ABSTRACT
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.
Subject(s)
Biomarkers , C-Reactive Protein , COVID-19 , Neopterin , Severity of Illness Index , Humans , Neopterin/blood , COVID-19/blood , COVID-19/immunology , Male , Female , Middle Aged , Biomarkers/blood , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Adult , SARS-CoV-2 , Aged , Serum Albumin/analysisABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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 (Aß)-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.
ABSTRACT
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.
Subject(s)
Anticonvulsants/adverse effects , Endocrine Disruptors/adverse effects , Hormones/metabolism , Hypothalamo-Hypophyseal System/drug effects , Infertility, Male/chemically induced , Reproduction/drug effects , Testis/drug effects , Animals , Gonadal Steroid Hormones/metabolism , Gonadotropin-Releasing Hormone/metabolism , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Infertility, Male/metabolism , Infertility, Male/physiopathology , Male , Risk Assessment , Risk Factors , Spermatogenesis/drug effects , Spermatozoa/drug effects , Spermatozoa/metabolism , Spermatozoa/pathology , Testis/metabolism , Testis/physiopathologyABSTRACT
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.
Subject(s)
Semen , Testis , Animals , Catalase/metabolism , Male , Malondialdehyde/metabolism , Oxidative Stress , Quetiapine Fumarate/metabolism , Quetiapine Fumarate/toxicity , Rats , Semen/metabolism , Sperm Count , Sperm Motility , Spermatozoa , Superoxide Dismutase/metabolism , Testosterone/metabolismABSTRACT
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 µM compared to reference drug moclobemide (IC50 value = 6.061 µM). These compounds (2a, 2k, 4a and 4i) were exposed to cytotoxicity tests to establish their preliminary toxicological profiles and were found to be non-cytotoxic. 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.
Subject(s)
Hydrazones/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/metabolism , Animals , Enzyme Assays , Humans , Hydrazones/metabolism , Hydrazones/pharmacokinetics , Hydrazones/toxicity , Kinetics , Mice , Molecular Docking Simulation , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/pharmacokinetics , Monoamine Oxidase Inhibitors/toxicity , NIH 3T3 Cells , Protein BindingABSTRACT
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.
Subject(s)
Antipsychotic Agents/toxicity , Olanzapine/toxicity , Administration, Oral , Animals , DNA Damage/drug effects , Follicle Stimulating Hormone/blood , Luteinizing Hormone/blood , Male , Oxidative Stress/drug effects , Rats, Wistar , Sperm Count , Sperm Motility/drug effects , Spermatozoa/abnormalities , Spermatozoa/drug effects , Testis/drug effects , Testis/pathology , Testosterone/bloodABSTRACT
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.
Subject(s)
Leydig Cells , Risperidone , Animals , Male , Oxidative Stress , Rats , Reproduction , Risperidone/metabolism , Risperidone/toxicity , Spermatozoa , Testis/metabolism , Testosterone/metabolismABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzoxazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Cell Proliferation/drug effects , DNA, Neoplasm/antagonists & inhibitors , DNA, Neoplasm/biosynthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.
Subject(s)
Drug Design , Hydrazines/chemistry , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Chemistry Techniques, Synthetic , Computer Simulation , Kinetics , Mice , Molecular Docking Simulation , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/toxicity , NIH 3T3 Cells , Piperazines/metabolism , Piperazines/toxicity , Protein ConformationABSTRACT
Adverse effects of drugs on male reproductive system can be categorized as pre-testicular, testicular, and post-testicular. Pre-testicular adverse effects disrupt the hypothalamic-pituitary-gonadal (HPG) axis, generally by interfering with endocrine function. It is known that the HPG axis has roles in the maintenance of spermatogenesis and sexual function. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) which enters the hypophyseal portal system to stimulate the anterior pituitary. The anterior pituitary secretes gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which are vital for spermatogenesis, into the blood. The FSH stimulates the Sertoli cells for the production of regulatory molecules and nutrients needed for the maintenance of spermatogenesis, while the LH stimulates the Leydig cells to produce and secrete testosterone. Many neurotransmitters influence the hypothalamic-pituitary regulation, consequently the HPG axis, and can consequently affect spermatogenesis and sexual function. Psychotropic drugs including antipsychotics, antidepressants, and mood stabilizers that all commonly modulate dopamine, serotonin, and GABA, can affect male spermatogenesis and sexual function by impairment of the hypothalamic-pituitary regulation, act like endocrine-disrupting chemicals. Otherwise, studies have shown the relationship between decreased sperm quality and psychotropic drugs treatment. Therefore, it is important to investigate the adverse reproductive effects of psychotropic drugs which are frequently used during reproductive ages in males and to determine the role of the hypothalamic-pituitary regulation axis on possible pathologies.
Subject(s)
Endocrine Disruptors/adverse effects , Psychotropic Drugs/adverse effects , Reproduction/drug effects , Animals , Endocrine Disruptors/pharmacology , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamus/drug effects , Male , Pituitary Gland/drug effects , Psychotropic Drugs/pharmacology , Spermatogenesis/drug effects , Spermatozoa/drug effectsABSTRACT
In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC50 = 0.032 ± 0.042 µM, compared to IC50 = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a-5p) were calculated by QikProp 4.8 software.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aromatase Inhibitors/chemical synthesis , Benzimidazoles/chemical synthesis , Brain Neoplasms/enzymology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Brain Neoplasms/drug therapy , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Letrozole/chemistry , Letrozole/pharmacology , MCF-7 Cells , Molecular Docking SimulationABSTRACT
New sulfonamide-hydrazone derivatives (3a-3n) were synthesized to evaluate their inhibitory effects on purified human carbonic anhydrase (hCA) I and II. The inhibition profiles of the synthesized compounds on hCA I-II isoenzyme were investigated by comparing their IC50 and Ki values. Acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide, AZA) has also been used as a standard inhibitor. The compound 3e demonstrated the best hCA I inhibitory effect with a Ki value of 0.1676⯱â¯0.017⯵M. Besides, the compound 3m showed the best hCA II inhibitory effect with a Ki value of 0.2880⯱â¯0.080⯵M. Cytotoxicity of the compounds 3e and 3m toward NIH/3T3 mouse embryonic fibroblast cell line was observed and the compounds were found to be non-cytotoxic. Molecular docking studies were performed to investigate the interaction types between active compounds and hCA enzymes. Pharmacokinetic profiles of compounds were assessed by theoretical ADME predictions. As a result of this study a novel and potent class of CA inhibitors were identified with a good activity potential.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/pharmacology , Animals , Humans , Mice , Molecular Docking Simulation , Molecular Structure , NIH 3T3 Cells , Structure-Activity RelationshipABSTRACT
New twenty compounds bearing thiazole ring (3a-3t) were designed and synthesized as monoamine oxidase (MAO) inhibitors. The fluorometric enzyme inhibition assay was used to determine the biological effects of synthesized compounds. Most of them showed remarkable inhibitory activity against both MAO-A and MAO-B. By comparing their IC50 values, it can be seen that active derivatives displayed generally selectivity on MAO-B enzyme. Compounds 3j and 3t, which bear dihydroxy moiety at the 3rd and 4th position of phenyl ring, were the most active derivatives in the series against both isoenzymes. Compounds 3j and 3t showed significant inhibition profile on MAO-A with the IC50 values of 0.134⯱â¯0.004⯵M and 0.123⯱â¯0.005⯵M, respectively, while they performed selectivity against MAO-B with the IC50 values of 0.027⯱â¯0.001⯵M and 0.025⯱â¯0.001⯵M, respectively. Also, docking studies about these compounds were carried out to evaluate their binding modes on the active regions of MAO-A and MAO-B.
Subject(s)
Monoamine Oxidase Inhibitors/pharmacokinetics , Thiazoles/pharmacokinetics , Animals , Catalytic Domain , Dogs , Humans , Madin Darby Canine Kidney Cells , Mice , Molecular Docking Simulation , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/metabolism , NIH 3T3 Cells , Protein Binding , Thiazoles/chemical synthesis , Thiazoles/metabolismABSTRACT
[This corrects the article DOI: 10.1155/2018/7196142.].
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Genitalia, Male/drug effects , Oxidative Stress/drug effects , Sperm Motility/drug effects , Testis/drug effects , Trazodone/adverse effects , Adult , Animals , Humans , Male , Middle Aged , Rats , Rats, Sprague-Dawley , Young AdultABSTRACT
1,3-Oxazolidine-2-one is an important heterocyclic ring participating in the chemical structure of many drugs. In this research, 22 new amide/sulfonamide/thiourea derivatives (1-22) were obtained by the reaction of (S)-4-(4-aminobenzyl)-2(1H)-1,3-oxazolidinone with 4-substituted benzoyl chlorides, 4-substituted benzene sulfonyl chlorides, and 4-substituted phenyl isothiocyanates. The structures of all synthesized compounds were clarified by FT-IR, NMR, and mass spectroscopic and elemental analysis techniques. The synthesized compounds were screened for their antimicrobial activity. Antimicrobial susceptibility and cellular physiology were evaluated using the microbroth dilution assay and the flow cytometry method. As a result, it was determined that compound 16 displayed better antimicrobial activity than chloramphenicol against Gram-positive bacteria, especially Staphylococcus aureus. In order to understand the mechanism of effect of the compounds on the cell membrane, fluorescence microscopy was used. Cell membrane damage of the Gram positive bacteria treated with compound 16 was observed as a result of intense staining with propidium iodide. In addition, genotoxicity, cytotoxicity, and absorption, distribution, metabolism, and excretion (ADME) parameters of compound 16 were examined and it was found as non-mutagenic and non-cytotoxic at the concentration at which it showed antimicrobial activity. According to the calculated ADME parameters and drug likeness scores, the compounds can be good drug candidates, especially compound 16.
Subject(s)
Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Sulfonamides/pharmacology , Thiourea/pharmacology , Amides/chemistry , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Membrane/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Gram-Positive Bacteria/cytology , Male , Mice , Microbial Sensitivity Tests , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Microsomes, Liver/microbiology , Molecular Structure , NIH 3T3 Cells , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Rats , Rats, Sprague-Dawley , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Structure-Activity Relationship , Sulfonamides/chemistry , Thiourea/chemistryABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD.