RESUMO
Heavy metals are encountered in nature, and are used in several human endeavors, including in dental fillings. It is well known that the safety of metals depends on their chemical form, as well as the dose and route through which biological systems are exposed to them. Here, we used the Nauphoeta cinerea model to examine the mechanism by which salts of the heavy metals used in dental fillings - silver and mercury - exert their neurotoxicity. Nymphs exposed to heavy metals presented with reduced motor and exploratory abilities as they spent more time immobile, especially in the periphery of a novel object, and covered less distance compared with control nymphs. Exposure to AgNO3 and HgCl2 also exacerbated levels of oxidative stress markers (MDA & ROS) and the neurotransmitter regulators - AChE and MAO, while reducing antioxidant activity markers, both in biochemical (thiol & GST) and RT-qPCR (TRX, GST, SOD, Catalase) examinations, in neural tissues of the cockroach. The observed disruptions in neurolocomotor control, synaptic transmission and redox balance explain how heavy metal salts may predispose organisms to neurological disorders.
Assuntos
Oxirredução , Estresse Oxidativo , Animais , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Mercúrio/toxicidade , Prata/farmacologia , Prata/toxicidade , Neurotransmissores/metabolismo , Acetilcolinesterase/metabolismo , Ninfa/efeitos dos fármacos , Ninfa/metabolismo , Monoaminoxidase/metabolismo , Comportamento Animal/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Nitrato de Prata/farmacologia , Cloreto de Mercúrio/toxicidadeRESUMO
Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid ß (Aß) production through up-regulation of Aß precursor protein (APP) and ß secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.
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The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aß formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aß and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aß formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aß accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.
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Responsible for COVID-19, SARS-CoV-2 is a coronavirus in which contagious variants continue to appear. Therefore, some population groups have demonstrated greater susceptibility to contagion and disease progression. For these reasons, several researchers have been studying the SARS-CoV-2/human interactome to understand the pathophysiology of COVID-19 and develop new pharmacological strategies. D. melanogaster is a versatile animal model with approximately 90 % human protein orthology related to SARS-CoV-2/human interactome and is widely used in metabolic studies. In this context, our work assessed the potential interaction between human proteins (ZNF10, NUP88, BCL2L1, UBC9, and RBX1) and their orthologous proteins in D. melanogaster (gl, Nup88, Buffy, ubc9, and Rbx1a) with proteins from SARS-CoV-2 (nsp3, nsp9, E, ORF7a, N, and ORF10) using computational approaches. Our results demonstrated that all the proteins have the potential to interact, and we compared the binding sites between humans and fruit flies. The stability and consistency in the structure of the gl_nsp3 complex, specifically, could be crucial for its specific biological functions. Lastly, to enhance the understanding of the influence of host factors on coronavirus infection, we also analyse the mRNA expression of the five genes (mbo, gl, lwr, Buffy, and Roc1a) responsible for encoding the fruit fly proteins. Briefly, we demonstrated that those genes were differentially regulated according to diets, sex, and age. Two groups showed higher positive gene regulation than others: females in the HSD group and males in the aging group, which could imply a higher virus-host susceptibility. Overall, while preliminary, our work contributes to the understanding of host defense mechanisms and potentially identifies candidate proteins and genes for in vivo viral studies against SARS-CoV-2.
Assuntos
COVID-19 , Drosophila melanogaster , RNA Mensageiro , SARS-CoV-2 , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Animais , Humanos , COVID-19/virologia , COVID-19/metabolismo , COVID-19/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Feminino , Masculino , Interações Hospedeiro-Patógeno/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genéticaRESUMO
The reactivity of Zn2+ tetrahedral complexes with H2O2 was investigated in silico, as a first step in their disruption process. The substrates were chosen to represent the cores of three different zinc finger protein motifs, i. e., a Zn2+ ion coordinated to four cysteines (CCCC), to three cysteines and one histidine (CCCH), and to two cysteines and two histidines (CCHH). The cysteine and histidine ligands were further simplified to methyl thiolate and imidazole, respectively. H2O2 was chosen as an oxidizing agent due to its biological role as a metabolic product and species involved in signaling processes. The mechanism of oxidation of a coordinated cysteinate to sulfenate-κS and the trends for the different substrates were rationalized through activation strain analysis and energy decomposition analysis in the framework of scalar relativistic Density Functional Theory (DFT) calculations at ZORA-M06/TZ2P ae // ZORA-BLYP-D3(BJ)/TZ2P. CCCC is oxidized most easily, an outcome explained considering both electrostatic and orbital interactions. The isomerization to sulfenate-κO was attempted to assess whether this step may affect the ligand dissociation; however, it was found to introduce a kinetic barrier without improving the energetics of the dissociation. Lastly, ligand exchange with free thiolates and selenolates was investigated as a trigger for ligand dissociation, possibly leading to metal ejection; molecular docking simulations also support this hypothesis.
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The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.
Assuntos
Metais Pesados , Retina , Humanos , Retina/efeitos dos fármacos , Retina/patologia , Retina/metabolismo , Metais Pesados/toxicidade , Animais , Estresse Oxidativo/efeitos dos fármacos , Degeneração Macular/induzido quimicamenteRESUMO
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS: 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS: The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION: It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Oligoelementos , Adulto , Humanos , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Oligoelementos/análise , Aminoácidos , Minerais , ColesterolRESUMO
Neurotoxicity associated with chemotherapy is a debilitating side effect of cancer management in humans which reportedly involves inflammatory and oxidative stress responses. Diphenyl diselenide (DPDS) is an organoselenium compound which exhibits its anti-tumoral, anti-oxidant, anti-inflammatory and anti-mutagenic effects. Nevertheless, its possible effect on chemotherapy-induced neurotoxicity is not known. Using rat model, we probed the behavioral and biochemical effects accompanying administration of antineoplastic agent doxorubicin (7.5 mg/kg) and DPDS (5 and 10 mg/kg). Anxiogenic-like behavior, motor and locomotor insufficiencies associated with doxorubicin were considerably abated by both DPDS doses with concomitant enhancement in exploratory behavior as demonstrated by reduced heat maps intensity and enhanced track plot densities. Moreover, with exception of cerebral glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, biochemical data demonstrated reversal of doxorubicin-mediated decline in cerebral and cerebellar antioxidant status indices and the increase in acetylcholinesterase (AChE) activity by both doses of DPDS. Also, cerebellar and cerebral lipid peroxidation, hydrogen peroxide as well as reactive oxygen and nitrogen species levels were considerably diminished in rats administered doxorubicin and DPDS. In addition, DPDS administration abated myeloperoxidase activity, tumour necrosis factor alpha and nitric oxide levels along with caspase-3 activity in doxorubicin-administered rats. Chemoprotection of doxorubicin-associated neurotoxicity by DPDS was further validated by histomorphometry and histochemical staining. Taken together, DPDS through offsetting of oxido-inflammatory stress and caspase-3 activation elicited neuroprotection in doxorubicin-treated rats.
Assuntos
Compostos Organosselênicos , Temefós , Humanos , Ratos , Animais , Caspase 3 , Temefós/farmacologia , Acetilcolinesterase , Estresse Oxidativo , Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Derivados de Benzeno/uso terapêutico , Derivados de Benzeno/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Doxorrubicina/toxicidadeRESUMO
The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and their potential roles in the development of osteoporosis. Epidemiological findings have demonstrated an association between vitamin deficiency and a higher risk of developing osteoporosis; vitamins are positively related to bone health upon their intake at the physiological range. Excessive vitamin intake can also adversely affect bone formation, as clearly demonstrated for vitamin A. Vitamins E (tocopherols and tocotrienols), K2 (menaquinones 4 and 7) and C have also been shown to promote osteoblast development through bone morphogenetic protein (BMP)/Smad and Wnt/ßcatenin signaling, as well as the TGFß/Smad pathway (αtocopherol). Vitamin A metabolite (alltrans retinoic acid) exerts both inhibitory and stimulatory effects on BMP and Wnt/ßcateninmediated osteogenesis at the nanomolar and micromolar range, respectively. Certain vitamins significantly reduce receptor activator of nuclear factor kappaB ligand (RANKL) production and RANKL/RANK signaling, while increasing the level of osteoprotegerin (OPG), thus reducing the RANKL/OPG ratio and exerting antiosteoclastogenic effects. Ascorbic acid can both promote and inhibit RANKL signaling, being essential for osteoclastogenesis. Vitamin K2 has also been shown to prevent vascular calcification by activating matrix Gla protein through its carboxylation. Therefore, the maintenance of a physiological intake of vitamins should be considered as a nutritional strategy for the prevention of osteoporosis.
Assuntos
Osteoporose , Vitaminas , Humanos , Vitaminas/farmacologia , Colecalciferol/farmacologia , beta Catenina/metabolismo , Vitamina A , Densidade Óssea , Osteoporose/metabolismo , Vitamina K , Proteínas Morfogenéticas Ósseas , Via de Sinalização WntRESUMO
Several studies have demonstrated that rabbits can be maintained on diets containing high levels of Crude Fiber (CF) when compared to other monogastric animals. In the present study, we examined the effects of rice hulls and of bermuda grass (cv. Coast cross) on the growing performance of 30 day-old weaned rabbits. Rabbits were fed one of 5 diets containing rice hulls and/or bermuda grass as fiber source at the following proportions (BG/RH) 0/17.5, 15/11, 0/29, 14.7/19.1 and 48.5/0 for diets A, B, C, D and E, respectively. Body weight gain and voluntary feed intake were measured at 30, 44, 58 and 72 days. The time necessary to attain 2 kg of live body weight was not affected by the diets. However, daily weight gain differed significantly during the first two weeks after weaning among dietary groups. Diets C and D caused a lower body weight gain, probably because of the high level of Acid Detergent Fiber (ADF) in the diet (24 and 23). Voluntary feed intake increased with age in all treatments, but food intake was lower in treatments C and D when compared to animals receiving treatments B and E. The present results demonstrate that when rice hulls are used as fiber source, fiber must be given as ADF and not as CF because the difference between ADF and CF is enormous. Rice hull-containing diets balanced with CF give an inappropriate amount of components that seem to affect the growth performance of young animals.
Assuntos
Animais , Masculino , Feminino , Magnoliopsida , Oryza , Coelhos , Análise de Variância , Peso Corporal , Dieta , Fatores de TempoRESUMO
Protein malnutrition during suckling period or throughout the life affects the hypothalamic ß-endorphinergic system of adult rats. In the present study, rats were under nourished during suckling by feeding their dams an 8% casein diet whereas well-nourished dams recived a 25% casein diet from birth until weaning (21 day of postnatal life). After weaning, the offsprings were maintained with the same diet as their dams. When rats were 3 month-old, they were subjected to two-way active avoidance task. Protein malnutrition did not affect the performance in the two-way active avoidance task. Post-training ß-endorphin or Met-enkephalin administration impaired the retention of shuttle avoidance tast in both well-nourished and undernourished rats. However, the amnesic effect of the peptides was only achieved in undernourished rats with higher doses of apioids when compared to the well-nourished rats. These data suggest that undernourished rats present alterations in opioid sensitivity which may be related to changes in the levels of ß-endorphin previously observed both in brain and hypothalamus of early undernourished adults rats