Search Results (21)

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species and the body’s antioxidant defenses, plays an important role in the pathogenesis of various health conditions, including cancer and neurological disorders. For example, excessive ROS can lead to mutations, genomic instability, and uncontrolled cell proliferation in cancer. In neurological disorders, oxidative stress contributes to neuronal damage, inflammation, and the progression of diseases such as Alzheimer’s and Parkinson’s diseases. Adenosine, a nucleoside involved in energy transfer and signal transduction, is crucial to maintaining cellular homeostasis. Its role extends to modulating oxidative stress. Adenosine receptors are implicated in various physiological processes and in the pathophysiology of diseases. The interplay between oxidative stress and adenosine signaling is complex and critical. Adenosine can modulate oxidative stress responses, providing therapeutic potential for conditions where oxidative stress is a key player. Understanding this connection opens up avenues for novel therapeutic strategies targeting adenosine receptors to mitigate oxidative damage. Full article

Major depressive disorder (MDD), a prevalent mental illness, is marked by a complex mixture of biological factors. This review focuses on the roles of oxidative stress, tryptophan-serotonin metabolism, brain-derived neurotrophic factor (BDNF), and the hypothalamic–pituitary–adrenal (HPA) axis in MDD’s pathophysiology. Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants, is closely linked to MDD’s neurobiological changes. The tryptophan (TRP)-/serotonin (5-HT) metabolic pathway is also known to be crucial in mood regulation, with its dysregulation being a central aspect of MDD. Additionally, BDNF, key for neuronal growth and plasticity, often shows alterations in MDD patients, supporting its role in the disorder’s progression. Furthermore, the HPA axis, which manages stress response, is frequently disrupted in MDD, further contributing to its complex pathology. In addition to exploring these biological mechanisms, this review also explores the pharmacotherapy of MDD, including new advances. These advancements in treatment strategies are crucial for managing MDD effectively. Understanding these mechanisms and the latest pharmacological interventions is essential for developing more effective treatments for MDD. Full article

Indole-3-acetonitrile, a compound produced by bacteria and plants as a defense and survival signal in response to attacks, has been recently discovered as a metabolite produced by human cancer cells. This discovery suggests a potential association between IAN and cancer progression in patients. Consequently, the aim of this work was to study the effects of IAN on a specific cancer cell line, SH-SY5Y, and elucidate its connection to the serotonin and dopamine pathways by examining the precursors of these neurotransmitters. To achieve this, a cellular viability assay was conducted, along with a morphological evaluation of the cells under both normal and stress conditions. Our results demonstrated that for the highest concentrations in our study, IAN was able to reduce the cellular viability of the cells. Furthermore, when IAN was combined with the amino acids that originate the neurotransmitters, it was possible to observe that in both combinations there was a decrease in the viability of the cells. Thus, IAN may in fact have some influence on both the serotonin and dopamine pathways since changes in cell viability were observed when it was added together with the amino acids. This preliminary study indicates the presence of an interaction between IAN and neuroblastoma cells that justifies further exploration and study. Full article

High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood–brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1. Full article

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a significant role in the survival and development of neurons, being involved in several diseases such as Alzheimer’s disease and major depression disorder. The association between BDNF and major depressive disorder is the subject of extensive research. Indeed, numerous studies indicate that decreased levels of BDNF are linked to an increased occurrence of depressive symptoms, neuronal loss, and cortical atrophy. Moreover, it has been observed that antidepressive therapy can help restore BDNF levels. In this review, we will focus on the role of BDNF in major depression disorder serotonergic imbalance and associated stress conditions, particularly hypothalamic–pituitary–adrenal (HPA) axis dysregulation and oxidative stress. All of these features are highly connected to BDNF signaling pathways in the context of this disease, and exploring this topic will aim to advance our understanding of the disorder, improve diagnostic and treatment approaches, and potentially identify new therapeutic targets to alleviate the heavy burden of depression on society. Full article

Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment. Atorvastatin is a type of statin with several potentialities as an anti-cancer agent, supported by several studies. Our study aimed to explore the effect of this drug in SH-SY5Y human neuroblastoma cells. Additionally, we also aimed to understand how this drug acts under hypoxia and the inhibition of hypoxia-inducible factor-1 (HIF-1). For that purpose, we assessed cellular viability/morphology after exposure to different concentrations of atorvastatin, with or without chemically induced hypoxia with chloride cobalt (CoCl₂) and with or without echinomycin (HIF-1α inhibitor). Our results supported the cytotoxic effects of atorvastatin. Additionally, we also revealed that besides these effects, under hypoxia, this drug induced proliferation of the neuroblastoma cells, supporting the importance of different stimuli and environment on the effect of drugs on cancer cells. Full article

Chemotherapy still plays a central role in the treatment of cancer. However, it is often accompanied by off-target effects that result in severe side-effects and development of drug resistance. The aim of this work was to study the efficacy of different repurposed drugs on the viability of MCF-7 and SH-SY5Y breast cancer and neuroblastoma cells, respectively. In addition, combinations of these repurposed drugs with a classical chemotherapeutic drug (doxorubicin) were also carried out. The cytotoxic effects of the repurposed drugs were evaluated individually and in combination in both cancer cell lines, assessed by MTT assays and morphological evaluation of the cells. The results demonstrated that atorvastatin reduced the viability of both cell lines. However, nitrofurantoin was able to induce cytotoxic effects in MCF-7 cells, but not in SH-SY5Y cells. The combinations of the repurposed drugs with doxorubicin induced a higher inhibition on cell viability than the repurposed drugs individually. The combination of the two repurposed drugs demonstrated that they potentiate each other. Synergism studies revealed that the combination of doxorubicin with the two repurposed drugs was more effective in SH-SY5Y cells, compared to MCF-7 cells. Taken together, our preliminary study highlights the potential use of atorvastatin and nitrofurantoin in the context of breast cancer and neuroblastoma. Full article

L-tryptophan (L-Trp) is an important amino acid in several physiological mechanisms, being metabolized into two important pathways: the kynurenine and the serotonin (5-HT) pathways. It is important in processes such as mood and stress response, the 5-HT pathway begins with the conversion of L-Trp to 5-hydroxytryptophan (5-HTP), that is metabolized into 5-HT, converted to melatonin or to 5-hydroxyindoleacetic acid (5-HIAA). Disturbances in this pathway are reported to be connected with oxidative stress and glucocorticoid-induced stress, are important to explore. Thus, our study aimed to understand the role of hydrogen peroxide (H₂O₂) and corticosterone (CORT)-induced stress on the serotonergic pathway of L-Trp metabolism, and on SH-SY5Y cells, focusing on the study of L-Trp, 5-HTP, 5-HT, and 5-HIAA in combination with H₂O₂ or CORT. We evaluated the effect of these combinations on cellular viability, morphology, and on the extracellular levels of the metabolites. The data obtained highlighted the different ways that stress induction led to different extracellular medium concentration of the studied metabolites. These distinct chemical transformations did not lead to differences in cell morphology/viability. Additionally, serotonin may be the most sensitive metabolite to the exposure to the different stress inducers, being more promissory to study conditions associated with cellular stress. Full article

Depression is a prevalent, complex, and highly debilitating disease. The full comprehension of this disease is still a global challenge. Indeed, relapse, recurrency, and therapeutic resistance are serious challenges in the fight against depression. Nevertheless, abnormal functioning of the stress response, inflammatory processes, neurotransmission, neurogenesis, and synaptic plasticity are known to underlie the pathophysiology of this mental disorder. The role of oxidative stress in disease and, particularly, in depression is widely recognized, being important for both its onset and development. Indeed, excessive generation of reactive oxygen species and lack of efficient antioxidant response trigger processes such as inflammation, neurodegeneration, and neuronal death. Keeping in mind the importance of a detailed study about cellular and molecular mechanisms that are present in depression, this review focuses on the link between oxidative stress and the stress response, neuroinflammation, serotonergic pathways, neurogenesis, and synaptic plasticity’s imbalances present in depression. The study of these mechanisms is important to lead to a new era of treatment and knowledge about this highly complex disease. Full article

Hypoxia–ischemia encephalopathy results from the interruption of oxygen delivery and blood flow to the brain. In the developing brain, it can lead to a brain injury, which is associated with high mortality rates and comorbidities. The hippocampus is one of the brain regions that may be affected by hypoxia–ischemia with consequences on cognition. Unfortunately, clinically approved therapeutics are still scarce and limited. Therefore, in this study, we aimed to test three repurposed drugs with good pharmacological properties to evaluate if they can revert, or at least attenuate, the deleterious effects of hypoxia–ischemia in an in vitro model. Edaravone, perampanel, and metformin are used for the treatment of stroke and amyotrophic lateral sclerosis, some forms of epileptic status, and diabetes type 2, respectively. Through cell viability assays, morphology analysis, and detection of reactive oxygen species (ROS) production, in two different cell lines (HT-22 and SH-SY5Y), we found that edaravone and low concentrations of perampanel are able to attenuate cell damage induced by hypoxia and oxygen-glucose deprivation. Metformin did not attenuate hypoxic-induced events, at least in the initial phase. Among these repurposed drugs, edaravone emerged as the most efficient in the attenuation of events induced by hypoxia–ischemia, and the safest, since it did not exhibit significant cytotoxicity, even in high concentrations, and induced a decrease in ROS. Our results also reinforce the view that ROS and overexcitation play an important role in the pathophysiology of hypoxia–ischemia brain injury. Full article

Depression is a disease with several molecular mechanisms involved, such as problems in the serotonergic pathway. This disease is very complex and prevalent, and thus important to deeply study and aim to overcome high rates of relapse and therapeutic failure. In this study, two cellular lines were used (HT-22 and SH-SY5Y cells) to gain insight about the role of the serotonin type 3 (5-HT3) receptor in cellular stress induced by hydrogen peroxide and/or corticosterone. In research, these compounds are known to mimic the high levels of oxidative stress and dysfunction of the hypothalamus–hypophysis–adrenal axis by the action of glucocorticoids, usually present in depressed individuals. The receptor 5-HT3 is also known to be involved in depression, previously demonstrated in studies that highlight the role of these receptors as promising targets for antidepressant therapy. Indeed, the drugs used in this work (mirtazapine, scopolamine, and lamotrigine) interact with this serotonergic receptor. Thus, by using cell morphology, cell viability (neutral red and MTT), and HPLC assays, this work aimed to understand the role of these drugs in the stress induced by H₂O₂/corticosterone to HT-22 and SH-SY5Y cell lines. We concluded that the antagonism of the 5-HT3 receptor by these drugs may be important in the attenuation of H₂O₂-induced oxidative stress to the cells, but not in the corticosterone-induced stress. Full article

Depression is a prevalent and debilitating disease worldwide. This pathology is very complex and the lack of efficient therapeutic modalities, as well as the high rates of relapse, makes the study and treatment of depression a global healthcare challenge. Thus, an intense investigation of this disease is crucial and urgent. In this study, we focused on hydrogen peroxide and corticosterone-induced stress on SH-SY5Y and HT-22 cells. Additionally, we aimed to study the potential attenuation of these induced stress with the exposure of both cells to mirtazapine and L-tryptophan, focusing on cell viability assays (MTT and Neutral Red) and reactive oxygen species production assays (DCFDA fluorescence). Taken together, our results indicate that mirtazapine and L-tryptophan counteract the cellular stress induced by hydrogen peroxide but not by corticosterone, revealing a potential role of these agents on oxidative stress relief, highlighting the role of serotonergic pathways in the oxidative stress present in depressed individuals. This study allows the investigation of depression using cellular models, enabling the screening of compounds that may have potential to be used in the treatment of depression by acting on cellular mechanisms such as oxidative stress protection. Full article

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways. Full article

Depression is a very prevalent and complex disease. This condition is associated with a high rate of relapse, making its treatment a challenge. Thus, an intensive investigation of this disease and its treatment is necessary. In this work, through cell viability assays (MTT and neutral red assays) and alkaline comet assays, we aimed to test the induction of stress in human SH-SY5Y cells through the application of hydrocortisone and hydrogen peroxide and to test the reversal or attenuation of this stress through the application of mirtazapine to the cells. Our results demonstrated that hydrogen peroxide, and not hydrocortisone, can induce cellular stress, as evidenced by DNA damage and a global cellular viability reduction, which were alleviated by the antidepressant mirtazapine. The establishment of a cellular model of depression through stress induction is important to study new possibilities of treatment of this disease using cell cultures. Full article

Protein aggregation is a common characteristic of several human diseases such as Alzheimer’s disease. Recent evidence has indicated that the aggregation of peptides such as p53 is also marked in cancer cells. The aim of this study was to correlate Thioflavin T (ThT) data with different cellular viability assays (Neutral Red and MTT) in SH-SY5Y neuroblastoma cells and HT-29 colon cancer cells treated with doxorubicin, a classical antineoplastic agent. We also studied the effects of the well-known peptide Aβ42 on the aggregation process in these cells. Our data suggest that both cancer cell lines are responsive to doxorubicin and formed aggregates, highlighting a relationship between ThT and cellular viability methodologies. We observed that lower values of cell viability corresponded with pronounced aggregation. Thus, these results indicated that the ThT methodology used in cells may complement the cell viability assays. In addition, this methodology may be of interest to evaluate the role of protein aggregation in other cancer cells. Full article