Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition with multifactorial etiology involving genetic, neurobiological, and environmental determinants. Emerging evidence suggests that environmental exposures may influence neurodevelopmental pathways relevant to ADHD pathophysiology. Manganese is an essential trace element required for normal brain development; however, excessive or dysregulated exposure has been associated with neurotoxic effects. This systematic review aimed to synthesize human evidence on the association between manganese exposure and ADHD or ADHD-related neurobehavioral outcomes in children. METHODS:Four electronic databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Observational studies meeting predefined Population, Exposure, Comparison, Outcomes, and Study Design criteria were included. Methodological quality was assessed using Joanna Briggs Institute appraisal tools, and certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation framework. RESULTS:Thirty studies met the inclusion criteria. Elevated manganese exposure was more frequently associated with increased risk or severity of ADHD or ADHD-related neurobehavioral symptoms, although inverse and nonlinear (U-shaped) associations were also reported. CONCLUSIONS:The available evidence indicates a complex and potentially nonlinear relationship between manganese exposure and child neurobehavioral outcomes. These findings identify manganese exposure as a potentially modifiable environmental factor influencing neurodevelopmental mechanisms relevant to ADHD and highlight the need for longitudinal studies integrating exposure biomarkers with neurobiological and clinical outcomes to clarify causal pathways and therapeutic implications.

Tartrazine is a synthetic azo dye widely used in food, pharmaceutical, and cosmetic products, resulting in extensive human exposure, while its toxicity and that of its primary metabolite, sulfanilic acid, remain controversial. Considering the reported association of tartrazine with hypersensitivity and allergic-like reactions, human bronchial epithelial BEAS-2B cells, which are relevant for airway and allergy-related responses, were selected as the in vitro model. This study investigated the effects of tartrazine and sulfanilic acid on cell viability, apoptosis-related responses, and DNA damage. Cell viability was evaluated using the MTT and neutral red uptake assays. Apoptotic responses were assessed by annexin V/propidium iodide staining, mitochondrial membrane potential analysis, and caspase-3/7 activity measurement. DNA damage was examined using the alkaline comet assay. Tartrazine reduced cell viability in a concentration- and time-dependent manner in the MTT assay, whereas sulfanilic acid showed minimal cytotoxic effects. Both compounds increased apoptotic cell populations at selected concentrations. Tartrazine induced mitochondrial membrane potential depolarization, while caspase-3/7 activity decreased at higher concentrations of both compounds. No significant DNA strand breaks were detected under the experimental conditions applied. These findings suggest that tartrazine and sulfanilic acid predominantly affect cell viability and apoptosis-related processes in airway epithelial cells without detectable DNA strand breaks at the tested concentrations.

Acetaminophen (APAP) overdose is a major cause of acute hepatic and renal injury, primarily driven by excessive formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), glutathione depletion, and oxidative/nitrosative stress. Opuntia ficus-indica (L.) Mill. (OFI) fruit contains antioxidant and anti-inflammatory phytochemicals that may protect against xenobiotic-induced organ damage. This study investigated the hepatoprotective and nephroprotective effects of an aqueous OFI fruit extract against APAP-induced toxicity in rats, with emphasis on oxidative stress mechanisms. Adult male rats were pre-treated with OFI extract (100, 200, or 400 mg/kg, orally) for seven days, followed by a single APAP dose (3 g/kg) on day eight. After 24 h, serum biomarkers of hepatic and renal function (ALT, AST, ALP, total bilirubin, total protein, CREA, BUN, Na⁺, K⁺) and tissue oxidative stress indices (CAT, SOD, NO, and MDA) were evaluated. APAP administration caused substantial elevations in serum ALT, AST, ALP, CREA, and BUN, together with decreased antioxidant enzyme activities and increased lipid peroxidation in liver and kidney tissues. Pre-treatment with OFI at 100 and 200 mg/kg markedly ameliorated these alterations, improving biochemical markers and restoring antioxidant defence. In contrast, the 400 mg/kg dose failed to provide significant protection and exacerbated some parameters, indicating a biphasic, dose-dependent response. These findings demonstrate that low and moderate doses of OFI fruit aqueous extract exert significant hepatoprotective and nephroprotective effects against APAP-induced oxidative injury, likely through enhancement of antioxidant defence and attenuation of oxidative and nitrosative stress.

Obesity is a chronic metabolic condition characterized by low-grade inflammation and oxidative imbalance and is strongly associated with impaired male reproductive function. This study investigated whether prebiotic–probiotic supplementation could prevent or attenuate high-fat diet (HFD)-induced metabolic inflammation-associated reproductive toxicity in male rats. Animals were assigned to four groups: normal diet (ND), HFD, HFD with concurrent prebiotic–probiotic supplementation from the onset of feeding (P-HFD), and HFD followed by supplementation initiated after 5 weeks (HFD-P). Evaluations included body and reproductive organ weights, sperm parameters, testicular histopathology, reproductive hormones, oxidative stress and inflammatory biomarkers, and gut microbiome composition. HFD feeding induced pronounced reproductive impairment, evidenced by reduced relative testicular weight, disrupted spermatogenesis, decreased LH levels, elevated TNF-α, a paradoxical increase in intratesticular testosterone despite reduced LH, and marked gut dysbiosis, characterized by shifts in microbial community structure along with reduced microbial diversity. Prebiotic–probiotic supplementation did not fully restore microbial richness or return the microbiota to an ND-like configuration; however, concurrent supplementation induced more pronounced taxonomic restructuring than delayed supplementation. While P-HFD did not show significant improvements in sperm parameters or LH, it exhibited clear histological preservation of testicular structure, reduced TNF-α, and partial normalization of testosterone, indicating attenuation of HFD-induced inflammation-associated testicular toxicity rather than complete functional recovery. In contrast, delayed supplementation produced no meaningful improvement in reproductive, hormonal, or microbiome-related outcomes and, in several respects, more pronounced testicular inflammation and structural degeneration than HFD alone. Collectively, these findings indicate that intervention timing is critical: concurrent administration conferred greater structural and anti-inflammatory protection against HFD-induced testicular damage, whereas delayed intervention was insufficient—or even counterproductive—once testicular injury was established. This timing-dependent response highlights the potential of microbiota-targeted strategies as supportive, timing-sensitive approaches for mitigating obesity-related male reproductive toxicity.

Levothyroxine, the synthetic form of thyroxine, is widely prescribed for hypothyroidism, including in men of reproductive age. While generally considered safe, its potential direct effects on male reproductive somatic cells remain poorly defined. This study investigated the in vitro reproductive toxicity of levothyroxine by evaluating its cytotoxic, oxidative, and genotoxic effects on murine TM3 Leydig and TM4 Sertoli cells. Cells were exposed to levothyroxine at 0.1-200 μM for 24 h. Cytotoxicity was assessed using MTT and neutral red uptake assays, intracellular ROS by DCFDA fluorescence, and DNA damage by alkaline comet assay. Levothyroxine significantly reduced cell viability in a concentration-dependent manner. Based on MTT results, the IC50 values were 121.22 μM for TM3 cells and 114.16 μM for TM4 cells, whereas neutral red uptake assays yielded IC50 values of 104.16 and 104.61 μM, respectively. ROS levels increased with dose but did not reach statistical significance. Comet assay results revealed mild, nonsignificant DNA damage in TM3 cells at 100 μM and a nonmonotonic pattern in TM4 cells, peaking at 1 μM. These findings reveal subtle, cell-type-specific responses to supraphysiological exposure to levothyroxine. Importantly, TM4 Sertoli cells exhibited slightly greater sensitivity than TM3 Leydig cells across assays, consistent with their critical role in supporting the seminiferous epithelium. Although direct clinical extrapolation is not possible, this represents the first comparative analysis of levothyroxine's effects on Leydig and Sertoli cells in vitro. In conclusion, levothyroxine induces modest, dose-dependent cytotoxicity and subtle oxidative/genotoxic alterations in testicular somatic cells, with Sertoli cells being more susceptible.

Background/Objectives: Asymptomatic carotid artery stenosis is usually detected by physicians in patients, coincidentally, during an ultrasound examination of the neck. Therefore, measurable biomarkers in blood are needed to define the presence and severity of atherosclerotic plaque in patients to identify and manage it. We hypothesized that biomarkers that indicate pathways related to the pathogenesis of atherosclerosis could be used to identify the presence and severity of atherosclerotic plaque. For this purpose, the levels of participants’ inflammatory and oxidative stress biomarkers were determined. Kynurenine/tryptophan and neopterin levels were measured as relatively new biomarkers of inflammation in this study. Methods: Our study included 57 patients diagnosed with asymptomatic carotid artery stenosis and 28 healthy volunteers. Blood kynurenine and tryptophan levels were measured with LCMS/MS. Blood catalase, total superoxide dismutase (t-SOD), glutathione peroxidase (GPx), malondialdehyde, and neopterin levels were measured using the ELISA assay method. Result: The kynurenine/tryptophan ratio reflecting IDO activity was higher in patients than in healthy volunteers. Decreased tryptophan levels and increased kynurenine and neopterin levels were observed in patients who underwent carotid endarterectomy. In patients, catalase, t-SOD, and malondialdehyde levels were higher, while GPx activity was lower. These differences were found to be more significant in patients who underwent carotid endarterectomy. Conclusions: Increased kynurenine/tryptophan ratio and neopterin levels in patients with asymptomatic carotid artery stenosis were associated with the inflammatory status of the patients. Oxidative stress and inflammatory biomarkers can be considered effective diagnostic and severity indicators for asymptomatic carotid artery stenosis.

Dünya genelinde ölümlerin başlıca nedeni olarak ifade edilen kardiyovasküler hastalıkların altında yatan etken genellikle aterosklerozdur. Ateroskleroz, intimal düşük yoğunluklu lipoprotein birikiminin artmasıyla başlayan ve endotel hücre geçirgenliğinin arttığı kronik inflamatuar bir durumdur. İnflamasyonun aterosklerotik olayların temel etkeni olduğu vurgulanmaktadır. Bilindiği gibi inflamasyon, vücudu enfeksiyonlara ve diğer hasarlara karşı koruyan ve iyileşmeyi destekleyen fizyolojik bir süreçtir. Ancak inflamatuar süreçler sırasında kalıcı immün reaksiyonlar aterosklerotik sürecin belirgin özelliğidir. Aterosklerozun farklı aşamalarında birçok immün sistem hücresi rol oynamaktadır. Son yıllarda, bazı amino asitlerin metabolik yolakları, inflamasyon ile ilgili mekanizmaların kontrolünde kritik kontrol noktaları olarak ifade edilmektedir. İmmün ve inflamatuar yanıtların önemli düzenleyicileri olarak ortaya çıkan farklı metabolik yolaklar arasında triptofan metabolizması kardiyovasküler hastalıkların gelişiminde önemli bir rol oynamaktadır. Triptofan metabolizmasındaki değişiklikler ile aterosklerozun başlangıcı ve ilerlemesi arasındaki ilişki tanımlanmıştır. Triptofan metabolizmasının %95'inden sorumlu olan metabolik yolak kinürenin yolağıdır. Sistemik düşük dereceli immün aracılıklı inflamasyon, interferon-γ gibi proinflamatuar sitokinlerin rol oynadığı aterosklerozda belirleyicidir. İnterferon-γ, indolamin 2,3-dioksijenaz enzimini yukarı regüle ederek triptofanın serum seviyelerini azaltmakta ve kinürenin yolağının metabolit düzeylerini artırmaktadır. Artan indolamin 2,3-dioksijenaz ekspresyonu ve aktivitesi ateroskleroz sürecini hızlandırmaktadır. Çalışmalar kinürenin yolağının biyoaktif metabolitlerinin ateroskleroz gelişiminde inflamatuar sürece katkısını göstermiştir. Bu derlemede, kinürenin yolağı temelinde triptofan metabolizması ve aterosklerotik kardiyovasküler hastalıklar arasındaki ilişkiye dikkat çeken güncel araştırmalar özetlemektedir.

In patients with coronavirus disease (COVID-19), a massive inflammatory response is a significant cause of morbidity and mortality. Inflammatory markers are prognostic indicators of disease severity and the ultimate clinical outcome. Several studies have demonstrated a correlation between serum levels of neopterin, which can be an immune system marker, disease severity, and poor outcomes in COVID-19 patients. Our study aimed to determine the diagnostic significance of neopterin in conjunction with routinely measured inflammatory markers in patients with severe COVID-19. Serum neopterin, C-reactive protein (CRP), albumin levels, and complete blood count were determined in 39 patients with severe COVID-19 and 30 healthy individuals. Demographic characteristics, serum neopterin levels, and other laboratory data were compared between patients and healthy volunteers and statistically analyzed. High neopterin levels were observed in patients with severe COVID-19 compared to healthy volunteers. Furthermore, albumin levels were decreased, while CRP levels were increased in patients, statistically significantly. Also, positive correlations were shown between serum neopterin levels and serum CRP levels, while negative correlations were shown between serum neopterin levels and serum albumin levels. Systemic inflammation markers, CRP/albumin ratio, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio were significantly higher, while lymphocyte/monocyte ratio was also significantly lower in patients with severe COVID-19 than in healthy volunteers. However, serum neopterin levels were not linked to the CRP/albumin ratio, the neutrophil/lymphocyte ratio, or the platelet/lymphocyte ratio. On the other hand, they were linked negatively to the lymphocyte/monocyte ratio. Our findings highlight the association between high neopterin levels and patients with severe COVID-19. Neopterin is correlated with traditional inflammatory biomarkers and may indicate general immune and inflammatory activation in patients with severe COVID-19.

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.

In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new compounds containing thiazolylhydrazone groups were synthesized. The structures of the obtained compounds were elucidated by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) methods. The inhibitory effects of the final compounds on MAO enzymes were investigated by means of in vitro methods. In addition to enzyme inhibition studies, enzyme kinetic studies of compounds with high inhibitory activity were examined, and their effects on substrate-enzyme relations were investigated. Additionaly, cytotoxicity tests were carried out to determine the toxicities of the selected compounds, and the compounds were found to be nontoxic. The interactions of the active compound with the active site of the enzyme were characterized by in silico methods.

Asymptomatic carotid artery stenosis is usually detected by physicians in patients, coincidentally, during an ultrasound examination of the neck. Therefore, measurable biomarkers in blood are needed to define the presence and severity of atherosclerotic plaque in patients to identify and manage it. We hypothesized that biomarkers that indicate pathways related to the pathogenesis of atherosclerosis could be used to identify the presence and severity of plaque in patients. For this purpose, we determined the levels of participants' inflammatory and oxidative stress biomarkers. On the other hand, kynurenine/tryptophan and neopterin levels were measured as relatively new biomarkers of inflammation in this study. Our study included 57 patients diagnosed with asymptomatic carotid artery stenosis and 28 healthy volunteers. Blood kynurenine and tryptophan levels were measured with LCMS/MS. The ELISA assay was used to measure blood catalase, total superoxide dismutase, glutathione peroxidase, malondialdehyde, and neopterin levels. According to our results, while the kynurenine and neopterin levels were higher, the tryptophan levels were lower in patients. Furthermore, the kynurenine to tryptophan ratio, which reflects IDO-1 activity, was higher in patients. On the other hand, catalase, total superoxide dismutase, and malondialdehyde levels were higher, while the glutathione peroxidase activity was lower in patients. Increasing the kynurenine/tryptophan ratio and neopterin level in patients with asymptomatic carotid artery stenosis have been associated with an inflammatory state. The oxidative stress and inflammatory response biomarkers may be an effective diagnostic and prognostic tool for asymptomatic carotid artery stenosis.

Within the scope of this study, the design and synthesis of new triazole and oxadiazole compounds containing piperidine ring were carried out. The anticancer effects of the obtained compounds have been tested on lung and colon cancers. Especially in colon cancer, compounds 4Id, 4Ie, 4If and 4Ih exhibited significant activity profiles. Compounds 4Id, 4Ie, 4If and 4Ih showed activity against HT-29 cell line with IC50=19.238±0.652 μM, 14.861±0.409 μM, 20.876±0.374 μM and 16.132±0.787 μM, respectively. Compound 4Ie has an IC50 value greater than 100 μM against healthy cells (NIH3T3). While this compound (4Ie) effectively eliminates colon cancer cells, it exhibits a lower tendency to harm healthy cells. Since the importance of VEGFR-2 inhibition in colon cancer, the active compounds were evaluated by means of in vitro enzyme inhibition test. Compounds 4Id, 4Ie, 4If and 4Ih showed activity against VEGFR-2 enzyme with IC50=0.105±0.002 μM; 0.055±0.003 μM; 1.096±0.005 μM; 0.159±0.002 μM; 0.039±0.001 μM respectively. As a result of molecular docking and dynamics studies, it is seen that the stability of all compounds is excellent. However, especially compound 4Ie exhibited a strong inhibitory potential with its continuous interactions with Cys919, Glu885 and Asp1046. Dynamic investigations reveal the enzyme's stability within the active site, with particular emphasis on the cyano group's capability to engage with Cys919, rendering this compound the most potent derivative.

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.

The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the in vitro fluorometric method. Additionally, amyloid beta (Aβ)-aggregation inhibitory effects of active compounds were evaluated by means of an in vitro kit-based method. The biological evaluation showed that compounds 4a, 4d, 4f, 4h, 4k and 4m displayed significant activity against AChE and MAO-B enzymes. Compound 4f displayed inhibitory activity against AChE and MAO-B enzyme with IC50 values of 23.4 ± 1.1 nM and 40.3 ± 1.7 nM, respectively. It has been revealed that compound 4f may have the potential to inhibit AChE and MAO-B enzymes, as well as the ability to prevent the formation of beta amyloid plaques accumulated in the brains of patients suffering from AD. In silico studies also support the obtained biological activity findings. Compound 4f provided strong interactions with the active site of both enzymes. In particular, the interaction of compound 4f with flavin adenine dinucleotide (FAD) in the MAO-B enzyme active site is a promising and exciting finding.

A novel series of hydrazone derivatives were designed and synthesized. Their structures were characterized by IR, 1H NMR, 13C NMR and HR-MS spectroscopic methods. The newly synthesized compounds were evaluated for their inhibitory activity against monoamine oxidase enzymes (MAO-A and MAO-B). Compounds 2a, 2k, 4a and 4i showed significant inhibitory activity against MAO-A, with IC50 value in the range of 0.084-0.207 mu M compared to reference drug moclobemide (IC50 value = 6.061 mu M). These compounds (2a, 2k, 4a and 4i) were exposed to cytotoxicity tests to establish their preliminary toxicological profiles and were found to be noncytotoxic. Moreover, the most effective compound 4i was evaluated using enzyme kinetics and docking studies to elucidate the plausible mechanisms of inhibition of MAO-A. According to enzyme kinetic studies, compound 4i was a reversible and competitive inhibitor with similar inhibition features as the substrates. Also, it was seen that this compound was settled down very properly at the active site of MAO-A enzyme by doing important interactions owing to the docking studies. Finally, ADME predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. According to calculated ADME predictions, all parameters of the compounds were within the standard ranges in terms of "Rule of Five" and "Rule of Three" and it was detected that the synthesized compounds (2a-4i) have good and promising pharmacokinetic profiles.

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress.

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.