Melatonin effects on oxidative stress and on TLR4/NF-kß inflammatory pathway in the right ventricle of rats with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure and a compromised the right ventricle (RV), together with progression to heart failure and premature death. Studies have evaluated the role of melatonin as a promising therapeutic strategy for PAH. The objective of this study was to evaluate melatonin's effects on oxidative stress and on the TLR4/NF-kß inflammatory pathway in the RV of rats with PAH. Male Wistar rats were divided into the following groups: control, monocrotaline (MCT), and monocrotaline plus melatonin groups. These two last groups received one intraperitoneal injection of MCT (60 mg/kg) on the first day of experimental protocol. The monocrotaline plus melatonin group received 10 mg/kg/day of melatonin by gavage for 21 days. Echocardiographic analysis was performed, and the RV was collected for morphometric analysis oxidative stress and molecular evaluations. The main findings of the present study were that melatonin administration attenuated the reduction in RV function that was induced by monocrotaline, as assessed by TAPSE. In addition, melatonin prevented RV diastolic area reduction caused by PAH. Furthermore, animals treated with melatonin did not show an increase in ROS levels or in NF-kß expression. In addition, the monocrotaline plus melatonin group showed a reduction in TLR4 expression when compared with control and monocrotaline groups. To our knowledge, this is the first study demonstrating a positive effect of melatonin on the TLR4/NF-kß pathway in the RV of rats with PAH. In this sense, this study makes it possible to think of melatonin as a possible ally in mitigating RV alterations caused by PAH.

Melatonin improves nitric oxide bioavailability in isoproterenol induced myocardial injury.

Isoproterenol administration is associated with cardiac inflammation and decreased NO availability. Melatonin has been reported to have cardioprotective effect. The aim of this study was to investigate the effect of melatonin on NO bioavailability and inflammation in myocardial injury induced by isoproterenol. Isoproterenol was administrated in male Wistar rats for 7 days to induce cardiac injury. The animals were divided into 3 groups: Control, Isoproterenol, Isoproterenol + Melatonin. Animals received melatonin for 7 days. Echocardiographic analysis was performed and the hearts were collected for molecular analysis. Animals that received isoproterenol demonstrated a reduction in left ventricle systolic and diastolic diameter, indicating the presence of concentric hypertrophy. Melatonin was able to attenuate this alteration. Melatonin also improved NO bioavailability and decreased NF-κß, TNFα and IL-1ß expression. In conclusion, melatonin exhibited a cardioprotective effect which was associated with improving NO bioavailability and decreasing the pro-inflammatory proteins.

Effects of Pterostilbene on Heart and Lung Oxidative Stress Parameters in 2 Experimental Models of Cardiovascular Disease: Myocardial Infarction and Pulmonary Arterial Hypertension.

ABSTRACT: Myocardial infarction (MI) and pulmonary arterial hypertension (PAH) are 2 prevalent cardiovascular diseases. In both conditions, oxidative stress is associated with a worse prognosis. Pterostilbene (PTE), an antioxidant compound, has been studied as a possible therapy for cardiovascular diseases. This study aims to evaluate the effect of PTE on oxidative stress in the hearts of animals with MI and in the lungs of animals with PAH. Male Wistar rats were used in both models. In the MI model, the experimental groups were sham, MI, and MI + PTE. In the PAH model, the experimental groups were control, PAH, and PAH + PTE. Animals were exposed to MI through surgical ligation of the left coronary artery, or to PAH, by the administration of monocrotaline (60 mg/kg). Seven days after undergoing cardiac injury, the MI + PTE animals were treated with PTE (100 mg/kg day) for 8 days. After this, the heart was collected for molecular analysis. The PAH + PTE animals were treated with PTE (100 mg/kg day) for 14 days, beginning 7 days after PAH induction. After this, the lungs were collected for biochemical evaluation. We found that PTE administration attenuated the decrease in ejection fraction and improved left ventricle end-systolic volume in infarcted animals. In the PAH model, PTE improved pulmonary artery flow and decreased reactive oxygen species levels in the lung. PTE administration promoted protective effects in terms of oxidative stress in 2 experimental models of cardiac diseases: MI and PAH. PTE also improved cardiac function in infarcted rats and pulmonary artery flow in animals with PAH.

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.

Effect of free and nanoemulsified ß-caryophyllene on monocrotaline-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), right ventricular (RV) failure and premature death. Compounds with vasodilatory characteristics, such as ß-caryophyllene, could be promising therapeutics for PAH. This study aimed to determine the effects of free and nanoemulsified ß-caryophyllene in lung oxidative stress and heart function in PAH rats. Male Wistar rats (170 g, n = 6/group) were divided into four groups: control (CO), monocrotaline (MCT), monocrotaline + ß-caryophyllene (MCT-Bcar) and monocrotaline + nanoemulsion with ß-caryophyllene (MCT-Nano). PAH was induced by MCT (60 mg/kg i.p.), and 7 days later, treatment with ß-caryophyllene, either free or in a nanoemulsion (by gavage, 176 mg/kg/day) or vehicle was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and after, the RV was collected for morphometry and the lungs for evaluation of oxidative stress, antioxidant enzymes, total sulfhydryl compounds, nitric oxide synthase (NOS) activity and endothelin-1 receptor expression. RV hypertrophy, increased PVR and RV systolic and diastolic pressures (RVSP and RVEDP, respectively) and increased mean pulmonary arterial pressure (mPAP) were observed in the MCT group. Treatment with both free and nanoemulsified ß-caryophyllene reduced RV hypertrophy, mPAP, RVSP and lipid peroxidation. The reduction in RVSP was more pronounced in the MCT-Nano group. Moreover, RVEDP decreased only in the MCT-Nano group. These treatments also increased superoxide dismutase, catalase and NOS activities and decreased endothelin-1 receptors expression. Both ß-caryophyllene formulations improved mPAP, PVR and oxidative stress parameters. However, ß-caryophyllene in a nanoemulsion was more effective in attenuating the effects of PAH.

Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin).

Leishmaniasis, caused by protozoa of the genus Leishmania, encompasses a group of neglected diseases with diverse clinical and epidemiological manifestations that can be fatal if not adequately and promptly managed/treated. The current chemotherapy options for this disease are expensive, require invasive administration and often lead to severe side effects. In this regard, our research group has previously reported the potent anti-Leishmania activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)3].(ClO4)2.4H2O and [Ag(phendione)2].ClO4. The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all Leishmania species that plays multiple functions and is recognized as a potential target for antiparasitic drugs. The results showed that both Ag-phendione (-74.82 kcal/mol) and Cu-phendione (-68.16 kcal/mol) were capable of interacting with the amino acids comprising the active site of the gp63 protein, exhibiting more favorable interaction energies compared to phendione alone (-39.75 kcal/mol) or 1,10-phenanthroline (-45.83 kcal/mol; a classical gp63 inhibitor) as judged by molecular docking assay. The analysis of kinetic parameters using the fluorogenic substrate Z-Phe-Arg-AMC indicated Vmax and apparent Km values of 0.064 µM/s and 14.18 µM, respectively, for the released gp63. The effects of both complexes on gp63 proteolytic activity were consistent with the in silico assay, where Ag-phendione exhibited the highest gp63 inhibition capacity against gp63, with an IC50 value of 2.16 µM and the lowest inhibitory constant value (Ki = 5.13 µM), followed by Cu-phendione (IC50 = 163 µM and Ki = 27.05 µM). Notably, pretreatment of live L. amazonensis promastigotes with the complexes resulted in a significant reduction in the expression of gp63 protein, including the isoforms located on the parasite cell surface. Both complexes markedly decreased the in vitro association indexes between L. amazonensis promastigotes and THP-1 human macrophages; however, this effect was reversed by the addition of soluble gp63 molecules to the interaction medium. Collectively, our findings highlight the potential use of these potent complexes in antivirulence therapy against Leishmania, offering new insights for the development of effective treatments for leishmaniasis.

Influence of carvedilol and thyroid hormones on inflammatory proteins and cardioprotective factor HIF-1α in the infarcted heart.

Inflammatory pathways of Toll-like receptor 4 (TLR4) and NLRP3 inflammasome contribute to acute myocardial infarction (AMI) pathophysiology. The hypoxia-inducible factor 1α (HIF-1α), however, is a key transcription factor related to cardioprotection. This study aimed to compare the influence of carvedilol and thyroid hormones (TH) on inflammatory and HIF-1α proteins and on cardiac haemodynamics in the infarcted heart. Male Wistar rats were allocated into five groups: sham-operated group (SHAM), infarcted group (MI), infarcted treated with the carvedilol group (MI + C), infarcted treated with the TH group (MI + TH), and infarcted co-treated with the carvedilol and TH group (MI + C + TH). Haemodynamic analysis was assessed 15 days post-AMI. The left ventricle (LV) was collected for morphometric and Western blot analysis. The MI group presented LV systolic pressure reduction, LV end-diastolic pressure elevation, and contractility index decrease compared to the SHAM group. The MI + C, MI + TH, and MI + C + TH groups did not reveal such alterations compared to the SHAM group. The MI + TH and MI + C + TH groups presented reduced MyD88 and NLRP3 and increased HIF-1α levels. In conclusion, all treatments preserve the cardiac haemodynamic, and only TH, as isolated treatment or in co-treatment with carvedilol, was able to reduce MyD88 and NLRP3 and increase HIF-1α in the infarcted heart.

Assessing the Therapeutic and Toxicological Profile of Novel Acetylcholinesterase Reactivators: Value of In Silico And In Vitro Data.

Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.

Cardioprotective doses of thyroid hormones improve NO bioavailability in erythrocytes and increase HIF-1α expression in the heart of infarcted rats.

CONTEXT: Infarction leads to a decrease in NO bioavailability in the erythrocytes. Thyroid hormones (TH) present positive effects after infarction. However, there are no studies evaluating the effects of cardioprotective doses of TH in the erythrocytes after infarction. OBJECTIVE: This study aimed to evaluate the effects of TH in NO bioavailability and oxidative stress parameters in the erythrocytes of infarcted rats. MATERIAL AND METHODS: Wistar rats were allocated into the three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). AMIT rats received T4 and T3 for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and the LV and erythrocytes were collected. RESULTS: TH improved NO bioavailability and increased catalase activity in the erythrocytes. Besides that, TH increased HIF-1α in the heart. CONCLUSION: TH seems to be positive for erythrocytes preventing a decrease in NO bioavailability and increasing antioxidant enzymatic defense after infarction.

Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective.

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

Bulk and surface theoretical investigation of Nb-doped δ-FeOOH as a promising bifunctional catalyst.

The development of bifunctional catalysts is of great interest in fine chemistry, since they are capable of promoting multicatalytic reactions involved in several important industrial processes. Iron oxyhydroxides have been identified as low-cost bifunctional catalysts. However, their applications are limited due to their weak acid character. Thus, elaborated modifications of these systems can significantly contribute to increasing their activities and selectivity. This work consists in the study, through DFT calculations, of the properties of the bulk and the surface of feroxyhyte (δ-FeOOH) doped with niobium, as a potential bifunctional catalyst. We identified the formation of stronger van der Waals interactions among the doped δ-FeOOH layers, which can increase the thermal stability of the catalyst. In addition, evidence has been found that the insertion of Nb increases Brönsted acidity and gives rise to new Lewis acid sites on the catalyst surface.

Computational evidence for nitro derivatives of quinoline and quinoline N-oxide as low-cost alternative for the treatment of SARS-CoV-2 infection.

A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time-space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.

Cathepsin K inhibitors based on 2-amino-1,3,4-oxadiazole derivatives.

Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (-134.36 kcal mol-1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.

Effects of Carvedilol and Thyroid Hormones Co-administration on Apoptotic and Survival Proteins in the Heart After Acute Myocardial Infarction.

Cellular death and survival signaling plays a key role in the progress of adverse cardiac remodeling after acute myocardial infarction (AMI). Therapeutic strategies, such as co-treatment with beta-blocker carvedilol and thyroid hormones (THs), give rise to new approaches that can sustain the cellular homeostasis after AMI. Therefore, we sought to investigate the effects of carvedilol and TH co-administration on apoptosis and survival proteins and on cardiac remodeling after AMI. Male Wistar rats were distributed in 5 groups as follows: sham-operated group (SHAM), infarcted group (MI), infarcted plus carvedilol group (MI+C), infarcted plus TH group (MI+TH), and infarcted plus carvedilol and TH co-treatment group (MI+C+TH). Echocardiographic analysis was performed, and hearts were collected for western blot evaluation. The MI group presented systolic posterior wall thickness loss, an increase in the wall tension index, and an increase in atrial natriuretic peptide tissue levels than the SHAM group. However, in the MI+C+TH group, these parameters were equally to the SHAM group. Moreover, whereas the MI group showed Bax protein expression elevated in relation to the SHAM group, the MI+C+TH group presented Bax reduction and also Akt activation compared with the MI group. In addition, the MI+TH group revealed beta-1 adrenergic receptor (ß1AR) upregulation compared with the MI and MI+C groups, whereas the MI+C+TH group presented lower levels of ß1AR in relation to the SHAM and MI+TH groups. In conclusion, we suggest that carvedilol and TH co-administration may mediate its cardioprotective effects against adverse cardiac remodeling post-AMI through the Bax reduction, Akt activation, and ß1AR decrease.

Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects.

Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

Identificação odontolegal por meio de tomografia computadorizada para planejamento de implantes ­ relato de caso pericial / Dental identification using computed tomography for implant planning ­forensic case report

A identificação humana post mortem é uma área de estudo e pesquisa de extensa atuação da Odontologia Legal. Nessa área do conhecimento, a forma mais utilizada é a da comparação dos registros ante mortem (AM) com os achados post mortem (PM). Em casos de cadáveres carbonizados, geralmente os elementos dentários são capazes de resistir à ação térmica. Dessa forma, os exames de imagens que integram os prontuários odontológicos, quando em boa qualidade, possibilitam sua comparação com os mesmos exames realizados no cadáver. O propósito desse artigo foi o de relatar um caso em que a comparação de tomografias computadorizadas AM e PM permitiu a identificação positiva de um cadáver carbonizado. A comparação das imagens tomográficas AM, utilizadas para um planejamento reabilitador com implantes, com as imagens PM, realizadas no Instituto Médico Legal da Polícia Civil do Distrito Federal, permitiu, de forma rápida, eficaz e econômica, a identificação positiva do cadáver devido à quantidade e à qualidade dos pontos semelhantes encontrados nas imagens, associados à ausência de divergências inexplicáveis

Experimental and theoretical affinity and catalysis studies between halogenated phenols and peroxidases: Understanding the bioremediation potential.

Halogenated phenols, such as 2,4-dichlorophenol (2,4-DCP) and 4-bromophenol (4-BP) are pollutants generated by a various industrial sectors like chemical, dye, paper bleaching, pharmaceuticals or in an agriculture as pesticides. The use of Horseradish peroxidase (HRP) in the halogenated phenols treatment has already been mentioned, but it is not well understood how the different phenolic substrates can bind in the peroxidase active site nor how these specific interactions can influence in the bioremediation potential. In this work, different removal efficiencies were obtained for phenolic compounds investigated using HRP as catalyst (93.87 and 59.19% to 4BP and 2,4 DCP, respectively). Thus, to rationalize this result based on the interactions of phenols with active center of HRP, we combine computational and experimental methodologies. The theoretical approaches utilized include density functional theory (DFT) calculations, docking simulation and quantum mechanics/molecular mechanics (QM/MM) technique. Michaelis Menten constant (Km) obtained through experimental methodologies were 2.3 and 0.95 mM to 2,4-DCP and 4-BP, respectively, while the specificity constant (Kcat/Km) found was 1.44 mM-1 s-1 and 0.62 mM-1 s-1 for 4-BP and 2,4-DCP, respectively. The experimental parameters appointed to the highest affinity of HRP to 4-BP. According to the molecular docking calculations, both ligands have shown stabilizing intermolecular interaction energies within the HRP active site, however, the 4-BP showed more stabilizing interaction energy (-53.00 kcal mol-1) than 2,4-dichlorophenol (-49.23 kcal mol-1). Besides that, oxidative mechanism of 4-BP and 2,4-DCP was investigated by the hybrid QM/MM approach. This study showed that the lowest activation energy values for transition states investigated were obtained for 4-BP. Therefore, by theoretical approach, the compound 4-BP showed the more stabilizing interaction and activation energy values related to the interaction within the enzyme and the oxidative reaction mechanism, respectively, which corroborates with experimental parameters obtained. The combination between experimental and theoretical approaches was essential to understand how the degradation potential of the HRP enzyme depends on the interactions between substrate and the active center cavity of the enzyme.

Thyroid hormone treatment improved the response to maximum exercise test and preserved the ventricular geometry in myocardial infarcted rats.

NEW FINDINGS: What is the central question of this study? Does thyroid hormone treatment given after myocardial infarction preserve left ventricular function and treadmill exercise performance, and improve parameters of oxidative stress in the right ventricle and lungs of Wistar rats? What is the main finding and its importance? Thyroid hormone treatment improved the performance of the maximum exercise test in infarcted rats and induced effects in the heart and lungs that were similar to those observed with exercise training. This suggests there is a significant value of thyroid hormones for preserving exercise tolerance after myocardial infarction. ABSTRACT: Left ventricular myocardial infarction (MI) provokes damage in the heart and in other tissues, such as right ventricle and lungs. The present study elucidated whether thyroid hormone treatment (THT) may present positive effects in heart and lungs after MI, and whether or not these effects are similar to those of exercise training (ET). Male Wistar rats were divided into four groups: sham operated (SHAM), infarcted (MI), infarcted + exercise training (MIE), and infarcted + thyroid hormones (MIH). A maximum exercise test, left ventricle echocardiography, pulmonary histology, and oxidative stress in the right ventricle and lung were evaluated. THT and ET both reduced left ventricular dilatation and end-diastolic wall stress indexes to a similar extent. MI accentuated the content of macrophages and inflammatory infiltrate in the lungs, which was partially prevented in the MIH and MIE groups. THT and ET presented similar effects in the heart and lungs, and both improved the performance of the maximum exercise test in infarcted animals.

Pterostilbene improves cardiac function in a rat model of right heart failure through modulation of calcium handling proteins and oxidative stress.

This study explored the effect of pterostilbene (PTS) complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on right heart function, glutathione and glutaredoxin systems, and the expression of redox-sensitive proteins involved with regulation calcium levels in the experimental model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). After 7 days of PAH induction, rats received daily doses of the PTS:HPßCD complex (corresponding to 25, 50, or 100 mg·kg-1 of PTS) or vehicle (control group, CTR0) (an aqueous solution containing HPßCD; CTR0 and MCT0 (MCT group that did not receive PTS treatment)) via oral administration for 2 weeks. The results showed that the PTS:HPßCD complex increased the content of reduced glutathione and the activity of glutathione-S-transferase and glutaredoxin in the right ventricle (RV) of MCT-treated rats in a dose-dependent manner. Additionally, at higher doses, it also prevented the reduction of stroke volume and cardiac output, prevented myocardial performance index (MPI) increase, reduced lipoperoxidation, reduced total phospholamban, and increased the expression of sarcoplasmic reticulum calcium ATPase in the RV of MCT-treated rats. These results demonstrate that the PTS:HPßCD complex has a dose-dependent antioxidant mechanism that results in improved cardiac function in experimental right heart failure. Our results open a field of possibilities to PTS administration as new therapeutic approach to conventional therapy for right ventricular dysfunction. Novelty Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin could be a new therapeutic approach. Pterostilbene complexed with hydroxypropyl-ß-cyclodextrin reestablishes redox homeostasis through glutathione metabolism modulation, leading to an improved MPI in pulmonary arterial hypertension-provoked right heart failure.

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016-2019).

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.