RESUMO
Gray level co-occurrence matrix (GLCM) analysis is a contemporary and innovative computer-based algorithm that can be used for the quantification of subtle changes in a cellular structure. In this work, we use this method for the detection of discrete alterations in hepatocyte chromatin distribution after in vivo exposure to iron oxide nanoparticles (IONPs). The study was performed on 40 male, healthy C57BL/6 mice divided into four groups: three experimental groups that received different doses of IONPs and 1 control group. We describe the dose-dependent reduction of chromatin textural uniformity measured as GLCM angular second moment. Similar changes were detected for chromatin textural uniformity expressed as the value of inverse difference moment. To the best of our knowledge, this is the first study to investigate the impact of iron-based nanomaterials on hepatocyte GLCM parameters. Also, this is the first study to apply discrete wavelet transform analysis, as a supplementary method to GLCM, for the assessment of hepatocyte chromatin structure in these conditions. The results may present the useful basis for future research on the application of GLCM and DWT methods in pathology and other medical research areas.
Assuntos
Cromatina , Hepatócitos , Nanopartículas Magnéticas de Óxido de Ferro , Algoritmos , Animais , Hepatócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Nonalcoholic fatty liver disease (NAFLD) represents a hepatic manifestation of metabolic syndrome. The aim of this study was to examine the effect of betaine on ultrastructural changes in the mouse liver with methionine- and choline-deficient (MCD) diet-induced NAFLD. Male C57BL/6 mice were divided into groups: Control-fed with standard chow, BET-standard chow supplemented with betaine (1.5% w/v drinking water), MCD-fed with MCD diet, and MCD + BET-MCD diet with betaine supplementation for 6 weeks. Liver samples were taken for pathohistology and transmission electron microscopy. The MCD diet-induced steatosis, inflammation, and balloon-altered hepatocytes were alleviated by betaine. MCD diet induced an increase in mitochondrial size versus the control group (p < 0.01), which was decreased in the betaine-treated group. In the MCD diet-fed group, the total mitochondrial count decreased versus the control group (p < 0.01), while it increased in the MCD + BET group versus MCD (p < 0.01). Electron microscopy showed an increase in the number of autophagosomes in the MCD and MCD + BET group versus control, and a significant difference in autophagosomes number was detected in the MCD + BET group by comparison with the MCD diet-treated group (p < 0.05). Betaine decreases the number of enlarged mitochondria, alleviates steatosis, and increases the number of autophagosomes in the liver of mice with NAFLD.
Assuntos
Betaína/farmacologia , Colina/metabolismo , Dieta , Suplementos Nutricionais , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Colágeno , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Periportal hepatocytes (PPHs) and perivenous hepatocytes (PVHs) in standard optical microscopy appear to be morphologically identical. However, the functional properties of these two cell populations and their roles in liver lobules are not the same. Despite significant differences in gene expression between these two hepatocyte populations, it is still unclear whether the differences are present at the higher levels of chromatin organization. In this study, we present results, indicating that periportal and perivenous hepatocytes, when stained using toluidine blue histological dye, have different chromatin textural patterns quantified with gray-level co-occurrence matrix (GLCM) method. Hepatic tissue was obtained from ten male, healthy mice. Chromatin structures were analyzed using GLCM. For each structure, we measured the values of angular second moment, inverse difference moment, GLCM Contrast, GLCM Variance, and GLCM Sum Variance. The results indicate that there is a statistically significant difference in all GLCM mathematical parameters except the contrast. In addition, some chromatin GLCM features were in correlation with serum aminotransferase levels in perivenous, but not in periportal hepatocytes. To the best of our knowledge, this is the first study to test the nuclear morphological differences between hepatocytes using GLCM and to investigate the respective relation with serum liver enzymes.
Assuntos
Algoritmos , Cromatina/metabolismo , Hepatócitos/metabolismo , Animais , Corantes/química , Expressão Gênica , Hepatócitos/citologia , Histocitoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Coloração e Rotulagem , Cloreto de Tolônio/químicaRESUMO
In high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD), there is an increase in the endocannabinoid system activity, which significantly contributes to steatosis development. The aim of our study was to investigate the effects of cannabinoid receptor type 1 blockade on adipokine and proinflammatory cytokine content in adipose and hepatic tissue in mice with NAFLD. Male mice C57BL/6 were divided into a control group fed with a control diet for 20 weeks (C, n = 6) a group fed with a HFD for 20 weeks (HF, n = 6), a group fed with a control diet and treated with rimonabant after 18 weeks (R, n = 9), and a group fed with HFD and treated with rimonabant after 18 weeks (HFR, n = 10). Rimonabant significantly decreased leptin, resistin, apelin, visfatin, interleukin 6 (IL-6), and interferon-γ (IFN-γ) concentration in subcutaneous and visceral adipose tissue in the HFR group compared to the HF group (p < 0.01). Rimonabant reduced hepatic IL-6 and IFN-γ concentration as well as plasma glucose and insulin concentration and the homeostatic model assessment index in the HFR group compared to the HF group (p < 0.01). It can be concluded that the potential usefulness of CB1 blockade in the treatment of HFD-induced NAFLD is due to modulation of the adipokine profile and proinflammatory cytokines in both adipose tissues and liver as well as glucose metabolism.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Citocinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Rimonabanto/uso terapêuticoRESUMO
The effects of betaine on hepatocytes chromatin architecture changes were examined by using fractal and gray-level co-occurrence matrix (GLCM) analysis in methionine/choline-deficient (MCD) diet-induced, nonalcoholic fatty liver disease (NAFLD). Male C57BL/6 mice were divided into groups: (1) Control: standard diet; (2) BET: standard diet and betaine supplementation through drinking water (solution 1.5%); (3) MCD group: MCD diet for 6 weeks; (4) MCD+BET: fed with MCD diet + betaine for 6 weeks. Liver tissue was collected for histopathology, immunohistochemistry, and determination of fractal dimension and GLCM parameters. MCD diet induced diffuse micro- and macrovesicular steatosis accompanied with increased Ki67-positive hepatocyte nuclei. Steatosis and Ki67 immunopositivity were less prominent in the MCD+BET group compared with the MCD group. Angular second moment (ASM) and inverse difference moment (IDM) (textural homogeneity markers) were significantly increased in the MCD+BET group versus the MCD group (p<0.001), even though no difference between the MCD and the control group was evident. Heterogeneity parameters, contrast, and correlation were significantly increased in the MCD group versus the control (p<0.001). On the other hand, betaine treatment significantly reduced correlation, contrast, and entropy compared with the MCD group (p<0.001). Betaine attenuated MCD diet-induced NAFLD by reducing fat accumulation and inhibiting hepatocyte proliferation. Betaine supplementation increased nuclear homogeneity and chromatin complexity with reduction of entropy, contrast, and correlation.
Assuntos
Betaína/administração & dosagem , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Fármacos Gastrointestinais/administração & dosagem , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Hepatócitos/fisiologia , Histocitoquímica , Imuno-Histoquímica , Antígeno Ki-67/análise , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
Although there are numerous recent works focusing on fractal properties of DNA and chromatin, many issues regarding changes in chromatin fractality during physiological aging remain unclear. In this study, we present results indicating that in mice, there is an age-related reduction of chromatin fractal complexity in a population of spleen follicular cells (SFCs). Spleen tissue was obtained from 16 mice and fixated in Carnoy solution. The youngest animal was newborn, and each animal was exactly 1 month older than the previous. We performed fractal analysis of SFC chromatin structure, stained using Giemsa technique. Fractal analysis was done in a plugin algorithm of ImageJ software. We also performed gray-level co-occurrence matrix (GLCM) analysis of all chromatin structures with the calculation of parameters such as angular second moment and inverse difference moment. Giemsa-stained SFC chromatin exhibited an age-dependent reduction of fractal dimension with statistically significant (p<0.01) linear trend. Moreover, there was a statistically significant increase of SFC chromatin lacunarity. The chromatin GLCM parameters did not significantly change. To our knowledge, this is the first study to perform fractal and GLCM analyses of SFC chromatin and to investigate potential changes of fractal parameters during postnatal development.
Assuntos
Envelhecimento/fisiologia , Cromatina/ultraestrutura , Fractais , Baço/citologia , Animais , Corantes Azur , Processamento de Imagem Assistida por Computador/métodos , Masculino , Camundongos , Coloração e RotulagemRESUMO
Choline and methionine are precursors of acetylcholine, whose hydrolysis is catalyzed by acetylcholinesterase (AChE). Considering the possibility of their common deficiency, we investigated the influence of methionine-choline deprivation on AChE activity in liver and various brain regions (hypothalamus, hippocampus, cerebral cortex and striatum) in mice fed with methionine-choline deficient (MCD) diet. Male C57BL/6 mice (n = 28) were randomly and equally divided into following groups: control group fed with standard diet for 6 weeks (C) and groups fed with MCD diet for 2 weeks (MCD2), 4 weeks (MCD4) and for 6 weeks (MCD6). After the diet, mice were sacrificied and AChE activity in liver and brain was determined spectrophotometrically. Hepatic AChE activity was higher in MCD2, MCD4 and MCD6 compared to control (p < 0.01), with most prominent increase in MCD6. AChE activity in hypothalamus was higher in MCD4 and MCD6 vs. control (p < 0.05 and p < 0.01, respectively), as well as in MCD6 compared to MCD4 (p < 0.01). In hippocampus, increase in AChE activity was shown in MCD6 compared to control (p < 0.01). In cortex and striatum, increase in AChE activity was noted in MCD6 compared to control (p < 0.05). Our findings indicate the increase of hepatic and brain AChE activity in mice caused by methionine-choline deprivation.
Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/enzimologia , Deficiência de Colina/metabolismo , Fígado/enzimologia , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Ativação Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição TecidualRESUMO
Epilepsy is a chronic neurological condition characterized by unprovoked, recurrent seizures. There are several types of epilepsy, and the cause of the condition can vary. Some cases of epilepsy have a genetic component, while others may be caused by brain injuries, infections, or other underlying conditions. Treatment for epilepsy typically involves anti-seizure medications (ASMs), although different approaches, such as surgery or a special diet, may be considered in specific cases. The treatment aims to effectively manage and potentially eliminate seizures while minimizing any accompanying side effects. Many different ASMs are available, and the choice of medication depends on several factors, including the type of seizures, the patient's age, general health, and potential drug interactions. For the treatment of epilepsy, there have been significant advancements in recent decades, which have led to the approval of many different ASMs. Newer ASMs offer a broader range of mechanisms of action, improved tolerability profiles, and reduced drug interactions compared to older drugs. This review aims to discuss the pharmacological characteristics, clinical applications, effectiveness, and safety of ASMs, with a particular emphasis on various age groups, especially children. Moreover, this review seeks to provide a comprehensive understanding of ASM therapy for epilepsy management, assisting physicians in selecting suitable ASMs for their patients.
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Anticonvulsivantes , Epilepsia , Convulsões , Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Interações MedicamentosasRESUMO
Arterial hypertension (AH) is recognized as the most common illness within the group of cardiovascular diseases and the most massive chronic non-infectious disease in the world. The number of hypertensive patients worldwide has reached 1.28 billion, contributing to an increase in cardiovascular diseases and premature death globally. The high prevalence of hypertension emphasizes the importance of effectively treating this condition. Elevated blood pressure often leads to lethal complications (heart failure, stroke, renal disorders, etc.) if left untreated. Considering an increase in AH prevalence in the future, a successful therapeutical approach to this disease and its complications is essential. The goal of AH treatment is to maintain normotensive blood pressure through various approaches, including lifestyle changes, a well-balanced diet, increased physical activity, psychoeducation, and, when necessary, pharmacotherapy. The evolving pharmacotherapeutic landscape reflects the progress made in our understanding of hypertension and emphasizes the need for continuous innovation to meet the challenges posed by this prevalent global health concern. The journey toward more effective and tailored treatments for hypertension is ongoing, and the introduction of new medications plays a pivotal role in shaping the future of antihypertensive pharmacotherapy.
Assuntos
Anti-Hipertensivos , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacosRESUMO
Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF-/- C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF-/-; MIF-/-+Bet; TAA group, which received TAA; TAA+Bet; MIF-/-+TAA; and MIF-/-+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-ß1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-ß1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-ß1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.
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This study focuses on developing machine learning models to detect subtle alterations in hepatocyte chromatin organization due to Iron (II, III) oxide nanoparticle exposure, hypothesizing that exposure will significantly alter chromatin texture. A total of 2000 hepatocyte nuclear regions of interest (ROIs) from mouse liver tissue were analyzed, and for each ROI, 5 different parameters were calculated: Long Run Emphasis, Short Run Emphasis, Run Length Nonuniformity, and 2 wavelet coefficient energies obtained after the discrete wavelet transform. These parameters served as input for supervised machine learning models, specifically random forest and gradient boosting classifiers. The models demonstrated relatively robust performance in distinguishing hepatocyte chromatin structures belonging to the group exposed to IONPs from the controls. The study's findings suggest that iron oxide nanoparticles induce substantial changes in hepatocyte chromatin distribution and underscore the potential of AI techniques in advancing hepatocyte evaluation in physiological and pathological conditions.
Assuntos
Cromatina , Hepatócitos , Aprendizado de Máquina , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Animais , Cromatina/metabolismo , Camundongos , Nanopartículas Magnéticas de Óxido de Ferro/toxicidade , Nanopartículas Magnéticas de Óxido de Ferro/química , Fígado/metabolismo , Fígado/efeitos dos fármacos , Compostos Férricos , MasculinoRESUMO
Moderate caloric restriction prolongs lifespan. Changes in oxidative stress and hormesis may be involved in this process. The aim of this study is to examine the effects of different levels of chronic caloric restriction (CR) and acute fasting on stress response and oxidative stress parameters in rat liver and plasma. Forty-two rats were divided into groups: control group, calorie-restricted groups with intake of 80-90%, 60-70%, 40-50%, 20-30% of daily caloric needs and acute fasting group. To determine alanine aminotransferase (ALT), aspartate aminotransferase (AST) and superoxide dismutase (SOD) activity, concentration of corticosterone, nitrites and nitrates (NOx), malondialdehyde (MDA) and glutathione (GSH), liver samples and blood were collected. Increase in plasma corticosterone concentration and AST and ALT activity was found in severe CR. Ingestion 40-50% daily caloric needs or less increased liver MDA and NOx concentration and decreased SOD activity. Ingestion 60-70% daily caloric needs increased Mn-SOD activity, GSH and NOx. In acute fasting group and group taking 20-30% daily caloric needs, GSH was significantly lower than in control group. Severe CR and acute fasting increase oxidative damage and decrease antioxidative capacity of hepatocytes. Moderate CR increases antioxidative capacity of hepatocytes due to increase in Mn-SOD activity and GSH concentration, which might have a role in anti-aging and hormetic mechanism of CR.
Assuntos
Restrição Calórica/métodos , Citocinas/sangue , Hormese/fisiologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/sangue , Animais , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine properties released by various immune and non-immune cells. It contributes to the pathogenesis of many inflammatory, autoimmune diseases and malignant tumors. OBJECTIVE: Our study aimed to investigate the role of betaine in the modulation of MIF-mediated oxidative stress, inflammation, and fibrogenesis during toxic kidney damage induced by thioacetamide (TAA). METHODS: The experiment is performed on wild-type and knockout MIF-/- C57BL/6 mice. They are randomly divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/- + Bet; TAA-group, treated with TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/- + TAA+Bet group. After eight weeks of treatment, animals are sacrificed and kidney samples are taken to determine oxidative stress parameters, proinflammatory cytokines, profibrogenic factors, and histopathology of renal tissue. RESULTS: In MIF-/-mice, TAA decreases malondialdehyde (MDA) concentration, IL-6, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-ß1) and platelet-derived growth factor-BB (PDGF-BB) and increases superoxide dismutases (SOD) and catalase (CAT) activities, as well as glutathione (GSH) content in kidneys, compared to TAA group. Betaine alleviates the mechanism of MIF-mediated effects in TAA-induced nephrotoxicity, reducing MDA, IL-6, TNF-α, TGF-ß1, and PDGF-BB, and increasing SOD and CAT activity, as well as GSH levels. CONCLUSION: MIF mediates TAA-induced nephrotoxicity by increasing oxidative stress, inflammation, and profibrogenic mediators. MIF-targeted therapy could potentially alleviate oxidative stress and inflammation in the kidney, as well as pathohistological changes in renal tissue, but the exact mechanism of its action is not completely clear. Betaine alleviates MIF nephrotoxic effects by increasing the antioxidative capacity of kidney cells, and decreasing lipid peroxidation and cytokine production in the renal tissue. It suggests that betaine can be used for the prevention of kidney damage.
Assuntos
Nefropatias , Fatores Inibidores da Migração de Macrófagos , Animais , Antioxidantes/farmacologia , Becaplermina/metabolismo , Becaplermina/farmacologia , Betaína/metabolismo , Betaína/farmacologia , Betaína/uso terapêutico , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Nefropatias/metabolismo , Fígado/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Tioacetamida/metabolismo , Tioacetamida/toxicidade , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Artificial intelligence (AI) and machine learning models are today frequently used for classification and prediction of various biochemical processes and phenomena. In recent years, numerous research efforts have been focused on developing such models for assessment, categorization, and prediction of oxidative stress. Supervised machine learning can successfully automate the process of evaluation and quantification of oxidative damage in biological samples, as well as extract useful data from the abundance of experimental results. In this concise review, we cover the possible applications of neural networks, decision trees and regression analysis as three common strategies in machine learning. We also review recent works on the various weaknesses and limitations of artificial intelligence in biochemistry and related scientific areas. Finally, we discuss future innovative approaches on the ways how AI can contribute to the automation of oxidative stress measurement and diagnosis of diseases associated with oxidative damage.
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Inteligência Artificial , Aprendizado de Máquina , Redes Neurais de Computação , Estresse OxidativoRESUMO
BACKGROUND: Peripheral facial nerve palsy is a relatively frequent, rather idiopathic, and isolated nonprogressive disorder with a tendency toward spontaneous recovery in children. It is primarily characterized by unilateral paresis or paralysis of the mimic musculature affecting verbal communication, social interactions, and quality of life. OBJECTIVE: This study aimed to evaluate the clinical aspects and efficacy of different therapeutic modalities in the population of children and adolescents with acute peripheral facial nerve palsy, the quality and recovery rate in comparison to different therapy modalities and etiological factors as well as to determine parameters of recovery according to the age of patients. METHODS: The retrospective study included children and adolescents (n=129) with an acute onset of peripheral facial nerve palsy, diagnosed and treated in the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade (2000-2018). The mean age of the patients was 11.53 years (SD±4.41). Gender distribution: 56.6% female and 43.4% male patients. RESULTS: There were 118 (91.5%) patients with partial and 11 (8.5%) patients with complete paralysis. Left-sided palsy occurred in 67 (51.9%) patients, right-sided in 58 (45.0%), while there were 4 (3.1%) bilateral paralyses. The most common etiological factor was idiopathic (Bell's palsy) - 74 (57.4%) patients followed by middle ear infections - 16 (12.4%). Regardless of etiology, age, and therapy protocols, there was a significant recovery in most of the patients (p<0.001), without significant differences in recovery rate. Comparison of inpatient and outpatient populations showed significant differences regarding the number of relapses, severity of clinical presentation, and recovery rate in relation to etiology. CONCLUSION: Bell's palsy is shown to be the most common cause of peripheral facial nerve palsy in children and adolescents, regardless of gender. It is followed by mid-ear infections, respiratory infections, and exposure to cold. Most children and adolescents recovered in three weeks after initial presentation, regardless of etiology, age, and therapy.
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Dysfunction of the endocannabinoid system (ES) has been identified in nonalcoholic fatty liver disease (NAFLD) and associated metabolic disorders. Cannabinoid receptor type 1 (CB1) expression is largely dependent on nutritional status. Thus, individuals suffering from NAFLD and metabolic syndrome (MS) have a significant increase in ES activity. Furthermore, oxidative/ nitrosative stress and inflammatory process modulation in the liver are highly influenced by the ES. Numerous experimental studies indicate that oxidative and nitrosative stress in the liver is associated with steatosis and portal inflammation during NAFLD. On the other hand, inflammation itself may also contribute to reactive oxygen species (ROS) production due to Kupffer cell activation and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The pathways by which endocannabinoids and their lipid-related mediators modulate oxidative stress and lipid peroxidation represent a significant area of research that could yield novel pharmaceutical strategies for the treatment of NAFLD. Cumulative evidence suggested that the ES, particularly CB1 receptors, may also play a role in inflammation and disease progression toward steatohepatitis. Pharmacological inactivation of CB1 receptors in NAFLD exerts multiple beneficial effects, particularly due to the attenuation of hepatic oxidative/nitrosative stress parameters and significant reduction of proinflammatory cytokine production. However, further investigations regarding precise mechanisms by which CB1 blockade influences the reduction of hepatic oxidative/nitrosative stress and inflammation are required before moving toward the clinical phase of the investigation.
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Estresse Nitrosativo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that contributes to the inflammatory response to chemical liver injury. This cytokine exhibits pro- and anti-inflammatory effects depending on the etiology and stage of liver disease. OBJECTIVE: Our study aimed to investigate the role of MIF in oxidative stress and inflammation in the liver, and modulatory effects of betaine on MIF in thioacetamide (TAA)-induced chronic hepatic damage in mice. METHODS: The experiment was performed on wild type and knockout MIF-/- C57BL/6 mice. They were divided into the following groups: control; Bet-group that received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/-+Bet; TAA-group that received TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/-+TAA+Bet. In TAA- and Bet-treated groups, animals received the same doses. After eight weeks of treatment, blood samples were collected for biochemical analysis, and liver specimens were prepared for the assessment of parameters of oxidative stress and inflammation. RESULTS: In MIF-/-mice, TAA reduced transaminases, γ-glutamyltranspeptidase, bilirubin, malondialdehyde (MDA), oxidative protein products (AOPP), total oxidant status (TOS), C-reactive protein (CRP), IL-6, IFN-γ, and increased thiols and total antioxidant status (TAS). Betaine attenuated the mechanism of MIF and mediated effects in TAA-induced liver injury, reducing transaminases, γ-glutamyltranspeptidase, bilirubin, MDA, AOPP, TOS, CRP, IL-6, IFN-g, and increasing thiols. CONCLUSION: MIF is a mediator in hepatotoxic, pro-oxidative, and proinflammatoryeffects of TAA-induced liver injury. MIF-targeted therapy can potentially mitigate oxidative stress and inflammation in the liver, but the exact mechanism of its action requires further investigation. Betaine increases anti-oxidative defense and attenuates hepatotoxic effects of MIF, suggesting that betaine can be used for the prevention and treatment of liver damage.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Fatores Inibidores da Migração de Macrófagos , Animais , Betaína/metabolismo , Betaína/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Tioacetamida/metabolismo , Tioacetamida/toxicidadeRESUMO
Recently, there have been several studies indicating that iron-based nanomaterials may exhibit certain toxic properties. Compared to conventional iron and iron oxides, iron nanoparticles (FeNPs) have some unique physical and chemical traits which impact their absorption, biodistribution and elimination. Facilitated passage through biological barriers enables FeNPs to reach various tissues and cells, and interact with a variety of different compounds. Currently, most of the recent research is focused on the potential cytotoxicity of FeNPs, and its implications on cell viability and functions. Some studies suggested that, in certain cell types, FeNPs may increase levels of oxidative stress and induce generation of reactive oxygen species. Oxidative stress may be one of the most important mechanisms by which FeNPs exhibit cytotoxic effects. Some authors have also suggested that, in certain conditions, exposure to FeNPs, in combination with other factors, may lead to changes in intracellular signaling resulting in programmed cell death. In this short review, we focus on the recent research on potential cytotoxicity of iron-based nanomaterials, and the potential implications of this new knowledge in medicine, chemistry and biology.
Assuntos
Apoptose/efeitos dos fármacos , Compostos Férricos/química , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
The aim of our study was to investigate the possible involvement of acetylcholinesterase (AchE) in mediating the early phase of acute lindane neurotoxicity in rats. Male Wistar rats (n = 48) were divided into following groups: 1. control, saline-treated group; 2. dimethylsulfoxidetreated group; 3. group that received lindane dissolved in dimethylsulfoxide, in a dose of 8 mg/kg intraperitoneally. Eight animals from each group were sacrificed 0.5 and 4 h after treatment and brain samples were prepared for further analysis. AchE activity (mitochondrial and synaptosomal fraction) was determined in cerebral cortex, thalamus, hippocampus and nc. caudatus spectrophotometrically. A significant increase in mitochondrial AchE activity was detected in cortex and nc. caudatus of lindane-treated animals 0.5 h after administration (p < 0.05). This rise was sustained in nc. caudatus within 4 h after treatment (p < 0.05). In contrast, activity of synaptosomal AchE fraction was significantly increased only in thalamus 4 h after lindane administration (p < 0.05). An increase in AchE activity may be involved in mediating acute neurotoxic effects of lindane, at least in some brain structures in rats.
Assuntos
Acetilcolinesterase/metabolismo , Hexaclorocicloexano/toxicidade , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/enzimologia , Praguicidas/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Masculino , Ratos , Ratos WistarRESUMO
The effects of ethanol on epilepsy are very complex. Ethanol can have depressant as well as excitatory effect on different animal models of epilepsy. Systemic administration of homocysteine can trigger seizures. The aim of the present study was to examine the changes of total spectral power density after ethanol alone and together with homocysteine thiolactone in adult rats. Adult male Wistar rats were divided into following groups: 1. saline-injected, (control) C; 2. D, L-homocysteine thiolactone, H (8 mmol/kg); 3. ethanol, E (E(0.5), 0.5 g/kg; E(1), 1 g/kg; E(2), 2 g/kg) and 4. E (E(0.5), E(1), and E(2)) 30 min prior to H, EH (E(0.5)H, E(1)H and E(2)H). For EEG recordings three gold-plated screws were implanted into the skull. Our results demonstrate that ethanol, when applied alone, increased total EEG spectral power density of adult rats with a marked spectrum shift toward low frequency waves. In EH groups, increasing doses of ethanol exhibited a dose-dependent effect upon spectral power density. Ethanol increased EEG spectral power density in E(0.5)H and E(1)H group, comparing to the H group (p > 0.05), the maximal increase was recorded with the lowest ethanol dose applied. The highest dose of ethanol (E(2)H) significantly decreased total power spectra density, comparing to the H group. We can conclude that high doses of ethanol depressed marked increase in EEG power spectrum induced by D,L-homocysteine thiolactone.