RESUMO
Resistance exercise training (RET) is considered an excellent tool for preventing diseases with an inflammatory background. Its neuroprotective, antioxidant, and anti-inflammatory properties are responsible for positively modulating cholinergic and oxidative systems, promoting neurogenesis, and improving memory. However, the mechanisms behind these actions are largely unknown. In order to investigate the pathways related to these effects of exercise, we conducted a 12-week long-term exercise training protocol and used lipopolysaccharide (LPS) to induce damage to the cortex and hippocampus of male Wistar rats. The cholinergic system, oxidative stress, and histochemical parameters were analyzed in the cerebral cortex and hippocampus, and memory tests were also performed. It was observed that LPS: (1) caused memory loss in the novel object recognition (NOR) test; (2) increased the activity of acetylcholinesterase (AChE) and Iba1 protein density; (3) reduced the protein density of brain-derived neurotrophic factor (BDNF) and muscarinic acetylcholine receptor M1 (CHRM1); (4) elevated the levels of lipid peroxidation (TBARS) and reactive species (RS); and (5) caused inflammatory damage to the dentate gyrus. RET, on the other hand, was able to prevent all alterations induced by LPS, as well as increase per se the protein density of the alpha-7 nicotinic acetylcholine receptor (nAChRα7) and Nestin, and the levels of protein thiols (T-SH). Overall, our study elucidates some mechanisms that support resistance physical exercise as a valuable approach against LPS-induced neuroinflammation and memory loss.
Assuntos
Lipopolissacarídeos , Transtornos da Memória , Doenças Neuroinflamatórias , Condicionamento Físico Animal , Ratos Wistar , Animais , Masculino , Lipopolissacarídeos/toxicidade , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Ratos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Treinamento Resistido/métodos , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Receptor Muscarínico M1/metabolismoRESUMO
This study evaluated the effect of vitamin D3 (VIT D3) supplementation on the enzymatic activities and density of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-5-nucleotidase (E-5'-NT), adenosine deaminase (ADA), as well as the density of P2 × 7R, P2Y12R, A1R, A2AR receptors, IL-1ß, and oxidative parameters in type 2 diabetic rats. Forty male Wistar rats were fed a high carbohydrate-high fat diet (HCHFD) and received an intraperitoneal injection containing a single dose of streptozotocin (STZ, 35 mg/kg). Animals were divided into four groups: 1) control; 2) control/VIT D3 12 µg/kg; 3) diabetic; and 4) diabetic/VIT D3 12 µg/kg. Results show that VIT D3 reduced blood glucose, ATP hydrolysis, ADA activity, P2Y12R density (platelets), as well as ATP, ADP, and AMP hydrolysis and ADA activity (synaptosomes). Moreover, VIT D3 increased insulin levels and AMP hydrolysis (platelets) and improved antioxidant defense. Therefore, we suggest that VIT D3 treatment modulates hyperglycemia-induced changes via purinergic enzymes and receptor expression, consequently attenuating insulin homeostasis dysregulation in the diabetic state.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insulinas , Ratos , Masculino , Animais , Ratos Wistar , Colecalciferol/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Vitaminas , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismoRESUMO
Physical exercise is recognized as a non-pharmacological approach to treat and protect against several neuroinflammatory conditions and thus to prevent brain disorders. However, the interest in ergogenic resources by athletes and bodybuilding practitioners is widespread and on the rise. These substances shorten the process of performance gain and improve aesthetics, having led to the prominent use and abuse of hormones in the past years. Recent evidence has shown that the purinergic system, composed of adenine nucleotides, nucleosides, enzymes, and receptors, participates in a wide range of processes within the brain, such as neuroinflammation, neuromodulation, and cellular communication. Here, we investigated the effects of the anabolic androgenic steroid (AAS) testosterone (TES) at a dose of 70 mg/kg/week in female rats and the neuroprotective effect of resistance exercise related to the purinergic system and oxidative stress parameters. Our findings showed a decrease in ATP and ADO hydrolysis in treated and trained animals. Furthermore, there was an increase in the density of purinoceptors (P2X7 and A2A) and inflammatory markers (IBA-1, NRLP3, CASP-1, IL-1ß, and IL-6) in the cerebral cortex of animals that received AAS. On the other hand, exercise reversed neuroinflammatory parameters such as IBA-1, NLRP3, CASP-1, and IL-1ß and improved antioxidant response and anti-inflammatory IL-10 cytokine levels. Overall, this study shows that the use of TES without indication or prescription disrupts brain homeostasis, as demonstrated by the increase in neuroinflammation, and that the practice of exercise can protect brain health.
Assuntos
Anabolizantes , Treinamento Resistido , Humanos , Ratos , Feminino , Animais , Testosterona , Anabolizantes/farmacologia , Doenças Neuroinflamatórias , Congêneres da Testosterona/farmacologia , EncéfaloRESUMO
Resistance physical exercise has neuroprotective and anti-inflammatory effects on many known diseases and, therefore, it has been increasingly explored. The way in which this type of exercise exerts these actions is still under investigation. In this study, we aimed to analyze the enzymes and components of the purinergic system involved in the inflammatory process triggered by the P2X7R. Rats were divided into four groups: control, exercise (EX), lipopolysaccharide (LPS), and EX + LPS. The animals in the exercise groups were subjected to a 12-week ladder-climbing resistance physical exercise and received LPS after the last session for sepsis induction. Enzymes activities (NTPDase, 5'-nucleotidase, and adenosine deaminase), purinoceptors' density (P2X7R, A1, and A2A), and the levels of inflammatory indicators (pyrin domain-containing protein 3 (NLRP3), Caspase-1, interleukin (IL)- 6, IL-1B, and tumor necrosis factor (TNF) -α) were measured in the cortex and hippocampus of the animals. The results show that exercise prevented (in the both structures) the increase of: 1) nucleoside-triphosphatase (NTPDase) and 5'-nucleotidase activities; 2) P2X7R density; 3) NLRP3 and Caspase-1; and 4) IL-6, IL-1ß, and TNF-α It is suggested that the purinergic system and the inflammatory pathway of P2X7R are of fundamental importance and influence the effects of resistance physical exercise on LPS-induced inflammation. Thus, the modulation of the P2X7R by resistance physical exercise offers new avenues for the management of inflammatory-related illnesses.
Assuntos
Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/toxicidade , 5'-Nucleotidase/metabolismo , Doenças Neuroinflamatórias , Hipocampo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Exercício Físico , Caspases/metabolismo , Receptores Purinérgicos P2X7/metabolismoRESUMO
OBJECTIVES: Our aim in this study was to identify predictors for diabetes among the characteristics of the glycemic curve and glycated hemoglobin (A1C) in healthy, young adults. METHODS: We used a cross-sectional study to establish predictors for diabetes based on earlier studies and evaluated occurrence of the condition in 81 healthy, young adult subjects. These volunteers underwent analysis of fasting plasma glucose, oral glucose tolerance test plasma glucose, A1C, and inflammatory markers (leukocytes, monocytes, and C-reactive protein). The nonparametric Mann-Whitney U test, Fisher's exact test, chi-square test, Kruskal-Wallis test, and multiple-comparisons test were used to analyze the data. RESULTS: We studied 2 age groups, homogeneous in terms of family history of diabetes: one group ranged in age from ≥18 to <28 years (median 20 years; body mass index [BMI] 24 kg/m2) and the other group ranged in age from ≥28 to <45 years (median 35 years; BMI 24 kg/m2). The older group had a higher incidence of predictors (p=0.0005) and was associated with the predictors 30-minute blood glucose ≥164 mg/dL (p=0.0190), 60-minute blood glucose ≥125 mg/dL (p=0.0346), and A1C ≥5.5% (p=0.0162), with a monophasic glycemic curve (p=0.007). The younger group was associated with the 2-hour plasma glucose predictor ≥140 mg/dL (p=0.014). All subjects had fasting glucose in the normal range. CONCLUSIONS: Healthy, young adults may already have predictors of diabetes, identified mainly by aspects of the glycemic curve and A1C, but at more modest levels than those with prediabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Hemoglobinas Glicadas , Diabetes Mellitus Tipo 2/epidemiologia , Glicemia/análise , Estudos Transversais , Estado Pré-Diabético/epidemiologiaRESUMO
The present study evaluated the effect of caffeic acid (CA) on behavioral learning and memory tasks in the diabetic state. We also evaluated the effect of this phenolic acid on the enzymatic activities of acetylcholinesterase, ecto-nucleoside triphosphate diphosphohydrolase, ecto-5-nucleotidase and adenosine deaminase as well as on the density of M1R, α7nAChR, P2×7R, A1R, A2AR, and inflammatory parameters in the cortex and hippocampus of diabetic rats. Diabetes was induced by a single intraperitoneal dose of streptozotocin (55 mg/kg). The animals were divided into six groups: control/vehicle; control/CA 10 and 50 mg/kg; diabetic/vehicle; diabetic/CA 10 and 50 mg/kg, treated by gavage. The results showed that CA improved learning and memory deficits in diabetic rats. Also, CA reversed the increase in acetylcholinesterase and adenosine deaminase activities and reduced ATP and ADP hydrolysis. Moreover, CA increased the density of M1R, α7nAChR, and A1R receptors and reversed the increase in P2×7R and A2AR density in both evaluated structures. In addition, CA treatment attenuated the increase in NLRP3, caspase 1, and interleukin 1ß density in the diabetic state; moreover, it increased the density of interleukin-10 in the diabetic/CA 10 mg/kg group. The results indicated that CA treatment positively modified the activities of cholinergic and purinergic enzymes and the density of receptors, and improved the inflammatory parameters of diabetic animals. Thus, the outcomes suggest that this phenolic acid could improve the cognitive deficit linked to cholinergic and purinergic signaling in the diabetic state.
Assuntos
Disfunção Cognitiva , Diabetes Mellitus Experimental , Ratos , Animais , Ratos Wistar , Adenosina Desaminase/metabolismo , Acetilcolinesterase/metabolismo , Estreptozocina , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Doenças Neuroinflamatórias , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Transdução de Sinais , Colinérgicos/uso terapêuticoRESUMO
Several studies have indicated the vitamin D deficiency in the development of macro- and microvascular complications of diabetes mellitus (DM) including DM-related cognitive dysfunction. The purinergic system plays an important role in the modulation of a variety of mechanisms, including neuroinflammation, plasticity, and cell-cell communication. In addition, purines, their receptors, and enzymes can regulate the purinergic axis at different levels in type 1 DM (T1DM). This study evaluated the effects of vitamin D3 alone or in combination with metformin in the behavioral performance of streptozotocin-induced T1DM rats. The effects of this combination on the metabolism of ATP and ADP were also studied by NTPDase (CD39), AMP by 5'-nucleotidase (CD73), and adenosine by adenosine deaminase (E-ADA) in the brain and peripheral lymphocytes of type 1 diabetic STZ-induced rats. The results showed that anxiety and memory loss from the DM condition reverted after 30 days of vitamin D3 treatment. Furthermore, the DM state affected systemic enzymes, with no effect on the central enzymes hydrolyzing extracellular nucleotides and nucleosides. Vitamin D3 treatment positively regulated ectonucleotidase (NTPDase and 5'-nucleotidase) activity, E-ADA, and the purinergic receptors as a mechanism to prevent oxidative damage in the cerebral cortex of T1DM rats. A neuroprotector effect of vitamin D3 through adenosine signaling was also observed, by regulating A1 and A2A receptors proteins levels. The present findings suggest that purinergic signaling through vitamin D3 modulation may be a novel alternative strategy for T1DM treatment, and may compensate for the negative changes in the central nervous system.
Assuntos
Diabetes Mellitus Tipo 1 , Metformina , Ratos , Animais , Colecalciferol , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , 5'-Nucleotidase/metabolismo , Metformina/farmacologia , Adenosina/farmacologiaRESUMO
Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis, and its congenital transmission is of paramount concern. During embryonic development, infection with the parasite causes irreversible damage to the still-forming fetus's central nervous system (CNS). In the pathogenesis of neurotoxoplasmosis, purinergic receptors prejudice neuroprotection, neuroinflammation, and activation of microbicide mechanisms against the parasitic vacuole. This study used curcumin as a treatment for neural precursor cells (NPCs) infected with T. gondii. The congenital toxoplasmosis induction consisted of maternal infection with the VEG strain, and NPCs were obtained from the telencephalon of mouse embryos. Curcumin at increasing concentrations was administered in vitro to analyze NPC metabolic activity, cell number, and size, as well as neurogliogenesis, proving to be effective in recovering the size of infected NPCs. Curcumin partially re-established impaired neurogenesis. Purinergic A1, A2A, and P2X7 receptors may be related to neuroprotection, neuroinflammatory control, and activation of mechanisms for inducing the parasite's death. ERK 1/2 was highly expressed in infected cells, while its expression rates decreased after the addition of the treatment, highlighting the possible anti-inflammatory action of curcumin. These findings suggest that curcumin treats neurological perturbations induced by toxoplasmosis.
Assuntos
Curcumina , Células-Tronco Neurais , Toxoplasma , Toxoplasmose Cerebral , Toxoplasmose Congênita , Feminino , Gravidez , Animais , Camundongos , Toxoplasma/fisiologia , Curcumina/farmacologia , Toxoplasmose Congênita/parasitologiaRESUMO
Curcumin is an active polyphenol substance found in the highest concentrations in the roots of Curcuma longa. Its health benefits have led to recent increases in the consumption of curcumin. It has anti-inflammatory and antioxidant activities and is a potent neuroprotective against diseases of the brain. Nevertheless, its low bioavailability and its relative difficulty crossing the blood-brain barrier limit curcumin's use for these purposes. Curcumin-loaded nanoparticles may be an effective treatment for several diseases although there is a paucity of studies reporting its safety in the central nervous system (CNS). Therefore, this study aimed to identify non-neurotoxic concentrations of free curcumin and two nanoformulations of curcumin. Cell lines BV-2 and SH-SY5Y, both originating from the CNS, were evaluated after 24, 48, and 72 h of treatment with free curcumin and nanocapsules We measured viability, proliferation, and dsDNA levels. We measured levels of reactive oxygen species and nitric oxide as proxies for oxidative stress in culture supernatants. We found that free curcumin was toxic at 10 and 20 µM, principally at 72 h. Nanoformulations were more neurotoxic than the free form. Safe concentrations of free curcumin are between 1-5 µM, and these concentrations were lower for nanoformulations. We determined the ideal concentrations of free curcumin and nanocapsules serving as a basis for studies of injuries that affect the CNS.
Assuntos
Curcumina , Nanocápsulas , Neuroblastoma , Humanos , Curcumina/farmacologia , Nanocápsulas/toxicidade , Linhagem Celular , Estresse OxidativoRESUMO
BACKGROUND: Melanoma is the most lethal form of skin cancer, and its incidence has increased considerably in the last decades. Melanoma presents difficult treatment with strong resistance of tumor cells, due to its extremely invasive nature with high capacity to metastases. Berberine (BBR), an isoquinoline alkaloid, is a molecule found in several medicinal plants, and has been studied in several diseases, demonstrating antimicrobial, antidiabetic and anti-inflammatory properties and anti-tumorigenic effects. METHODS AND RESULTS: In SK-MEL-28 cells, 50 µM BBR treatment for 24 h decreased cell viability by 50 percent. This concentration generated cell death both by early apoptosis and necrosis, with an increase in the DNA damage index. BBR increased (*p < 0.05) the proportion of cells in G1/G0 phase and decreased (###p < 0.005) the percentage of cells in S phase. The alcaloid increased (****p < 0.001) ROS production compared to untreated controls with an increase in activated caspase 3 and phosphorylated p53 protein levels. In addition, BBR significantly enhanced ERK as well as both pro- and anti-inflammatory cytokine expression compared to untreated controls. CONCLUSIONS: BBR has important antiproliferative effects and may be alone or in adjunct therapy a promising candidate for melanoma treatment, a cancer with great incidence and high lethality.
Assuntos
Berberina , Melanoma , Apoptose , Berberina/farmacologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Melanoma/tratamento farmacológicoRESUMO
In hypertensive individuals, platelet morphology and function have been discovered to be altered, and this has been linked to the development of vascular disease, including erectile dysfunction (ED). The impact of nutritional supplementation with Cyperus esculentus (tiger nut, TN) and Tetracarpidium conophorum (walnut, WN) on androgen levels, ectonucleotidases, and adenosine deaminase (ADA) activities in platelets from L-NAME (Nω-nitro-L-arginine methyl ester hydrochloride) challenged rats were investigated. We hypothesized that these nuts may show a protective effect on platelets aggregation and possibly enhance the sex hormones, thereby reverting vasoconstriction. Wistar rats (male; 250-300 g; n = 10) were grouped into seven groups as follows: basal diet control group (I); basal diet/L-NAME/Viagra (5 mg/kg/day) as positive control group (II); ED-induced group (basal diet/L-NAME) (III); diet supplemented processed TN (20%)/L-NAME (IV); diet supplemented raw TN (20%)/L-NAME (V); diet supplemented processed WN (20%)/L-NAME (VI); and diet supplemented raw WN (20%)/L-NAME (VII). The rats were given their regular diet for 2 weeks prior to actually receiving L-NAME (40 mg/kg/day) for ten days to induce hypertension. Platelet androgen levels, ectonucleotidases, and ADA were all measured. L-NAME considerably lowers testosterone levels (54.5 ± 2.2; p < 0.05). Supplementing the TN and WN diets revealed improved testosterone levels as compared to the control (306.7 ± 5.7), but luteinizing hormone levels remained unchanged. Compared to control groups, the L-NAME-treated group showed a rise in ATP (127.5%) hydrolysis and ADA (116.7%) activity, and also a decrease in ADP (76%) and AMP (45%) hydrolysis. Both TN and WN supplemented diets resulted in substantial (p < 0.05) reversal effects. Enhanced testosterone levels and modulation of the purinergic system in platelets by TN and WN could be one of the mechanisms by which they aid in vasoconstriction control.
Assuntos
Plaquetas/efeitos dos fármacos , Cyperus , Suplementos Nutricionais , Hipertensão/terapia , Juglans , NG-Nitroarginina Metil Éster/farmacologia , Adenosina Desaminase/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Dieta/métodos , Hidrólise/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Masculino , Proteínas de Membrana/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Purinérgicos/farmacologia , Ratos , Ratos Wistar , Testosterona/sangue , Vasoconstrição/efeitos dos fármacosRESUMO
This study examined the behavioral responses, purinergic receptor densities, ectonucleotidases (E-NTPDase), adenosine deaminase (ADA) activity, and nitric oxide (NO) levels along with the parameters of oxidative stress-related to erectile function in the cerebral cortex (CC) of L-NAME-challenged rats pretreated with tigernut (TN) and walnut (WN) dietary supplementation. Wistar rats (male) of 70 total animals (250-300 g) were used in this research and hence separated into seven groups (n = 10): Group I: normal control-fed basal diet; Group II: positive control-fed basal diet/L-NAME/Sildenafil citrate (5 mg kg-1 day-1 ); Group III: ED-induced (placed on a basal diet/L-NAME); Group IV: diet supplemented with processed TN (20%)/L-NAME; Group V: diet supplemented with raw TN (20%)/L-NAME; Group VI: diet supplemented with processed WN (20%)/L-NAME; and Group VII placed on a diet supplemented with raw WN (20%)/L-NAME. The rats were pretreated for 2 weeks before the L-NAME (40 mg kg-1 day-1 ) challenge on their respective diet. L-NAME brought about a decrease in the sexual behaviors evaluated while the effect was significantly reversed by supplemented diets containing TN and WN. L-NAME increased the levels of reactive oxygen species and malondialdehyde, E-NTPDase as well as ADA activities, and caused the level of NO in the CC as well as the purinoreceptor densities to be downregulated. Treatments with enriched diets, however, greatly reverse these effects. The behavioral responses and neuromodulatory capacity of the nuts displayed on the CC can, therefore, further support their aphrodisiac property. PRACTICAL APPLICATIONS: The results revealed the ability of tigernut (TN; Cyperus esculentus L.) and walnut (WN; Tetracarpidium conophorum Müll. Arg.) to enhance behavioral responses; modulate purinergic receptor densities, E-NTPDase, and ADA activities; increase NO levels; and prevent oxidative stress related to erectile function in the CC of L-NAME-challenged Wistar rats. The results show that these nuts are useful feeds for both animal and human nutrition.
RESUMO
Nutraceuticals have been the focus of numerous research in recent years and accumulating data support their use for promoting some health benefits. Several nutraceuticals have been widely studied as supplements due to their functional properties ameliorating symptoms associated with neurological disorders, such as oxidative stress and chronic inflammatory states. This seems to be the case of some fruits and seeds from the Amazon Biome consumed since the pre-Columbian period that could have potential beneficial impact on the human nervous system. The beneficial activities of these food sources are possibly related to a large number of bioactive molecules including polyphenols, carotenoids, unsaturated fatty acids, vitamins, and trace elements. In this context, this review compiled the research on six Amazonian fruits and seeds species and some of the major nutraceuticals found in their composition, presenting brief mechanisms related to their protagonist action in improving inflammatory responses and neuroinflammation.
Assuntos
Suplementos Nutricionais , Inflamação/tratamento farmacológico , Doenças Neuroinflamatórias/tratamento farmacológico , Plantas Medicinais/química , Rios , Animais , Produtos Biológicos , Brasil , Doença Crônica , Fenômenos Eletrofisiológicos , HumanosRESUMO
The exposure to environmental stressors, such as organophosphate (OP) pesticides, has been associated with the development of neurodegenerative diseases. Chlorpyrifos (CPF) is the worldwide most used OP pesticide and one of the most hazardous pesticides as it can cross the blood-brain barrier. Since studies evaluating the effects of CPF on brain immune cells are scarce, this research investigated the oxidative and inflammatory responses of CPF exposure in murine microglial cells. BV-2 cells were exposed to different concentrations of CPF pesticide (0.3-300 µM). CPF induced activation of microglial cells, confirmed by Iba-1 and CD11b marking, and promoted microglial proliferation and cell cycle arrest at S phase. Moreover, CPF exposure increased oxidative stress production (NO, MDA, and O2â), and upregulated pro-inflammatory cytokines (IL-1ß and NLRP3) genes expression in BV-2 cells. Overall, data showed that CPF exposure, at the lowest concentrations, acted by promoting pro-oxidative and pro-inflammatory states in microglial cells. These results provide important information on the potential role of microglial activation in CPF-induced neuroinflammation and add to the expanding knowledge on the neurotoxicity of OP.
Assuntos
Clorpirifos , Inseticidas , Praguicidas , Animais , Clorpirifos/toxicidade , Camundongos , Microglia , Estresse Oxidativo , Praguicidas/toxicidadeRESUMO
Diabetes mellitus (DM) is a metabolic disorder characterized by a chronic hyperglycemia state, increased oxidative stress parameters, and inflammatory processes. AIMS: To evaluate the effect of caffeic acid (CA) on ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and adenosine deaminase (ADA) enzymatic activity and expression of the A2A receptor of the purinergic system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymatic activity and expression of the α7nAChR receptor of the cholinergic system as well as inflammatory and oxidative parameters in diabetic rats. METHODS: Diabetes was induced by a single dose intraperitoneally of streptozotocin (STZ, 55 mg/kg). Animals were divided into six groups (n = 10): control/oil; control/CA 10 mg/kg; control/CA 50 mg/kg; diabetic/oil; diabetic/CA 10 mg/kg; and diabetic/CA 50 mg/kg treated for thirty days by gavage. RESULTS: CA treatment reduced ATP and ADP hydrolysis (lymphocytes) and ATP levels (serum), and reversed the increase in ADA and AChE (lymphocytes), BuChE (serum), and myeloperoxidase (MPO, plasma) activities in diabetic rats. CA treatment did not attenuate the increase in IL-1ß and IL-6 gene expression (lymphocytes) in the diabetic state; however, it increased IL-10 and A2A gene expression, regardless of the animals' condition (healthy or diabetic), and α7nAChR gene expression. Additionally, CA attenuated the increase in oxidative stress markers and reversed the decrease in antioxidant parameters of diabetic animals. CONCLUSION: Overall, our findings indicated that CA treatment positively modulated purinergic and cholinergic enzyme activities and receptor expression, and improved oxi-inflammatory parameters, thus suggesting that this phenolic acid could improve redox homeostasis dysregulation and purinergic and cholinergic signaling in the diabetic state.
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Ácidos Cafeicos/farmacologia , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Acetilcolinesterase/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antioxidantes/farmacologia , Apirase/genética , Apirase/metabolismo , Butirilcolinesterase/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Aluminum (Al) is ubiquitously present in the environment and known to be a neurotoxin for humans. The trivalent free Al anion (Al3+) can cross the blood-brain barrier (BBB), accumulate in the brain, and elicit harmful effects to the central nervous system (CNS) cells. Thus, evidence has suggested that Al increases the risk of developing neurodegenerative diseases, particularly Alzheimer's disease (AD). Purinergic signaling has been shown to play a role in several neurological conditions as it can modulate the functioning of several cell types, such as microglial cells, the main resident immune cells of the CNS. However, Al effects on microglial cells and the role of the purinergic system remain elusive. Based on this background, this study is aimed at assessing the modulation of Al on purinergic system parameters of microglial cells. An in vitro study was performed using brain microglial cells exposed to Al chloride (AlCl3) and lipopolysaccharide (LPS) for 96 h. The uptake of Al, metabolism of nucleotides (ATP, ADP, and AMP) and nucleoside (adenosine), and the gene expression and protein density of purinoceptors were investigated. The results showed that both Al and LPS increased the breakdown of adenosine, whereas they decreased nucleotide hydrolysis. Furthermore, the findings revealed that both Al and LPS triggered an increase in gene expression and protein density of P2X7R and A2AR receptors, whereas reduced the A1R receptor expression and density. Taken together, the results showed that Al and LPS altered the setup of the purinergic system of microglial cells. Thus, this study provides new insights into the involvement of the purinergic system in the mechanisms underlying Al toxicity in microglial cells.
Assuntos
Alumínio/efeitos adversos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptores Purinérgicos/metabolismo , Animais , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/metabolismo , Linhagem Celular , Células Cultivadas , Imunofluorescência , Expressão Gênica , Humanos , Lipopolissacarídeos/imunologia , Camundongos , Microglia/imunologia , Receptores Purinérgicos/genéticaRESUMO
Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5'-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.
Assuntos
Diabetes Mellitus/metabolismo , Hipertensão/metabolismo , Purinas/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , 5'-Nucleotidase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Comunicação Celular , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Dieta Saudável , Exercício Físico , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipertensão/terapia , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Transdução de SinaisRESUMO
Both the cholinergic pathway and oxidative stress are important mechanisms involved in the pathogenesis of hypothyroidism, a condition characterized by low levels of thyroid hormone that predispose the patient to brain dysfunction. Phenolic compounds have numerous health benefits, including antioxidant activity. This study evaluates the preventive effects of resveratrol in the cholinergic system and redox status in rats with methimazole-induced hypothyroidism. Hypothyroidism increases acetylcholinesterase (AChE) activity and density in the cerebral cortex and hippocampus and decreases the α7 and M1 receptor densities in the hippocampus. Hypothyroidism also increases cellular levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), but reduces total thiol content, and catalase and superoxide dismutase activities in the serum. In the cerebral cortex and hippocampus, hypothyroidism increases the levels of ROS and nitrites. In this study, resveratrol (50 mg/kg) treatment prevents the observed increase in AChE in the cerebral cortex, and increases the protein levels of NeuN, a marker of mature neurons. Resveratrol also prevents changes in serum ROS levels and brain structure, as well as the levels of TBARS, total thiol content, and serum catalase enzyme activity. These collective findings suggest that resveratrol has a high antioxidant capacity and can restore hypothyroidism-triggered alterations related to neurotransmission. Thus, it is a promising agent for the prevention of brain damage resulting from hypothyroidism.
Assuntos
Colinérgicos/metabolismo , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Neuroproteção/efeitos dos fármacos , Resveratrol/farmacologia , Transdução de Sinais , Acetilcolinesterase/metabolismo , Animais , Antígenos Nucleares/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipotireoidismo/sangue , Masculino , Proteínas do Tecido Nervoso/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Receptores Colinérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
INTRODUCTION: Metabolic syndrome (MetS) is a disorder that is closely associated with risk factors that increase the chance of atherosclerosis and cardiovascular diseases. We demonstrate the presence of inflammation and oxidative stress in patients with MetS through levels of antioxidants and oxidative and inflammatory markers, in order to determine influential variables in therapy. METHODS: In this study, lipid peroxidation, carbonylated protein content and enzymatic and non-enzymatic antioxidants were evaluated in samples obtained from 30 patients with MetS and 30 control patients. In addition, acetylcholinesterase (AChE) activity, C-reactive protein (CRP) and uric acid (UA) levels were determined to investigate the inflammatory process in patients with MetS. RESULTS: Our results demonstrated an increase in the levels of oxidative markers, such as substances reactive to thiobarbituric acid (TBARS) and carbonyl protein. In addition, a decrease in the defense of non-enzymatic antioxidants, such as levels of vitamin C and glutathione (GSH) in patients with MetS. As for inflammatory markers, CRP and UA were increased in patients with MetS. Finally, activation of the cholinergic anti-inflammatory pathway was observed due to decreased AchE activity in patients with MetS. CONCLUSION: The analyzes indicated oxidative stress, together with a reduction in the levels of antioxidant enzymes, corroborating the high consumption of these proteins. In addition, inflammation and activation of the cholinergic anti-inflammatory pathway was observed by the AChE analysis. Thus, the activation of this pathway can be studied as a possible route to a potential therapy. In addition, the markers AChE, CRP and UA may be used as a focus for the treatment of MetS.
Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Síndrome Metabólica/patologia , Estresse Oxidativo , Adulto , Idoso , Proteína C-Reativa/metabolismo , Feminino , Seguimentos , Humanos , Peroxidação de Lipídeos , Masculino , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Ácido Úrico/metabolismoRESUMO
Glioblastoma multiforme (GM) is the most prevalent tumor among gliomas and presents the highest mortality rate among brain tumors. Berberine (BBR) is an alkaloid isoquinoline found in medicinal plants such as Coptis chinensis. Studies have been showed that BBR presents protective activity in mesenchymal cells and neurons, and antitumor properties in breast cancer and hepatocarcinoma. The aim of this study was to investigate the antitumor effects of BBR in GM U87MG cells, as well as to identify, whether such effects are mediated by oxidative stress and canonical apoptotic pathways. After treatment with several concentrations of BBR (10, 25, 100 and 250 µM) for 24, 48 and 72 h of exposure, BBR reduce cell viability of U87MG cells in a concentration- and time-dependent manner. Afterwards, it was observed that BBR, starting at a concentration of 25 µM of 24 h exposure, significantly suppressed proliferation and increased early apoptosis (53.5% ± 11.15 of annexin V+ propidium iodide- cells) compared to untreated cells (7.5% ± 4.6). BBR-induced apoptosis was independent from AMPK activity and did not change total caspase-3 and p-p53 levels. Moreover, BBR (25 µM/24 h) increased oxidative stress in U87MG cells, evidenced by high levels of reactive oxygen species, thiobarbituric acid reactive substance and protein carbonylation. Considering the antitumor effects of BBR in U87MG cells, this compound may be a potential candidate for adjuvant GM treatment.