The human immunodeficiency virus continues to pose a significant global public health challenge, affecting millions of individuals. The current treatment strategy has incorporated the utilization of combinations of antiretroviral drugs. The administration of these drugs is associated with many deleterious consequences on several physiological systems, notably the reproductive system. This study aimed to assess the toxic effects of abacavir sulfate, ritonavir, nevirapine, and zidovudine, as well as their combinations, on TM3 Leydig and TM4 Sertoli cells. The cell viability was gauged using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays. Reactive oxygen species (ROS) production was assessed via the 2',7'-dichlorofluorescein diacetate (DCFDA) test, and DNA damage was determined using the comet assay. Results indicated cytotoxic effects at low drug concentrations, both individually and combined. The administration of drugs, individually and in combination, resulted in the production of ROS and caused damage to the DNA at the tested concentrations. In conclusion, the results of this study suggest that the administration of antiretroviral drugs can lead to testicular toxicity by promoting the generation of ROS and DNA damage. Furthermore, it should be noted that the toxicity of antiretroviral drug combinations was shown to be higher compared to that of individual drugs.

Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (H-1, C-13 NMR, ESI-MS and IR). All hybrids (6-23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 2.82 to 12.59 mu M, while proving safe towards normal cells WI-38 (IC50 = 31.89 mu M) compared to the reference drug doxorubicin (IC50 = 6.72 mu M). The most active candidates 13, 20, 21, 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC50 of 6.72 and 8.18 mu M respectively compared to staurosporine (IC50 = 4.64 mu M). Further mechanistic studies for compound 13 showed cell cycle arrest at S-phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors' binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20, and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates.

Since the liver metabolizes many drugs, including antiepileptics, this organ is the main target of drug-induced damage. There is very little data on hepatotoxicity due to carbamazepine and perampanel metabolized in the liver. The available data are based solely on published case reports. For this reason, this study aims to evaluate the hepatotoxicity of carbamazepine and perampanel, which are frequently used in treating epilepsy and which do not have a detailed investigation, although they are suspected of hepatotoxicity. Hepatotoxicity in the HepG2 cell line, IC50 values were calculated by MTT cytotoxicity test, followed by determination of apoptosis/necrosis, various biochemical analyzes (ALT, AST, urea), which is currently a biomarker for liver injury, and hepatotoxicity by ROS and GSH determination. Both drugs increased liver biomarkers, oxidative stress, and cytotoxicity in HepG2 cells. The investigation found that the drugs triggered liver apoptosis, not necrosis. In conclusion, Perampanel may have hepatotoxicity similar to carbamazepine.

Although the correlation between citalopram and cardiovascular pathologies was realized via case studies, there is no experimental study that was performed independently of other risk factors related to cardiotoxicity. In the study reported here, we aimed to identify the cardiotoxic effects of citalopram by evaluating serum cardiac biomarkers, such as serum aspartate transaminase, creatine kinase-myoglobin binding, lactate dehydrogenase and troponin-T levels as well as electrocardiogram parameters, deoxyribonucleic acid damage in cardiomyocytes and histological findings of heart tissue in rats that were administered oral doses of 5, 10, or 20 mg/kg of citalopram for 28 d. Additionally, to investigate possible mechanisms underlying cardiotoxicity, glutathione and malondialdehyde levels in cardiac tissue were determined to evaluate oxidative stress. According to our results, heart rates were increased, PR intervals were prolonged, and T wave amplitudes were significantly decreased in the 20 mg/kg citalopram-administered groups when compared with the control group. Additionally, serum aspartate transaminase, lactate dehydrogenase and troponin-T levels were significantly increased in the 10 and 20 mg/kg citalopram-administered group compared to the control group. Significant deoxyribonucleic acid damages were observed in the 10 and 20 mg/kg citalopram-administered groups. Histopathological investigations revealed degenerative changes in the 10 and 20 mg/ kg citalopram-administered groups. In heart tissues, glutathione levels were decreased in the 10 and 20 mg/kg citalopram-administered groups significantly when compared with the control group. These findings indicated the relationship between high-dose and subtherapeutic-dose citalopram administration and cardiac morphological, biochemical and functional toxic effects.

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 PPAR gamma 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.

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 caspasemediated 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.

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.

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.

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.

Abstract 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.

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.

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 Schrödinger’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 14α-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.

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.

Abstract 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.

Zika virus (ZIKV) is a mosquito-borne pathogen belonging to Flaviviridae family whose primary transmission occurs via the infected Aedes sp mosquito. The feature that distinguishes this virus from other flaviviruses is related to its transmission. Especially, defining of sexual and transplacental transmission routes for ZIKV makes this virus unique. ZIKV infections generally remain asymptomatic while they can also cause mild febrile disease symptoms such as headache, myalgia, fever, rash and non-purulent conjunctivitis. Currently, there is no FDA approved drug or treatment technique to stop or cure the disease caused by ZIKV. However, many research groups are focusing on treating the ZIKV-associated diseases. DNA based vaccine is a new fashion technology using genetically engineered DNA to take an immunologic response. To succeed this goal, the main strategy is to use DNA plasmids having antigens encoded on them. Cost, long term persistence of immunogenicity, stability properties and inducing protective humoral and cellular immune responses are some advantages of the DNA vaccination.

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.

Oleic acid is an unsaturated fatty acid found in significant quantities in various edible oils. Scientific studies have shown that oleic acid and its derivatives exhibit a variety of biological activities including antimicrobial and anticancer activities. In the present work, biotransformation of oleic acid was carried out initially using 27 different microbial strains. Extracts obtained from biotransformation with Alternaria alternata (clinical isolate) and Aspergillus terreus var. africanus (clinical isolate) were used in antimicrobial and anticancer activity studies. The in vitro antimicrobial activities of the extracts were evaluated against 9 different pathogenic microorganisms. The results indicated that the microbial extracts were more active than oleic acid itself and showed good inhibitory activity against all tested microorganisms. In in vitro anticancer activity studies, extract 2 obtained from biotransformation with Alternaria alternata exhibited notable anticancer activity against A549 cell line with an IC50 value of 62.5 μg/ml whereas positive control cisplatin showed an IC50 value of 43.5 μg/ml. The anticancer activity of extract 2 was also found to be selective according to its higher IC50 value (122.7 μg/ml) obtained against the healthy cell line, mouse embryonic fibroblasts, NIH3T3. Due to its anticancer effect, extract 2 is considered to participate in further research.