Sulforaphane Improves Redox Homeostasis and Right Ventricular Contractility in a Model of Pulmonary Hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), imposing overload on the right ventricle (RV) and imbalance of the redox state. Our study investigated the influence of treatment with sulforaphane (SFN), found in cruciferous vegetables, on RV remodeling and redox homeostasis in monocrotaline (MCT)-induced PAH. Male Wistar rats were separated into 4 groups: control (CTR); CTR + SFN; MCT; and MCT + SFN. PAH induction was implemented by a single dose of MCT (60 mg/kg intraperitoneally). Treatment with SFN (2.5 mg/kg/day intraperitoneally) started on the seventh day after the MCT injection and persisted for 2 weeks. After 21 days of PAH induction, echocardiographic, hemodynamic, and oxidative stress evaluation was performed. The MCT group showed an increase in RV hypertrophy, RV systolic area, RV systolic, mean pulmonary artery pressure, and PVR and exhibited a decrease in the RV outflow tract acceleration time/ejection time ratio, RV fractional shortening, and tricuspid annular plane systolic excursion compared to CTR ( P < 0.05). SFN-treated PAH attenuated detrimental changes in tricuspid annular plane systolic excursion, mean pulmonary artery pressure, and PVR parameters. Catalase levels and the glutathione/Glutathione disulfide (GSSG) ratio were diminished in the MCT group compared to CTR ( P < 0.05). SFN increased catalase levels and normalized the glutathione/GSSG ratio to control levels ( P < 0.05). Data express the benefit of SFN treatment on the cardiac function of rats with PAH associated with the cellular redox state.

Exploring Enzymatic Conformational Dynamics at Surfaces through µ-FTIR Spectromicroscopy.

Immobilization of proteins onto solid supports has critical industrial, technological, and medical applications, and is a daily task in chemical research. Significant conformational rearrangements often occur due to enzyme-surface interactions, and it is of broad interest to develop methods to probe and better understand these molecular-level changes that contribute to the enzyme's catalytic activity and stability. While circular dichroism is a common method for solution-phase conformational study, the application to surface-supported proteins is not trivial and spatial mapping is not viable. On the other hand, a nonlinear laser spectroscopy technique used to analyze surfaces and interfaces is not often found in most laboratories, therefore requiring an alternative and reliable method. Here, we employed high-dimensional data spectromicroscopy analysis in the infrared region (µ-FTIR) to investigate the enzyme's conformational change when adsorbed onto solid matrices, across a ca. 20 mm2 area. Alcohol dehydrogenase (ADH) enzyme was adopted as a model enzyme to interact with CaF2, Au, and Au-thiol model substrates, strategically chosen for mapping the enzyme dynamics on solid surfaces with different polarity/hydrophobicity properties and extendable to other materials. Two-dimensional chemical maps indicate that the enzyme adsorbs with different patterns in which secondary structures dynamically adjust to optimize interprotein and enzyme-surface interactions. The results suggest an experimental approach to identify and map enzyme conformational dynamics onto different solid surfaces across space and provide insights into immobilized protein structure investigations for areas such as biosensing and bioenergy.

Low-dimensionality carbon-based biosensors: the new era of emerging technologies in bioanalytical chemistry.

Since the last decade, carbon nanomaterials have had a notable impact on different fields such as bioimaging, drug delivery, artificial tissue engineering, and biosensors. This is due to their good compatibility toward a wide range of chemical to biological molecules, low toxicity, and tunable properties. Especially for biosensor technology, the characteristic features of each dimensionality of carbon-based materials may influence the performance and viability of their use. Surface area, porous network, hybridization, functionalization, synthesis route, the combination of dimensionalities, purity levels, and the mechanisms underlying carbon nanomaterial interactions influence their applications in bioanalytical chemistry. Efforts are being made to fully understand how nanomaterials can influence biological interactions, to develop commercially viable biosensors, and to gain knowledge on the biomolecular processes associated with carbon. Here, we present a comprehensive review highlighting the characteristic features of the dimensionality of carbon-based materials in biosensing.

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline.

The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into 4 groups (n = 6 per group): sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM). MCT (60 mg·kg-1 i.p.) was injected 1 week after ovariectomy or sham surgery. Three weeks later, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through Western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared with SM, being accompanied by an elevation in the estrogen receptor ß (ER-ß). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling.

The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets.

OBJECTIVE: Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. METHOD: This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. RESULTS: Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1ß, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. CONCLUSIONS: This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders.

Aerobic Exercise Promotes a Decrease in Right Ventricle Apoptotic Proteins in Experimental Cor Pulmonale.

Pulmonary arterial hypertension is characterized by progressive increases in resistance and pressure in the pulmonary artery and Cor pulmonale. The effect of exercise on hydrogen peroxide-dependent signaling in the right ventricle (RV) of Cor pulmonale rats was analyzed. Rats were divided into sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM) groups. Rats underwent exercise training (60% of VO2 max) for 5 weeks, with 3 weeks after monocrotaline injection (60 mg/kg intraperitoneally). Pulmonary resistance was enhanced in SM (2.0-fold) compared with SC. Pulmonary artery pressure was increased in SM (2.7-fold) and TM (2.6-fold) compared with their respective controls (SC and TC). RV hypertrophy indexes increased in SM compared with SC. Hydrogen peroxide was higher in SM (1.7-fold) than SC and was reduced by 47% in TM compared with SM. p-Akt was increased in TM (2.98-fold) compared with SM. The Bax/Bcl-2 ratio and caspase 3 were also increased (2.9-fold and 3.9-fold, respectively) in SM compared with SC. Caspase 3 was decreased in TM compared with SM (P < 0.05). Therefore, exercise training promoted a beneficial response by decreasing hydrogen peroxide concentrations, and consequently, apoptotic signaling in RV.

Effects of exercise on monocrotaline-induced changes in right heart function and pulmonary artery remodeling in rats.

Pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) is an experimental protocol of right heart failure. We analyzed the role of exercise training on the right ventricle structure and function, pulmonary artery remodeling, and GSK-3ß expression. Rats were divided among the following groups: sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM). Rats underwent exercise training for a period of 5 weeks, with 3 weeks post-MCT injection. Rats in the SM and TM groups presented with an increase in right ventricle hypertrophy indexes and lung congestion. The right ventricular end diastolic pressure (RVEDP), right ventricular systolic pressure (RVSP), and its minimum and maximal pressure derivates were increased in the SM and TM groups. The right ventricle interstitial volume pulmonary artery thickness and p-GSK-3ß/GSK-3ß were increased in the MCT groups as compared with the control groups. The TM group had a reduction in interstitial volume, p-GSK-3ß/GSK-3ß ratio, pulmonary artery thickness, RVEDP, and an increase in intramyocardial vessels volume as compared with the SM group. The overall results have shown that the exercise protocol used promoted positive changes in right ventricle and pulmonary artery remodeling. These observations also suggest that structural remodeling may be influenced by signaling proteins, such as GSK-3ß.

Evidence of the Effects of Dance Interventions on Adults Mental Health: A Systematic Review.

BACKGROUND: Recent research has shown that dancing takes effect directly in improving mental health, by reducing rates of depression, anxiety, and enhancing the mood aspects in people of any age. AIM: This systematic review aimed to search for evidence of the effects of dance interventions on adults' mental health. METHODS: The eligibility criteria of the studies were defined by following the PICOS strategy, considering the population, intervention, comparison, result, and the study design. Only randomized clinical trials, conducted in adults of both sexes, with results related to mental health, including depression and/or anxiety and/or stress and/or mood disorder were considered eligible for this review. The search was conducted using 5 databases: PubMed, Cochrane Library, Web of Science, Scopus, and ScienceDirect from 2005 to 2020. The Cochrane Collaboration tool was used to assess the risk of bias in randomized clinical trials. The synthesis and presentation of results followed the guidelines of the PRISMA model. RESULTS: Of 425 selected studies, 10 randomized clinical trials were included in the review with a total of 933 participants between 18 and 62 years old. Studies included Dance Movement Therapy, Latin dance, tango, rumba, waltz, Nogma, quadrille, and Biodanza. The results indicate that regardless of style, adults who participated in dance interventions showed a reduction in symptoms of depression, anxiety, and stress compared to groups that did not participate in any type of intervention. DISCUSSION: In general, studies showed an unclear risk of bias in most items assessed. Based on these studies, it is possible to assume that the practice of dance contributes positively to the maintenance or improvement of mental health in adults.

Differentially regulated targets in the fast-acting antidepressant effect of (R)-ketamine: A systems biology approach.

Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are involved in the MDD pathophysiology. In this scenario, the glutamatergic system represents a promising therapeutic target for treatment-resistant depression. To our knowledge, this is the first study using semantic approach with systems biology to identify potential targets involved in the fast-acting antidepressant effects of ketamine and its enantiomers as well as identifying specific targets of (R)-ketamine. We performed a systematic review, followed by a semantic analysis and functional gene enrichment to identify the main biological processes involved in the therapeutic effects of these agents. Protein-protein interaction networks were constructed, and the genes exclusively regulated by (R)-ketamine were explored. We found that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits-Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by the three-antidepressant agents, reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects. Differential regulation of Transforming Growth Factor Beta 1 (TGF-ß1) receptors-Mitogen-Activated Protein Kinases (MAPK's), Receptor Activator of Nuclear Factor-Kappa Beta Ligand (RANKL), and Serotonin Transporter (SERT) seems to be particularly involved in (R)-ketamine antidepressant effects. Our data helps further studies investigating the relationship between these targets and the mechanisms of (R)-ketamine and searching for other therapeutic compounds that share the regulation of these specific biomolecules. Ultimately, this study could contribute to improve the fast management of depressive-like symptoms with less detrimental side effects than ketamine and (S)-ketamine.

Effects of purple grape juice in the redox-sensitive modulation of right ventricular remodeling in a pulmonary arterial hypertension model.

The effects of purple grape juice (PGJ) pretreatment in signaling proteins involved in cardiac remodeling in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) were investigated. Male Wistar rats (control, MCT, PGJ, and MCT + PGJ groups) were treated for 6 weeks with water or PGJ (10 mL·kg(-1)·d(-1)) by gavage. In the third week, they were administered a single dose of MCT (60 mg/kg i.p.). Pulmonary vascular resistance was determined by echocardiography, and hemodynamic analysis was performed in the right ventricle (RV). Hydrogen peroxide (H2O2) concentration and lipid peroxidation were quantified and thioredoxin-1 (Trx-1), p-ERK1/2/ERK1/2, p-Akt/Akt, p-JNK/JNK, and cleaved caspase-3 were detected at RV by Western blot. Pretreatment with PGJ attenuated pulmonary vascular resistance and improved hemodynamic parameters in MCT-induced PAH. PGJ and MCT groups exhibited increased H2O2 levels, which were reduced to baseline in MCT + PGJ. ERK1/2 phosphorylation showed the same profile of H2O2 changes. No changes in p-JNK/JNK and p-Akt/Akt expressions were found. An enhanced cleaved caspase-3 immunodetection was induced by the model, which was reversed in the MCT + PGJ group and associated with increased Trx-1 and reduced lipid peroxidation. Improvement in functional parameters mediated by PGJ pretreatment may be associated with the induction of Trx-1, influencing the expression of proteins involved in RV remodeling.

Potential Candidates for Biomarkers in Bipolar Disorder: A Proteomic Approach through Systems Biology.

Bipolar disorder (BD) is one of the most disabling diseases characterized by severe humor fluctuation. It is accompanied by cognitive and functional impairment in addiction to high suicide rates. BD is often underdiagnosed and treated incorrectly because many of the reported symptoms are not exclusive to the disorder. Once the diagnosis is exclusively clinical, it is not possible to state precisely. From that, proteomic approaches were used to identify, in a large scale, all proteins involved in cellular or tissue processes. This review aggregate data from blood proteomes, by using protein association network, of subjects with BD and healthy controls to suggest dysfunctional molecular pathways involved in disease. Original articles containing proteomic analysis were searched in PubMed. Seven studies were selected and data were extracted for posterior analysis. A protein-protein interaction network was created by STRING database. A final set of proteins in this network were employed as input in ClueGO and, the main biological process was visualized using R package pathview. The analysis revealed proteins associated with many biological processes, including growth and endocrine regulation, iron transportation, protease inhibition, protection against pathogens and cholesterol transport. Moreover, pathway analysis indicated the association of uncovered proteins with two main metabolic pathways: complement system and coagulation cascade. Thus, a better understanding on the pathophysiology of psychiatric disorders and the identification of potential biomarker candidates are essential to improve diagnostic, prognostic and design pharmacological strategies.

Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers.

Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.

COVID-19 and mental health in Brazil: Psychiatric symptoms in the general population.

Public health interventions at general population level are imperative in order to decrease the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but they may contribute to widespread emotional distress and increased risk for psychiatric illnesses. We report on the results of an investigation into the occurrence and determinants of psychiatric symptoms among the Brazilian general population (N = 1996). We assessed sociodemographic variables and general mental health (DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure), depression (PROMIS depression v.8a), anxiety (PROMIS anxiety v.8a), and post-traumatic stress symptoms (Impact of Event Scale-IES-R scale) using an online web-based survey. Anxiety (81.9%), depression (68%), anger (64.5%), somatic symptoms (62.6%) and sleep problems (55.3%) were the most common psychiatric symptoms. Younger age, female gender, low income, lower level of education, longer period of social distancing, and self-reported history of previous psychiatric illness were strongly associated with higher severity of symptoms. Our results support the negative impact of the COVID-19 pandemic on the mental health of the Brazilian population. The high prevalence of psychiatric symptoms observed in our sample indicates that the mental health impact of the COVID-19 pandemic should be considered a public health problem in Brazil. The health systems and individual clinicians must be prepared to offer and implement specific interventions in order to identify and treat psychiatric issues.

Spatially localized electrodeposition of multiple metals via light-activated electrochemistry for surface enhanced Raman spectroscopy applications.

Light can be used to address electrochemical reactions on a monolithic semiconducting electrode with spatial and temporal resolution. Herein, such principle was used for the electrodeposition of Au, Ag and Cu nanoparticles on a unique silicon-based electrode. The parallel nature of the process granted manufacturing speed and platforms were applied to discriminate molecules via multi-wavelength and multivariate Raman analysis.

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges.

The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients.

Porous Graphene Oxide Films Prepared via the Breath-Figure Method: A Simple Strategy for Switching Access of Redox Species to an Electrode Surface.

Porous materials can be modified with physical barriers to control the transport of ions and molecules through channels via an external stimulus. Such capability has brought attention toward drug delivery, separation methods, nanofluidics, and point-of-care devices. In this context, gated platforms on which access to an electrode surface of species in solution can be reversibly hindered/unhindered on demand are appearing as promising materials for sensing and microfluidic switches. The preparation of a reversible gated device usually requires mesoporous materials, nanopores, or molecularly imprinted polymers. Here, we show how the breath-figure method assembly of graphene oxide can be used as a simple strategy to produce gated electrochemical materials. This was achieved by forming an organized porous thin film of graphene oxide onto an ITO surface. Localized brushes of thermoresponsive poly(N-isopropylacrylamide) were then grown to specific sites of the porous film by in situ reversible addition-fragmentation chain-transfer polymerization. The gating mechanism relies on the polymeric chains to expand and contract depending on the thermal stimulus, thus modulating the accessibility of redox species inside the pores. The resulting platform was shown to reversibly hinder or facilitate the electron transfer of solution redox species by modulating temperature from the room value to 45 °C or vice versa.

Reduction of hippocampal IL-6 levels in LPS-injected rats following acute exendin-4 treatment.

Preclinical evidence on the role of glucagon-like peptide-1 receptor (GLP-1r) agonists in the brain led to an increased interest in repurposing these compounds as a therapy for central nervous system (CNS) disorders and associated comorbidities. We aimed to investigate the neuroprotective effects of acute treatment with exendin (EX)-4, a GLP-1r agonist, in an animal model of inflammation. We evaluated the effect of different doses of EX-4 on inflammatory, neurotrophic, and oxidative stress parameters in the hippocampus and serum of lipopolysaccharide (LPS)-injected animals. Male Wistar rats were injected with LPS (0.25 mg/kg i.p.) and treated with different doses of EX-4 (0.1, 0.3, or 0.5 µg/kg i.p.). Sickness behavior was assessed by locomotor activity and body weight, and depressive-like behavior was also evaluated using forced swim test (FST). Brain-derived neurotrophic factor (BDNF), thiobarbituric acid reactive species (TBARS), and interleukin (IL)-6 were quantified in the serum and hippocampus. Glycemia was also analyzed pre- and post-EX-4 treatment. LPS groups exhibited decreased frequency of crossing and reduced body weight (p < 0.001), while alterations on FST were not observed. The higher dose of EX-4 reduced IL-6 in the hippocampus of LPS-injected animals (p = 0.018), and EX-4 per se reduced TBARS serum levels with a modest antioxidant effect in the LPS groups (p ≤ 0.005). BDNF hippocampal levels seemed to be increased in the LPS+EX-4 0.5 group compared with LPS+Saline (p > 0.05). Our study provides evidence on acute anti-inflammatory effects of EX-4 in the hippocampus of rats injected with LPS, contributing to future studies on repurposing compounds with potential neuroprotective properties.

High-resolution light-activated electrochemistry on amorphous silicon-based photoelectrodes.

Light-activated electrochemistry (LAE) consists of employing a focused light beam to illuminate a semiconducting area and make it electrochemically active. Here, we show how to reduce the electrochemical spatial resolution to submicron by exploiting the short lateral diffusion of charge carriers in amorphous silicon to improve the resolution of LAE by 60 times.