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Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1ß, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.
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Biomarcadores , Hipocampo , Lipopolissacarídeos , Doenças Neuroinflamatórias , Aldeído Pirúvico , Aldeído Pirúvico/metabolismo , Lipopolissacarídeos/farmacologia , Animais , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Biomarcadores/metabolismo , Masculino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Glicólise/efeitos dos fármacos , Interleucina-1beta/metabolismo , Inflamação/metabolismo , Inflamação/induzido quimicamente , Proteína Glial Fibrilar Ácida/metabolismo , Lactoilglutationa Liase/metabolismo , Ratos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacosRESUMO
Astrocytes play fundamental roles in the maintenance of brain homeostasis. The dysfunction of these cells is widely associated with brain disorders, which are often characterized by variations in the astrocyte protein markers GFAP and S100B, in addition to alterations in some of its metabolic functions. To understand the role of astrocytes in neurodegeneration mechanisms, we induced some of these metabolic alterations, such as energy metabolism, using methylglyoxal (MG) or fluorocitrate (FC); and neuroinflammation, using lipopolysaccharide (LPS) and streptozotocin (STZ), which is used for inducing Alzheimer's disease (AD) in animal models. We showed that MG, LPS, STZ and FC similarly caused astrocyte dysfunction by increasing GFAP and reducing S100B secretion. In the context of AD, STZ caused an amyloid metabolism impairment verified by increases in Aß1-40 peptide content and decreases in the amyloid degradation enzymes, IDE and NEP. Our data contribute to the understanding of the role of astrocytes in brain injury mechanisms and suggest that STZ is suitable for use in vitro models for studying the role of astrocytes in AD.
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Metformin, a biguanide compound (N-1,1-dimethylbiguanide), is widely prescribed for diabetes mellitus type 2 (T2D) treatment. It also presents a plethora of properties, such as anti-oxidant, anti-inflammatory, anti-apoptosis, anti-tumorigenic, and anti-AGE formation activity. However, the precise mechanism of action of metformin in the central nervous system (CNS) needs to be clarified. Herein, we investigated the neuroprotective role of metformin in acute hippocampal slices exposed to methylglyoxal (MG), a highly reactive dicarbonyl compound and a key molecule in T2D developmental pathophysiology. Metformin protected acute hippocampal slices from MG-induced glutamatergic neurotoxicity and neuroinflammation by reducing IL-1ß synthesis and secretion and RAGE protein expression. The drug also improved astrocyte function, particularly with regard to the glutamatergic system, increasing glutamate uptake. Moreover, we observed a direct effect of metformin on glutamate transporters, where the compound prevented glycation, by facilitating enzymatic phosphorylation close to Lys residues, suggesting a new neuroprotective role of metformin via PKC ζ in preventing dysfunction in glutamatergic system induced by MG. Proposed neuroprotection role of metformin in acute hippocampal slices against impairment in glutamatergic system induced in a model of methylglyoxal glycotoxicity. Metformin reversed methylglyoxal (MG)-induced neuroinflammation by reducing pro-inflammatory IL-1ß synthesis and secretion and RAGE protein expression. Metformin did not alter the effect of MG on S100B secretion (1). Both MG and metformin also influenced astrocyte function in hippocampal slices. Metformin did not reverse the elevation in GLO1 activity induced by glycotoxicity; however, it abrogated the high GSH level and the expression of the co-factor of GLO1 (2). Both treatments per se changed bioenergetic metabolism and increased glucose uptake, extracellular lactate content, and pyruvate kinase (PK) activity. The increment in glucose uptake and lactate levels ceased during the co-incubation of MG with metformin. Metformin reversed the elevation of hexokinase activity by MG (3). We suggest a new role of metformin in the glutamate system, whereby it protects the hippocampus against the derangements of the glutamatergic system induced by MG, possibly by phosphorylation via PKC ζ (4). The neuroprotective action of metformin may be mediated by the phosphorylation of specific amino acid residues (Lysine) of the glutamate transporters (GLAST and GLT-1), since metformin activated the PKC ζ signaling and promoted cascades of phosphorylation in p38 MAPK and Akt proteins. The transporter protein phosphorylation prevented the Lys-glycation and the impairment of glutamate uptake induced by MG (5).
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Glycolytic overload in diabetes causes large accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO) and overproduction of advanced glycation end products (AGEs), which interact with their receptors (RAGE), leading to diabetes-associated macrovascular complications. The bladder is an organ that stays most in contact with dicarbonyl species, but little is known about the importance of the MGO-AGEs-RAGE pathway to diabetes-associated bladder dysfunction. Here, we aimed to investigate the role of the MGO-AGEs-RAGE pathway in bladder dysfunction of diabetic male and female ob/ob mice compared with wild-type (WT) lean mice. Diabetic ob/ob mice were treated with the AGE breaker alagebrium (ALT-711, 1 mg/kg) for 8 wk in drinking water. Compared with WT animals, male and female ob/ob mice showed marked hyperglycemia and insulin resistance, whereas fluid intake remained unaltered. Levels of total AGEs, MGO-derived hydroimidazolone 1, and RAGE in bladder tissues, as well as fluorescent AGEs in serum, were significantly elevated in ob/ob mice of either sex. Collagen content was also markedly elevated in the bladders of ob/ob mice. Void spot assays in filter paper in conscious mice revealed significant increases in total void volume and volume per void in ob/ob mice with no alterations of spot number. Treatment with ALT-711 significantly reduced the levels of MGO, AGEs, RAGE, and collagen content in ob/ob mice. In addition, ALT-711 treatment normalized the volume per void and increased the number of spots in ob/ob mice. Activation of AGEs-RAGE pathways by MGO in the bladder wall may contribute to the pathogenesis of diabetes-associated bladder dysfunction.NEW & NOTEWORTHY The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic ob/ob mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.
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Diabetes Mellitus Experimental , Produtos Finais de Glicação Avançada , Masculino , Feminino , Camundongos , Animais , Receptor para Produtos Finais de Glicação Avançada , Produtos Finais de Glicação Avançada/metabolismo , Aldeído Pirúvico/metabolismo , Diabetes Mellitus Experimental/complicações , Bexiga Urinária/metabolismo , Óxido de Magnésio , Obesidade/complicações , Camundongos EndogâmicosRESUMO
Methylglyoxal (MGO) is a reactive dicarbonyl compound formed as a byproduct of glycolysis. MGO is a major cell-permeant precursor of advanced glycation end products (AGEs), since it readily reacts with basic phospholipids and nucleotides, as well as amino acid residues of proteins, such as arginine, cysteine, and lysine. The AGEs production induced by MGO are widely associated with several pathologies, including neurodegenerative diseases. However, the impact of MGO metabolism and AGEs formation in the central nervous system (particularly in neurons, astrocytes and oligodendrocytes) on behavior and psychiatric diseases is not fully understood. Here, we briefly present background information on the biological activity of MGO in the central nervous system. It was gathered the available information on the role of MGO metabolism at the physiological processes, as well as at the neurobiology of psychiatry diseases, especially pain-related experiences, anxiety, depression, and cognition impairment-associated diseases. To clarify the role of MGO on behavior and associated diseases, we reviewed primarily the main findings at preclinical studies focusing on genetic and pharmacological approaches. Since monoamine neurotransmitter systems are implicated as pivotal targets on the pathophysiology and treatment of psychiatry and cognitive-related diseases, we also reviewed how MGO affects these neurotransmission systems and the implications of this phenomenon for nociception and pain; learning and cognition; and mood. In summary, this review highlights the pivotal role of glyoxalase 1 (Glo1) and MGO levels in modulating behavioral phenotypes, as well as related cellular and molecular signaling. Conclusively, this review signals dopamine as a new neurochemical MGO target, as well as highlights how MGO metabolism can modulate the pathophysiology and treatment of pain, psychiatric and cognitive-related diseases.
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Transtornos Mentais , Aldeído Pirúvico , Humanos , Aldeído Pirúvico/farmacologia , Aldeído Pirúvico/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Cisteína , Dopamina , Lisina , Óxido de Magnésio , Dor , Arginina , NucleotídeosRESUMO
The reactive dicarbonyl methylglyoxal (MG) behaves as a pro-oxidant agent, causing redox dysfunction and cell death by different mechanisms in mammalian cells. MG is also a mitochondrial toxicant, impairing the oxidative phosphorylation (OXPHOS) system and leading to bioenergetics and redox collapses. MG induces glycation and exerts an important role in neurodegenerative and cardiovascular diseases. Isoorientin (ISO), a C-glucosyl flavone found in Aspalathus linearis, Fagopyrum esculentum, and Passiflora edulis, among others, is an antioxidant and anti-inflammatory molecule. ISO is a potent inducer of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master modulator of the redox environment in mammals. We investigated here whether ISO would prevent the mitochondria-related redox and bioenergetics impairments induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were administrated with ISO at 20 µM for 18 h prior to the exposure to MG at 500 µM for further 24 h. It was observed that ISO efficiently prevented the mitochondrial impairments caused by MG. ISO upregulated the activity of the enzyme γ-glutamate-cysteine ligase (γ-GCL), consequently stimulating the synthesis of glutathione (GSH). The inhibition of γ-GCL, adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt) suppressed the beneficial effects induced by ISO on the MG-challenged cells. Moreover, silencing of Nrf2 blocked the ISO-dependent γ-GCL and GSH upregulation and the effects on the mitochondria of the MG-challenged cells. Then, ISO caused mitochondrial protection by an AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH-dependent manner in MG-administrated SH-SY5Y cells.
Assuntos
Neuroblastoma , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Glutamato-Cisteína Ligase/farmacologia , Aldeído Pirúvico/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Neuroblastoma/metabolismo , Glutationa/metabolismo , Luteolina/farmacologia , Luteolina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Linhagem Celular Tumoral , Mamíferos/metabolismoRESUMO
Methylglyoxal (MG) is a reactive dicarbonyl compound formed mostly via the glycolytic pathway. Elevated blood glucose levels can cause MG accumulation in plasma and cerebrospinal fluid in patients with diabetes mellitus and Alzheimer's disease. Under these disease conditions, the high reactivity of MG leads to modification of proteins and other biomolecules, generating advanced glycation end products (AGEs), which are considered mediators in neurodegenerative diseases. We investigated the integrity of the blood-brain barrier (BBB) and astrocyte response in the hippocampus to acute insult induced by MG when it was intracerebroventricularly administered to rats. Seventy-two hours later, BBB integrity was lost, as assessed by the entry of Evans dye into the brain tissue and albumin in the cerebrospinal fluid, and a decrease in aquaporin-4 and connexin-43 in the hippocampal tissue. MG did not induce changes in the hippocampal contents of RAGE in this short interval, but decreased the expression of S100B, an astrocyte-secreted protein that binds RAGE. The expression of two important transcription factors of the antioxidant response, NF-κB and Nrf2, was unchanged. However, hemeoxigenase-1 was upregulated in the MG-treated group. These data corroborate the idea that hippocampal cells are targets of MG toxicity and that BBB dysfunction and specific glial alterations induced by this compound may contribute to the behavioral and cognitive alterations observed in these animals.
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Aquaporinas , Aldeído Pirúvico , Albuminas/metabolismo , Animais , Antioxidantes/metabolismo , Aquaporinas/metabolismo , Glicemia/metabolismo , Barreira Hematoencefálica/metabolismo , Conexinas/metabolismo , Produtos Finais de Glicação Avançada/toxicidade , Hipocampo/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Aldeído Pirúvico/farmacologia , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismoRESUMO
Glycoxidative stress with the consequent generation of advanced glycation end products has been implied in the etiology of numerous non-communicable chronic diseases. During the postprandial state, the levels of 1,2-dicarbonyl compounds can increase, depending on numerous factors, including characteristics of the subjects mainly related to glucose metabolism disorders and nutritional status, as well as properties related to the chemical composition of meals, including macronutrient composition and the presence of dietary bioactive molecules and macromolecules. In this review, we examine the chemical, biochemical, and physiological pathways that contribute to postprandial generation of 1,2-dicarbonyl compounds. The modulation of postprandial 1,2-dicarbonyl compounds is discussed in terms of biochemical pathways regulating the levels of these compounds, as well as the effect of phenolic compounds, dietary fiber, and dietary patterns, such as Mediterranean and Western diets.
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Endophytes, microorganisms that live in the internal tissues and organs of the plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. For such reason, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest. Currently, many non-communicable diseases are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailment related to chronic inflammation and ageing. Intriguingly, the pathogenesis and development of these diseases have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs). AGEs are a heterogeneous group of compounds that can alter the conformation, function, and lifetime of proteins. Therefore, compounds that prevent the formation and consequent accumulation of AGEs (AntiAGEs compounds) could be useful to delay the progress of some chronic diseases, and/or harmful effects of undue AGEs accumulation. Despite the remarkable ability of endophytes to produce bioactive compounds, most of the natural antiAGEs compounds reported in the literature are derived from plants. Accordingly, this work covers 26 plant antiAGEs compounds and some derivatives that have been reported as endophytic metabolites, and discusses the importance, possible advantages, and challenges of using endophytes as a potential source of antiAGEs compounds.
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Endófitos , Produtos Finais de Glicação Avançada , Endófitos/química , Fungos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Compostos Fitoquímicos/metabolismo , Plantas/químicaRESUMO
One of the hallmarks of diabetes is an increased modification of cellular proteins. The most prominent type of modification stems from the reaction of methylglyoxal with arginine and lysine residues, leading to structural and functional impairments of target proteins. For lysine glycation, several algorithms allow a prediction of occurrence; thus, making it possible to pinpoint likely targets. However, according to our knowledge, no approaches have been published for predicting the likelihood of arginine glycation. There are indications that arginine and not lysine is the most prominent target for the toxic dialdehyde. One of the reasons why there is no arginine glycation predictor is the limited availability of quantitative data. Here, we used a recently published high-quality dataset of arginine modification probabilities to employ an artificial neural network strategy. Despite the limited data availability, our results achieve an accuracy of about 75% of correctly predicting the exact value of the glycation probability of an arginine-containing peptide without setting thresholds upon whether it is decided if a given arginine is modified or not. This contribution suggests a solution for predicting arginine glycation of short peptides.
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Arginina , Produtos Finais de Glicação Avançada , Produtos Finais de Glicação Avançada/química , Lisina/química , Redes Neurais de Computação , Peptídeos/química , Proteínas , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismoRESUMO
Mammillaria bombycina is a cactus distributed in the central region of Mexico. Cactaceae have the particularity of surviving drought and high temperatures, which is why in vitro propagation studies have been carried out successfully to preserve this species and use it as a study model in cacti. In this contribution, a de novo transcriptome of M. bombycina was produced under in vitro conditions for the identification and expression of genes related to abiotic stress. Samples were sequenced using an Illumina platform, averaging 24 million clean readings. From assembly and annotation, 84,975 transcripts were generated, 55% of which were unigenes. Among these, the presence of 13 isoforms of genes belonging to glyoxalase I, II and III were identified. An analysis of the qRT-PCR expression of these genes was performed under in vitro and ex vitro conditions and dehydration at 6 and 24 h. The highest expression was observed under greenhouse conditions and dehydration at 24 h, according to the control. The de novo assembly of the M. bombycina transcriptome remains a study model for future work in cacti.
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Alzheimer's disease (AD) is the leading cause of dementia in humans, with a high social and economic cost. AD is predominantly a sporadic disease, and the intracerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as an AD-like model of dementia. While the etiology of AD remains unknown, changes such as glucose metabolism and activation of receptors for advanced glycation end products (RAGE) seem to underlie its pathogenesis. We hypothesized that methylglyoxal, an endogenous toxin derived from the glycolytic pathway, could be the precursor of advanced glycated end products that activates RAGE and that, consequently, may activate membrane NADPH oxidase (NOX), contributing to the inflammatory status of the model and the disease. We administered ICV-STZ to Wistar rats and evaluated several neurochemical parameters in the hippocampus, particularly glyoxalase 1 (GLO-1) activity, which serves as an index of high levels of methylglyoxal, and the contents of RAGE and NOX-2, the most abundant brain NOX isoform. At the times evaluated (4 and 24 weeks after STZ), we observed cognitive deficit, increased beta-amyloid content, and increased tau phosphorylation. A persistent increase in GLO-1 activity was found, as well as increases in RAGE and NOX-2 contents, suggesting astroglial and microglial commitment. The increase in NOX-2 may reflect elevated microglial activity (confirmed by IBA-1 marker), which may contribute to the synaptic dysfunction and pruning described in the literature, both in this model and AD patients. Furthermore, reinforcing this possibility, we found a reduction in cholinergic communication in the hippocampus (as shown by decreased choline acetyltransferase), a reduction in BDNF, and an increase in TGF-ß, the combination of which may result in synaptic deterioration.
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Doença de Alzheimer , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Aprendizagem em Labirinto , Aldeído Pirúvico/metabolismo , Aldeído Pirúvico/toxicidade , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Estreptozocina/toxicidadeRESUMO
This work aimed to investigate the effects of early progeny exposure to methylglyoxal (MG), programming for metabolic dysfunction and diabetes-like complications later in life. At delivery (PN1), the animals were separated into two groups: control group (CO), treated with saline, and MG group, treated with MG (20 mg/kg of BW; i.p.) during the first 2 weeks of the lactation period. In vivo experiments and tissue collection were done at PN90. Early MG exposure decreased body weight, adipose tissue, liver and kidney weight at adulthood. On the other hand, MG group showed increased relative food intake, blood fructosamine, blood insulin and HOMA-IR, which is correlated with insulin resistance. Besides, MG-treated animals presented dyslipidaemia, increased oxidative stress and inflammation. Likewise, MG group showed steatosis and perivascular fibrosis in the liver, pancreatic islet hypertrophy, increased glomerular area and pericapsular fibrosis, but reduced capsular space. This study shows that early postnatal exposure to MG induces oxidative stress, inflammation and fibrosis markers in pancreas, liver and kidney, which are related to metabolic dysfunction features. Thus, nutritional disruptors during lactation period may be an important risk factor for metabolic alterations at adulthood.
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Estresse Oxidativo , Aldeído Pirúvico , Animais , Feminino , Fibrose , Inflamação/induzido quimicamente , Aldeído Pirúvico/toxicidade , Ratos , Ratos WistarRESUMO
Pioglitazone, an agonist at peroxisome proliferator-activated receptor gamma, is FDA-approved for the treatment of insulin resistance in type 2 diabetes. Numerous studies in male rodents suggest that pioglitazone inhibits inflammatory and neuropathic pain, but few included female subjects. To address this gap, we compared the effects of pioglitazone in both sexes in the intraplantar methylglyoxal model (MG) model of chemical pain and painful diabetic neuropathy (PDN), the plantar incision model (PIM) of postoperative pain, the spared nerve injury (SNI) model of traumatic nerve injury, and the ZDF rat and db/db mouse models of PDN. We administered pioglitazone by one-time intrathecal or intraperitoneal injection or by adding it to chow for 6 weeks, followed by measurement of hypersensitivity to non-noxious mechanical, noxious mechanical, heat, and/or cold stimuli. In all mouse models, injection of pioglitazone decreased pain-like behaviors with greater potency and/or efficacy in females as compared to males: heat and mechanical hypersensitivity in the MG model (0.1-10 mg/kg); mechanical hypersensitivity in the PIM model (10 µg); mechanical and cold hypersensitivity in the SNI model (100 mg/kg); and heat hypersensitivity in the db/db model (100 mg/kg). Furthermore, co-administration of low doses of morphine (1 mg/kg) and pioglitazone (10 mg/kg) decreased SNI-induced mechanical and cold hypersensitivity in female but not male mice. In the ZDF rat, pioglitazone (100 mg/kg) decreased heat and mechanical hypersensitivity with no sex difference. In the db/db model, pioglitazone had no effect when given into chow for 6 weeks at 0.3, 3 or 30 mg/kg doses. We conclude that females exhibit greater anti-hyperalgesic responses to pioglitazone in mouse models of chemical-induced nociception, postsurgical pain, neuropathic pain, and PDN. These findings set the stage for clinical trials to determine whether pioglitazone has analgesic properties across a broad spectrum of chronic pain conditions, particularly in women.
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Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , PPAR gama/agonistas , Dor Pós-Operatória/tratamento farmacológico , Pioglitazona/farmacologia , Analgésicos/administração & dosagem , Animais , Neuropatias Diabéticas/complicações , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Morfina/farmacologia , Neuralgia/etiologia , Dor Nociceptiva/induzido quimicamente , Dor Pós-Operatória/etiologia , Traumatismos dos Nervos Periféricos/complicações , Pioglitazona/administração & dosagem , Aldeído Pirúvico/farmacologia , Caracteres SexuaisRESUMO
Aminoacetone (1-aminopropan-2-one), a putative minor biological source of methylglyoxal, reacts like other α-aminoketones such as 6-aminolevulinic acid (first heme precursor) and 1,4-diaminobutanone (a microbicide) yielding electrophilic α-oxoaldehydes, ammonium ion and reactive oxygen species by metal- and hemeprotein-catalyzed aerobic oxidation. A plethora of recent reports implicates triose phosphate-generated methylglyoxal in protein crosslinking and DNA addition, leading to age-related disorders, including diabetes. Importantly, methylglyoxal-treated hemoglobin adds four water-exposed arginine residues, which may compromise its physiological role and potentially serve as biomarkers for diabetes. This paper reports on the co-oxidation of aminoacetone and oxyhemoglobin in normally aerated phosphate buffer, leading to structural changes in hemoglobin, which can be attributed to the addition of aminoacetone-produced methylglyoxal to the protein. Hydroxyl radical-promoted chemical damage to hemoglobin may also occur in parallel, which is suggested by EPR-spin trapping studies with 5,5-dimethyl-1-pyrroline-N-oxide and ethanol. Concomitantly, oxyhemoglobin is oxidized to methemoglobin, as indicated by characteristic CD spectral changes in the Soret and visible regions. Overall, these findings may contribute to elucidate the molecular mechanisms underlying human diseases associated with hemoglobin dysfunctions and with aminoacetone in metabolic alterations related to excess glycine and threonine.
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Hemoglobinas , Aldeído Pirúvico , Acetona/análogos & derivados , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Oxirredução , Espécies Reativas de OxigênioRESUMO
Methylglyoxal (MG) is an endogenously produced toxicant that induces mitochondrial dysfunction leading to impaired redox biology homeostasis, bioenergetics collapse, and cell death in mammalian cells. However, MG toxicity is particularly relevant to neurons and glia given their chemical and metabolic characteristics. Here, we have investigated whether a pretreatment with carnosic acid (CA) would be able to promote mitochondrial protection in human neuroblastoma SH-SY5Y cells exposed to MG. We found that a pretreatment with CA at 1 µM for 12 h prevented the MG-induced lipid peroxidation and protein carbonylation and nitration in the membranes of mitochondria obtained from the SH-SY5Y cells. CA also prevented the MG-elicited Complexes I and V dysfunction, adenosine triphosphate (ATP) levels decline, and loss of mitochondrial membrane potential (MMP). Moreover, CA also reduced the mitochondrial production of the radical anion superoxide (O2-â¢) in the MG-challenged cells. We found that CA upregulated the synthesis of glutathione (GSH) by increasing the activity of the γ-glutamylcysteine ligase (γ-GCL). Inhibition of the GSH synthesis by buthionine sulfoximine (BSO) abolished the CA-induced mitochondrial protection. Besides, inhibition of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, as well as silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), suppressed the CA-stimulated protection and the synthesis of GSH. Thus, CA promoted mitochondrial protection by a PI3K/Akt/Nrf2/γ-GCL/GSH axis in MG-treated SH-SY5Y cells.
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Abietanos/farmacologia , Glutationa/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Aldeído Pirúvico/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismoRESUMO
Methylglyoxal (MGO) is an endogenous toxin, mainly produced as a by-product of glycolysis that has been associated to aging, Alzheimer's disease, and inflammation. Cell culture studies reported that MGO could impair the glyoxalase, thioredoxin, and glutathione systems. Thus, we investigated the effect of in vivo MGO administration on these systems, but no major changes were observed in the glyoxalase, thioredoxin, and glutathione systems, as evaluated in the prefrontal cortex and the hippocampus of mice. A previous study from our group indicated that MGO administration produced learning/memory deficits and depression-like behavior. Confirming these findings, the tail suspension test indicated that MGO treatment for 7 days leads to depression-like behavior in three different mice strains. MGO treatment for 12 days induced working memory impairment, as evaluated in the Y maze spontaneous alternation test, which was paralleled by low dopamine and serotonin levels in the cerebral cortex. Increased DARPP32 Thr75/Thr34 phosphorylation ratio was observed, suggesting a suppression of phosphatase 1 inhibition, which may be involved in behavioral responses to MGO. Co-treatment with a dopamine/noradrenaline reuptake inhibitor (bupropion, 10 mg/kg, p.o.) reversed the depression-like behavior and working memory impairment and restored the serotonin and dopamine levels in the cerebral cortex. Overall, the cerebral cortex monoaminergic system appears to be a preferential target of MGO toxicity, a new potential therapeutic target that remains to be addressed.
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Depressão/fisiopatologia , Inibidores da Captação de Dopamina/farmacologia , Dopamina/deficiência , Memória de Curto Prazo , Norepinefrina/metabolismo , Aldeído Pirúvico/efeitos adversos , Animais , Bupropiona/farmacologia , Dopamina/metabolismo , Feminino , Glutationa/metabolismo , Imobilização , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Aldeído Pirúvico/administração & dosagem , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Methylglyoxal (MG) is a highly reactive aldehyde able to form covalent adducts with proteins and nucleic acids, disrupting cellular functions. In this study, we performed a screening of Saccharomyces cerevisiae (S. cerevisiae) strains to find out which genes of cells are responsive to MG, emphasizing genes against oxidative stress and DNA repair. Yeast strains were grown in the YPD-Galactose medium containing MG (0.5 to 12 mM). The tolerance to MG was evaluated by determining cellular growth and cell viability. The toxicity of MG was more pronounced in the strains with deletion in genes engaged with DNA repair checkpoint proteins, namely Rad23 and Rad50. MG also impaired the growth and viability of S. cerevisiae mutant strains Glo1 and Gsh1, both components of the glyoxalase I system. Differently, the strains with deletion in genes encoding for antioxidant enzymes were apparently resistant to MG. In summary, our data indicate that DNA repair and MG detoxification pathways are keys in the control of MG toxicity in S. cerevisiae.
Assuntos
Lactoilglutationa Liase , Proteínas de Saccharomyces cerevisiae , Reparo do DNA , Proteínas de Ligação a DNA , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Estresse Oxidativo , Aldeído Pirúvico/toxicidade , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
Mitochondrial dysfunction is part of the mechanism of several human diseases. This negative circumstance may be induced by certain toxicants, as methylglyoxal (MG). MG is a reactive dicarbonyl presenting both endogenous and exogenous sources and is also able to induce protein cross-linking and glycation. Emodin (EM; 1,3,8-trihydroxy-6-methylanthracene-9,10-dione; C15H10O5) is a cytoprotective agent. Nonetheless, it was not previously demonstrated whether EM would be able to promote mitochondrial protection in cells challenged with MG. Therefore, we investigated here whether and how EM would prevent the MG-induced mitochondrial collapse in the human neuroblastoma SH-SY5Y cells. We found that a pretreatment (for 4 h) with EM at 40 µM prevented the MG-induced mitochondrial dysfunction (i.e., decreased activity of the complexes I and V, reduced adenosine triphosphate levels, and loss of mitochondrial membrane potential) in the SH-SY5Y cells. EM also prevented the redox impairment induced by MG in mitochondrial membranes. Inhibiting the adenosine monophosphate-activated protein kinase (AMPK) or silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2), transcription factor abolished the EM-induced protection. Inhibition of heme oxygenase-1 (HO-1) also blocked the EM-induced mitochondrial protection. Therefore, EM protected the mitochondria by a mechanism dependent on the AMPK/Nrf2/HO-1 signaling pathway in MG-challenged SH-SY5Y cells.
Assuntos
Emodina/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Aldeído Pirúvico/toxicidade , Transdução de Sinais/efeitos dos fármacos , Adenilato Quinase/metabolismo , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
Perinatal early nutritional disorders are critical for the developmental origins of health and disease. Glycotoxins, or advanced glycation end-products, and their precursors such as the methylglyoxal, which are formed endogenously and commonly found in processed foods and infant formulas, may be associated with acute and long-term metabolic disorders. Besides general aspects of glycotoxins, such as their endogenous production, exogenous sources, and their role in the development of metabolic syndrome, we discuss in this review the sources of perinatal exposure to glycotoxins and their involvement in metabolic programming mechanisms. The role of perinatal glycotoxin exposure in the onset of insulin resistance, central nervous system development, cardiovascular diseases, and early aging also are discussed, as are possible interventions that may prevent or reduce such effects.