Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole ... more Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR.
Clinical Background: Mental disorders, especially depression, are associated with several comorbi... more Clinical Background: Mental disorders, especially depression, are associated with several comorbidities in the kidneys. Depression is the psychiatric disorder that mostly affects individuals with chronic kidney disease (CKD) and end-stage kidney disease. Epidemiology: The mainly prescribed drugs involved in overdose cases are opioids, benzodiazepines, and antidepressants. Antidepressants are the main psychiatric drugs that lead to kidney injury, mainly the second-generation ones. However, the prevalence of depression in dialysis patients varies from 22.8 to 39.3%. Therefore, psychiatric patients have 1.5-3 times more hospitalization compared to patients having only CKD. Challenges: Randomized clinical studies should be encouraged. Studies have shown an association between depression and progression of kidney disease. The mechanisms are not completely clear, but changes on neurotransmitter release and endocrine functions appear to be related to it. Additionally, the use of antidepressant and other psychoactive drugs can induce kidney injury. Hyponatremia induced by second-generation antidepressant drugs is an important feature and can be a risk factor for elderly or patients with comorbidities such as cerebral edema, brain damage or coma. Besides this class, drugs used for anxiety and bipolar disorders or sympathomimetic drugs of abuse can trigger acute kidney injury, possibly due to endothelial dysfunction and thromboembolic and ischemic events. Prevention and Treatment: The early detection of renal impairment and the prescription of nephroprotective strategies has been a clinical challenge. Some studies aim to describe the biochemical mechanisms involved and develop clinical management strategies for these patients. This chapter brings attention to this topic, discussing the major mechanisms and clinical features of kidney injury associated with mental illness, and the most relevant clinical strategies.
Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxie... more Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxiety and seizures involve the use of benzodiazepines, a class of drugs that have many adverse effects such as decreased motor coordination, drowsiness, and sedation. Thus, new types of drugs with minimal side effects are of immediate requirement. Chalcones comprise a class of compounds with important therapeutic potential and have recently been investigated for their potential as anxiolytic and anticonvulsant agents. Therefore, this study aimed to evaluate the anxiolytic and anticonvulsant effects of the synthetic chalcone (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one (FURCHAL) using adult zebrafish as an animal model. Anxiolytic potential was assessed using the light/dark test and the anticonvulsant effect in 3-stage pentylenetetrazol (PTZ)-induced seizure tests. The mechanisms of the anxiolytic effect were analyzed using γ-aminobutyric acid (GABA) and the serotoninergic system. The anxiolytic effect of FURCHAL was verified by a reduction in fish locomotion, similar to diazepam (DZP), which may involve the GABAA receptor, as there was no reversal in the anxiolytic behavior of animals treated with FURCHAL by serotonergic antagonists. In addition, pretreatment with flumazenil blocked the anticonvulsant effect of FURCHAL and DZP at all three stages, indicating that FURCHAL also has anticonvulsant effects and that the presence of the α,β unsaturated aromatic system and heterocyclic moiety in FURCHAL provided greater affinity for the GABAA receptors. Molecular docking revealed that the interactions involved in the formation of the protein-binding complex FURCHAL-GABAA are formed by three H-bonds involving the oxygen atoms of FURCHAL, and notably, complexes operated in the same region of the DZP site. Thus, this study adds new evidence and highlights that FURCHAL can potentially be used to develop compounds with anxiolytic and anticonvulsant properties.
Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole ... more Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR.
Clinical Background: Mental disorders, especially depression, are associated with several comorbi... more Clinical Background: Mental disorders, especially depression, are associated with several comorbidities in the kidneys. Depression is the psychiatric disorder that mostly affects individuals with chronic kidney disease (CKD) and end-stage kidney disease. Epidemiology: The mainly prescribed drugs involved in overdose cases are opioids, benzodiazepines, and antidepressants. Antidepressants are the main psychiatric drugs that lead to kidney injury, mainly the second-generation ones. However, the prevalence of depression in dialysis patients varies from 22.8 to 39.3%. Therefore, psychiatric patients have 1.5-3 times more hospitalization compared to patients having only CKD. Challenges: Randomized clinical studies should be encouraged. Studies have shown an association between depression and progression of kidney disease. The mechanisms are not completely clear, but changes on neurotransmitter release and endocrine functions appear to be related to it. Additionally, the use of antidepressant and other psychoactive drugs can induce kidney injury. Hyponatremia induced by second-generation antidepressant drugs is an important feature and can be a risk factor for elderly or patients with comorbidities such as cerebral edema, brain damage or coma. Besides this class, drugs used for anxiety and bipolar disorders or sympathomimetic drugs of abuse can trigger acute kidney injury, possibly due to endothelial dysfunction and thromboembolic and ischemic events. Prevention and Treatment: The early detection of renal impairment and the prescription of nephroprotective strategies has been a clinical challenge. Some studies aim to describe the biochemical mechanisms involved and develop clinical management strategies for these patients. This chapter brings attention to this topic, discussing the major mechanisms and clinical features of kidney injury associated with mental illness, and the most relevant clinical strategies.
Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxie... more Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxiety and seizures involve the use of benzodiazepines, a class of drugs that have many adverse effects such as decreased motor coordination, drowsiness, and sedation. Thus, new types of drugs with minimal side effects are of immediate requirement. Chalcones comprise a class of compounds with important therapeutic potential and have recently been investigated for their potential as anxiolytic and anticonvulsant agents. Therefore, this study aimed to evaluate the anxiolytic and anticonvulsant effects of the synthetic chalcone (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one (FURCHAL) using adult zebrafish as an animal model. Anxiolytic potential was assessed using the light/dark test and the anticonvulsant effect in 3-stage pentylenetetrazol (PTZ)-induced seizure tests. The mechanisms of the anxiolytic effect were analyzed using γ-aminobutyric acid (GABA) and the serotoninergic system. The anxiolytic effect of FURCHAL was verified by a reduction in fish locomotion, similar to diazepam (DZP), which may involve the GABAA receptor, as there was no reversal in the anxiolytic behavior of animals treated with FURCHAL by serotonergic antagonists. In addition, pretreatment with flumazenil blocked the anticonvulsant effect of FURCHAL and DZP at all three stages, indicating that FURCHAL also has anticonvulsant effects and that the presence of the α,β unsaturated aromatic system and heterocyclic moiety in FURCHAL provided greater affinity for the GABAA receptors. Molecular docking revealed that the interactions involved in the formation of the protein-binding complex FURCHAL-GABAA are formed by three H-bonds involving the oxygen atoms of FURCHAL, and notably, complexes operated in the same region of the DZP site. Thus, this study adds new evidence and highlights that FURCHAL can potentially be used to develop compounds with anxiolytic and anticonvulsant properties.
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