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In the pediatric population, epilepsy is one of the most common neurological disorders that often results in cognitive dysfunction. It affects patients’ life quality by limiting academic performance and self-esteem and increasing social rejection. There are several interventions for the neurohabilitation of cognitive impairment, including LEGO®-based therapy (LEGO® B-T), which promotes neuronal connectivity and cortical plasticity through the use of assembly sets and robotic programming. Therefore, the aim of this study was to analyze the effect of LEGO® B-T on cognitive processes in pediatric patients with epilepsy. Eligible patients were identified; in the treatment group, an initial evaluation was performed with the NEUROPSI and BANFE-2 neuropsychological tests. Then, the interventions were performed once a week, and a final test was performed. In the control group, after the initial evaluation, the final evaluation was performed. An overall improvement was observed in the LEGO® B-T patients, with a significant increase in BANFE-2 scores in the orbitomedial, anterior prefrontal, and dorsolateral areas. In addition, in the gain score analysis, the orbitomedial and memory scores were significantly different from the control group. LEGO® B-T neurohabilitation is a remarkable option for epilepsy patients, who are motivated when they observe improvements.

Epilepsy is a neurological disorder in which it has been shown that the presence of oxidative stress (OS) is implicated in epileptogenesis. The literature has shown that some antiseizure drugs (ASD) have neuroprotective properties. Levetiracetam (LEV) is a drug commonly used as an ASD, and in some studies, it has been found to possess antioxidant properties. Because the antioxidant effects of LEV have not been demonstrated in the chronic phase of epilepsy, the objective of this study was to evaluate, for the first time, the effects of LEV on the oxidant–antioxidant status in the hippocampus of rats with temporal lobe epilepsy (TLE). The in vitro scavenging capacity of LEV was evaluated. LEV administration in rats with TLE significantly increased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, but did not change glutathione peroxidase (GPx) activity, and significantly decreased glutathione reductase (GR) activity in comparison with epileptic rats. LEV administration in rats with TLE significantly reduced hydrogen peroxide (H2O2) levels but did not change lipoperoxidation and carbonylated protein levels in comparison with epileptic rats. In addition, LEV showed in vitro scavenging activity against hydroxyl radical (HO•). LEV showed significant antioxidant effects in relation to restoring the redox balance in the hippocampus of rats with TLE. In vitro, LEV demonstrated direct antioxidant activity against HO•.

Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. Aim: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. Method: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. Results: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. Conclusions: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.

Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies.

Transcription factor EB (TFEB) is considered the master transcriptional regulator of autophagy and lysosomal biogenesis, which regulates target gene expression through binding to CLEAR motifs. TFEB dysregulation has been linked to the development of numerous pathological conditions; however, several other lines of evidence show that TFEB might be a point of convergence of diverse signaling pathways and might therefore modulate other important biological processes such as cellular senescence, DNA repair, ER stress, carbohydrates, and lipid metabolism and WNT signaling-related processes. The regulation of TFEB occurs predominantly at the post-translational level, including phosphorylation, acetylation, SUMOylating, PARsylation, and glycosylation. It is noteworthy that TFEB activation is context-dependent; therefore, its regulation is subjected to coordinated mechanisms that respond not only to nutrient fluctuations but also to stress cell programs to ensure proper cell homeostasis and organismal health. In this review, we provide updated insights into novel post-translational modifications that regulate TFEB activity and give an overview of TFEB beyond its widely known role in autophagy and the lysosomal pathway, thus opening the possibility of considering TFEB as a potential therapeutic target.

Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. Aim: Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. Method: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. Conclusion: Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.

Helicobacter pylori (H. pylori) has been proposed as the foremost risk factor for the development of gastric cancer. We found that H. pylori express the enzyme glucose-6-phosphate dehydrogenase (HpG6PD), which participates in glucose metabolism via the pentose phosphate pathway. Thus, we hypothesized that if the biochemical and physicochemical characteristics of HpG6PD contrast with the host G6PD (human G6PD, HsG6PD), HpG6PD becomes a potential target for novel drugs against H. pylori. In this work, we characterized the biochemical properties of the HpG6PD from the H.pylori strain 29CaP and expressed the active recombinant protein, to analyze its steady-state kinetics, thermostability, and biophysical aspects. In addition, we analyzed the HpG6PD in silico structural properties to compare them with those of the HsG6PD. The optimal pH for enzyme activity was 7.5, with a T1/2 of 46.6 °C, at an optimum stability temperature of 37 °C. The apparent Km values calculated for G6P and NADP+ were 75.0 and 12.8 µM, respectively. G6P does not protect HpG6PD from trypsin digestion, but NADP+ does protect the enzyme from trypsin and guanidine hydrochloride (Gdn-HCl). The biochemical characterization of HpG6PD contributes to knowledge regarding H. pylori metabolism and opens up the possibility of using this enzyme as a potential target for specific and efficient treatment against this pathogen; structural alignment indicates that the three-dimensional (3D) homodimer model of the G6PD protein from H. pylori is different from the 3D G6PD of Homo sapiens.

Ketogenic diet, a high fat and low carbohydrate diet, has been used as a non-pharmacological treatment in refractory epilepsy since 1920. In recent years, it has demonstrated to be effective in the treatment of numerous neurological and non-neurological diseases. Some neurological and neuropsychiatric disorders are known to be caused by gamma-aminobutyric acid (GABA)-mediated neurotransmission dysfunction. The strength and polarity of GABA-mediated neurotransmission are determined by the intracellular chloride concentration, which in turn is regulated by cation-chloride cotransporters NKCC1 and KCC2. Currently, it is unknown if the effect of ketogenic diet is due to the modulation of these cotransporters. Thus, we analyzed the effect of a ketogenic diet on the cation-chloride cotransporters expression in the dentate gyrus. We estimated the total number of NKCC1 immunoreactive (NKCC1-IR) neuronal and glial cells by stereology and determined KCC2 labeling intensity by densitometry in the molecular and granule layers as well as in the hilus of dentate gyrus of rats fed with normal or ketogenic diet for 3 months. The results indicated that ketogenic diet provided during 3 months increased KCC2 expression, but not NKCC1 in the dentate gyrus of the rat. The significant increase of KCC2 expression could explain, at least in part, the beneficial effect of ketogenic diet in the diseases where the GABAergic system is altered by increasing its inhibitory efficiency.

Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel drugs, new molecular targets, and a better understanding of the mechanisms of action of existing drugs is still crucial. Levetiracetam (LEV) is an AED that has been shown to be effective in seizure control and is well-tolerable, with a novel mechanism of action through an interaction with the synaptic vesicle protein 2A (SV2A). Moreover, LEV has other molecular targets that involve calcium homeostasis, the GABAergic system, and AMPA receptors among others, that might be integrated into a single mechanism of action that could explain the antiepileptogenic, anti-inflammatory, neuroprotective, and antioxidant properties of LEV. This puts it as a possible multitarget drug with clinical applications other than for epilepsy. According to the above, the objective of this work was to carry out a comprehensive and integrative review of LEV in relation to its clinical uses, structural properties, therapeutical targets, and different molecular, genetic, and systemic action mechanisms in order to consider LEV as a candidate for drug repurposing.

Permethrin (PERM) is a member of the class I family of synthetic pyrethroids. Human use has shown that it affects different systems, with wide health dysfunctions. Our aim was to determine bioenergetics, neuroinflammation and morphology changes, as redox markers after subacute exposure to PERM in rats. We used MDA determination, protein carbonyl assay, mitochondrial O2 consumption, expression of pro-inflammatory cytokines and a deep histopathological analysis of the hippocampus. PERM (150 mg/kg and 300 mg/kg body weight/day, o.v.) increased lipoperoxidation and carbonylated proteins in a dose-dependent manner in the brain regions. The activities of antioxidant enzymes glutathione peroxidase, reductase, S-transferase, catalase, and superoxide dismutase showed an increase in all the different brain areas, with dose-dependent effects in the cerebellum. Cytokine profiles (IL-1β, IL-6 and TNF-α) increased in a dose-dependent manner in different brain tissues. Exposure to 150 mg/kg of permethrin induced degenerated and/or dead neurons in the rat hippocampus and induced mitochondrial uncoupling and reduction of oxidative phosphorylation and significantly decreased the respiratory parameters state 3-associated respiration in complex I and II. PERM exposure at low doses induces reactive oxygen species production and imbalance in the enzymatic antioxidant system, increases gene expression of pro-inflammatory interleukins, and could lead to cell damage mediated by mitochondrial functional impairment.

Health and lifespan are influenced by dietary nutrients, whose balance is dependent on the supply or demand of each organism. Many studies have shown that an increased carbohydrate–lipid intake plays a critical role in metabolic dysregulation, which impacts longevity. Caenorhabditis elegans has been successfully used as an in vivo model to study the effects of several factors, such as genetic, environmental, diet, and lifestyle factors, on the molecular mechanisms that have been linked to healthspan, lifespan, and the aging process. There is evidence showing the causative effects of high glucose on lifespan in different diabetic models; however, the precise biological mechanisms affected by dietary nutrients, specifically carbohydrates and lipids, as well as their links with lifespan and longevity, remain unknown. Here, we provide an overview of the deleterious effects caused by high-carbohydrate and high-lipid diets, as well as the molecular signals that affect the lifespan of C. elegans; thus, understanding the detailed molecular mechanisms of high-glucose- and lipid-induced changes in whole organisms would allow the targeting of key regulatory factors to ameliorate metabolic disorders and age-related diseases.

Around the world, species from the genus Tilia are commonly used because of their peripheral and central medicinal effects; they are prepared as teas and used as tranquilizing, anticonvulsant, and analgesic agents. In this study, we provide evidence of the protective effects of organic and aqueous extracts (100 mg/kg, i.p.) obtained from the leaves of Tilia americana var. mexicana on CCl4-induced liver and brain damage in the rat. Protection was observed in the liver and brain (cerebellum, cortex and cerebral hemispheres) by measuring the activity of antioxidant enzymes and levels of malondialdehyde (MDA) using spectrophotometric methods. Biochemical parameters were also assessed in serum samples from the CCl4-treated rats. The T. americana var. mexicana leaf extracts provided significant protection against CCl4-induced peripheral and central damage by increasing the activity of antioxidant enzymes, diminishing lipid peroxidation, and preventing alterations in biochemical serum parameters, such as the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-globulin (γ-GLOB), serum albumin (ALB), total bilirubin (BB), creatinine (CREA) and creatine kinase (CK), relative to the control group. Additionally, we correlated gene expression with antioxidant activity in the experimental groups treated with the organic and aqueous Tilia extracts and observed a non-statistically significant positive correlation. Our results provide evidence of the underlying biomedical properties of T. americana var. mexicana that confer its neuro- and hepatoprotective effects.

Giardia lamblia is a single-celled eukaryotic parasite with a small genome and is considered an early divergent eukaryote. The pentose phosphate pathway (PPP) plays an essential role in the oxidative stress defense of the parasite and the production of ribose-5-phosphate. In this parasite, the glucose-6-phosphate dehydrogenase (G6PD) is fused with the 6-phosphogluconolactonase (6PGL) enzyme, generating the enzyme named G6PD::6PGL that catalyzes the first two steps of the PPP. Here, we report that the G6PD::6PGL is a bifunctional enzyme with two catalytically active sites. We performed the kinetic characterization of both domains in the fused G6PD::6PGL enzyme, as well as the individual cloned G6PD. The results suggest that the catalytic activity of G6PD and 6PGL domains in the G6PD::6PGL enzyme are more efficient than the individual proteins. Additionally, using enzymatic and mass spectrometry assays, we found that the final metabolites of the catalytic reaction of the G6PD::6PGL are 6-phosphoglucono-δ-lactone and 6-phosphogluconate. Finally, we propose the reaction mechanism in which the G6PD domain performs the catalysis, releasing 6-phosphoglucono-δ-lactone to the reaction medium. Then, this metabolite binds to the 6PGL domain catalyzing the hydrolysis reaction and generating 6-phosphogluconate. The structural difference between the G. lamblia fused enzyme G6PD::6PGL with the human G6PD indicate that the G6PD::6PGL is a potential drug target for the rational synthesis of novels anti-Giardia drugs.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is an emergent infectious disease that has caused millions of deaths throughout the world. COVID-19 infection’s main symptoms are fever, cough, fatigue, and neurological manifestations such as headache, myalgias, anosmia, ageusia, impaired consciousness, seizures, and even neuromuscular junctions’ disorders. In addition, it is known that this disease causes a series of systemic complications such as adverse respiratory distress syndrome, cardiac injury, acute kidney injury, and liver dysfunction. Due to the neurological symptoms associated with COVID-19, damage in the central nervous system has been suggested as well as the neuroinvasive potential of SARS-CoV-2. It is known that CoV infections are associated with an inflammation process related to the imbalance of the antioxidant system; cellular changes caused by oxidative stress contribute to brain tissue damage. Although anti-COVID-19 vaccines are under development, there is no specific treatment for COVID-19 and its clinical manifestations and complications; only supportive treatments with immunomodulators, anti-vascular endothelial growth factors, modulating drugs, statins, or nutritional supplements have been used. In the present work, we analyzed the potential of antioxidants as adjuvants for the treatment of COVID-19 and specifically their possible role in preventing or decreasing the neurological manifestations and neurological complications present in the disease.

Most Lactobacillus species have beneficial immunological (“immunoprobiotic”) effects in the host. However, it is unclear how probiotic bacteria regulate immune responses. The present study investigated the effects of heat-killed Lactobacillus casei IMAU60214 on the activity of human monocyte-derived macrophages (MDMs). Human MDMs were treated with heat-killed L. casei at a ratio (bacteria/MDM) of 50:1, 100:1, 250:1, and 500:1, and then evaluated for the following: NO production, by Griess reaction; phagocytosis of FITC-labeled Staphylococcus aureus particles; cytokine secretion profile (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12p70, IL-10, and transforming growth factor (TGF)-β) by ELISA; and costimulatory molecule (CD80 and CD86) surface expression, by flow cytometry. Heat-killed L. casei IMAU60214 enhanced phagocytosis, NO production, cytokine release, and surface expression of CD80 and CD86 in a dose-dependent manner. All products were previously suppressed by pretreatment with a Toll-like receptor 2 (TLR2)-neutralizing antibody. Overall, our findings suggest that this probiotic strain promotes an M1-like pro-inflammatory phenotype through the TLR2 signaling pathway. These effects on macrophage phenotype help explain the probiotic efficacy of Lactobacillus and provide important information for the selection of therapeutic targets and treatments compatible with the immunological characteristics of this probiotic strain.

Giardia lambia is a flagellated protozoan parasite that lives in the small intestine and is the causal agent of giardiasis. It has been reported that G. lamblia exhibits glucose-6-phosphate dehydrogenase (G6PD), the first enzyme in the pentose phosphate pathway (PPP). Our group work demonstrated that the g6pd and 6pgl genes are present in the open frame that gives rise to the fused G6PD::6PGL protein; where the G6PD region is similar to the 3D structure of G6PD in Homo sapiens. The objective of the present work was to show the presence of the structural NADP+ binding site on the fused G6PD::6PGL protein and evaluate the effect of the NADP+ molecule on protein stability using biochemical and computational analysis. A protective effect was observed on the thermal inactivation, thermal stability, and trypsin digestions assays when the protein was incubated with NADP+. By molecular docking, we determined the possible structural-NADP+ binding site, which is located between the Rossmann fold of G6PD and 6PGL. Finally, molecular dynamic (MD) simulation was used to test the stability of this complex; it was determined that the presence of both NADP+ structural and cofactor increased the stability of the enzyme, which is in agreement with our experimental results.