the compounds was investigated using NIH/3T3 mouse embryonic fibroblast cell line. Results: 4-(4-Methylsulfonylphenyl)-2-(2-(4-phenylcyclohexylidene)hydrazinyl) thiazole (7) was found to be the most promising anticancer agent against HepG2 cell line with an IC50 value of 0.316 mM when compared with cisplatin (IC50=0.091 mM). Compounds 2 and 6 also exhibited cytotoxic effects on HepG2 cell line with IC50 values of 0.81 mM and 0.79 mM, respectively. Besides, compounds 2, 6 and 7 did not show any cytotoxicity against NIH/3T3 cell line. Conclusion: In particular, compound 7 was found to be a potent anticancer agent to go further studies due to its selective antitumor activity against HepG2 cell line., Anadolu University Scientific Research Projects Commission [1605S318], This study was supported by the Anadolu University Scientific Research Projects Commission under the grant no: 1605S318.

WOS: 000384977600010, Several novel thiazolylpyrazoline derivatives were synthesized by reacting substituted 3,5-diaryl-1-thiocarbamoyl-2-pyrazolines with phenacylbromides. The structures of the synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, and MS spectral data. Their antimicrobial activities against Staphylococcus Atreus (ATCC-25923), Enterococcus faecalis (ATCC-29212), Enterococcus faecalis (ATCC-51922), Listeria monocytogenes (ATCC-1911), Klebsiella pneumoniae (ATCC-700603), Pseudomonas aeruginosa (ATCC-27853), Escherichia coli (ATCC-35218), Escherichia coli (ATCC-25922), Candida albicans (ATCC-90028), Candida glabrata (ATCC-90030), Candida krusei (ATCC-6258), and Candida parapsilosis (ATCC-22019) were investigated. The compounds were also studied for their cytotoxic effects using a MIT assay. Compound 7c showed the highest antimicrobial activity, possessing the same potential as chloramphenicol against K. pneumonia, P. aeruginosa, and E. coli (ATCC-25923).

WOS: 000403217100005, PubMed ID: 27491937, Background: In recent years, the relationship between overexpression of matrix metalloproteinases ( MMPs) and tumor invasion/metastasis has prompted researchers to develop MMP inhibitors as anticancer drugs. Objective: The aim of this study was to design and synthesize new thiazole-based anticancer agents targeting MMPs. Method: New thiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. The potential inhibitory effects of the best candidates on gelatinases (MMP-2, MMP-9), and collagenases (MMP-1, MMP-8, MMP-13) were evaluated. Results: Ethyl 2-[2-((4-amino-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamido]-4-methylthiazole-5-carboxylate ( 3) was found to be the most promising anticancer agent against MCF-7 cell line due to its selective inhibitory effect on MCF-7 cells with an IC50 value of 20.6 +/- 0.3 mu g/mL when compared with cisplatin (IC50= 35.31 +/- 0.51 mu g/mL). Compound 3 also showed multiple MMP (MMP-1, MMP-8 and MMP-9) inhibitory activity (10.56 +/- 1.70, 20 and 7.28 +/- 1.49%, respectively). Conclusion: The notable anticancer activity and selectivity of compound 3 on MCF-7 cell line can be attributed to multiple MMP inhibition potential., Anadolu University Scientific Research Projects [1505S408], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1505S408.

52nd Congress of the European-Societies-of-Toxicology (EUROTOX) -- SEP 04-07, 2016 -- Seville, SPAIN, WOS: 000402436700392, …, European Soc Toxicol

52nd Congress of the European-Societies-of-Toxicology (EUROTOX) -- SEP 04-07, 2016 -- Seville, SPAIN, WOS: 000402436700398, …, European Soc Toxicol

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 (

Quetiapine is an atypical antipsychotic drug used for treatments of patients with schizophrenia. Although hepatotoxic effects related to quetiapine treatment were reported in a few studies, potential hepatotoxicity of this drug was not identified clearly. Therefore, it was aimed to evaluate possible hepatotoxic effects of quetiapine by oral administration of this drug at 10 and 20 mg/kg doses to rats for 30 days in our study. For this purpose, plasma aspartate aminotransferase, alanine aminotransferase, total bilirubin and direct bilirubin levels as markers of hepatotoxicity were determined and histopathological examination was performed in liver tissues. According to our results, serum aspartate aminotransferase and alanine aminotransferase levels were significantly increased in quetiapine-administered groups, whereas total and direct bilirubin levels were significantly increased in high dose group. Histopathological examination of liver tissue indicated that necrotic areas were observed in 10 mg/kg quetiapine-administered group whereas necrotic areas were present and sinusoidal dilatation was observed in 20 mg/kg quetiapine-administered group. According to these results, we concluded that quetiapine may induced hepatotoxic effects in rats, dose-dependently.

51st Congress of the European-Societies-of-Toxicology (EUROTOX) -- SEP 13-16, 2015 -- Portuguese Soc Pharmacol, Sect Toxicol, Porto, PORTUGAL, WOS: 000370693801623, …, European Soc Toxicol

WOS: 000408602900137, PubMed ID: 28825626, The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, H-1-NMR, C-13-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases., Anadolu University Scientific Research Projects Commission [1105S101, 1606S567], This study was financially supported by Anadolu University Scientific Research Projects Commission, Project no. 1105S101 and 1606S567.

WOS: 000413790500010, PubMed ID: 27976631, This study was conducted to clarify the toxic effects of sertraline (SRT) on the reproductive system of male rats and to elucidate the underlying mechanisms. Rats were treated orally with SRT at doses of 5, 10, and 20 mg kg(-1) for 28 consecutive days. At the end of the treatment period, sperm concentration, sperm motility, and sperm morphology were investigated by computer-assisted sperm analysis system whereas sperm DNA damage was detected by comet assay. The oxidative status of the testes was investigated, and a histopathological examination was conducted. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured to determine the effects of SRT on the spermatogenesis process. One-way ANOVA, post-hoc Dunnett's T3 test for the sperm comet assay, and post-hoc Tukey's test for the others were performed for statistical analysis. The results showed that SRT caused an increase in sperm DNA damage and induced histopathological lesions in all groups treated with SRT. There was abnormal sperm morphology and increased malondialdehyde (MDA) in the 10 mg kg(-1) treatment group. More dramatic changes were observed in the 20 mg kg(-1) treatment group. Decreased sperm count was accompanied by a significant increase in abnormal sperm morphology, DNA damage, and degeneration in cellular-tubular structures. Serum LH and testosterone levels were elevated in the 20 mg kg(-1) treatment group. Decreased glutathione (GSH) and increased MDA were signs of enhanced oxidative stress (OS). In conclusion, SRT induced testicular toxicity in a dose-dependent manner and OS is suggested as a crucial mechanism., Anadolu University Scientific Research Projects Commission [1404S128], This study was supported by the Anadolu University Scientific Research Projects Commission under the grant no. 1404S128.