RESUMEN
Introduction: Hexavalent chromium [Cr (VI)] has been identified as a human carcinogen and environmental pollutant capable of affecting multiple systems in the human body. However, the specific mechanisms by which Cr (VI) affects the human nervous system remain unclear. Objective: Following confirmation of Cr (VI)'s toxic effects on rat astrocytes, this study explores the metabolites and associated metabolic pathways of rat astrocytes under different doses of Cr (VI) exposure. Methods: Cell viability was assessed using CCK8 assays, intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA fluorescent probes, intracellular 8-hydroxydeoxyguanosine (8-OHdG) content was determined by Elisa, mitochondrial membrane potential was observed using JC-1 probes, and key metabolites were identified through untargeted metabolomics analysis. Results: With increasing Cr (VI) doses, significant decreases in cell viability were observed in the 4, 8, and 16 mg/L dose groups (p < 0.05). Elevated levels of ROS and 8-OHdG, increased caspase-3 activity, and significant reductions in mitochondrial membrane potential were observed in the 2 and 4 mg/L dose groups (p < 0.05). Untargeted metabolomics analysis revealed Cr (VI)'s impact on key metabolites such as sphingosine and methionine. Enrichment analysis of KEGG pathways highlighted the critical roles of sphingolipid metabolism and the methionine-cysteine cycle in the effects of Cr (VI) on rat astrocytes. Conclusion: Our study underscores the potential neuro-health risks associated with environmental and occupational exposure to Cr (VI) and provides new perspectives and directions for investigating neurotoxic mechanisms.
RESUMEN
BACKGROUND: Low-carbohydrate (e.g., Atkins) dietary pattern is one of the most effective diets for weight loss, but little is known about the characteristics of the gut microbiota accompanying low-carbohydrate diets-induced weight loss. This study aims to profile dynamics of gut bacteria and fungi accompanying modified Atkins diets-induced weight loss among overweight and obese adults. METHODS: Overweight and obese adults were screened to follow a modified Atkins diet plan (30% of energy from protein, 40% from carbohydrate and 30% from fat). We longitudinally profiled dynamics of gut bacteria and fungi based on 16S rRNA and ITS rRNA gene sequencing data, respectively. RESULTS: A total of 65 participants followed the modified Atkins diets for 20-231 days, with 61 and 27 participants achieving a weight loss of at least 5 and 10%, respectively. Most of the participants who achieved 10% weight loss also experienced improvements on metabolic health. The diversity of gut bacteria and fungi increased after a weight loss of 5% and kept stable thereafter. Bacteria genera including Lachnoclostridium and Ruminococcus 2 from Firmicutes phylum were depleted, while Parabacteroides and Bacteroides from Bacteroidetes phylum were enriched after weight loss. The inter-kingdom analysis found an intensive covariation between gut fungi and bacteria, involving more than half of the weight loss-associated bacteria. CONCLUSIONS: This study confirmed the modulation of bacterial and fungal composition during weight loss with the low-carbohydrate diets and showed previously unknown links between intestinal bacteria and fungi accompanying the weight loss.
RESUMEN
Brain edema caused by subacute poisoning with 1,2-dichloroethane (1,2-DCE) has gained much attention during recent years, but its underlying mechanism is poorly understood. As an intermediate metabolite of 1,2-DCE in vivo, 2-chloroethanol (2-CE) can be transformed into chloroacetaldehyde and reactive oxygen species (ROS) through cytochrome P450 2E1 (CYP2E1) mediated metabolism. In previous studies, it was found that CYP2E1 expression is enhanced in the brain of mice treated with 1,2-DCE. This study was designed to verify the roles of CYP2E1 overexpression in 2-CE induced cytotoxicity in rat astrocytes, and the contribution of specific signaling molecules to the upregulation of CYP2E1 expression caused by 2-CE. The results of this study demonstrate that treatment with 2-CE can enhance CYP2E1 protein and mRNA levels, cause an increase in ROS and MDA levels, and higher percentages of apoptotic cells in rat astrocytes. Pretreatment with either diallyl sulfide or vitamin C, the inhibitor of CYP2E1 or scavenger of ROS, respectively, can suppress the levels of CYP2E1 expression, ROS and MDA, ameliorate cell apoptosis, and attenuate phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in these cells. Additionally, pretreatment with the inhibitor of either ERK1/2 or transcriptional factor specificity protein 1 (SP1) can suppress the CYP2E1 expression, and alleviate the oxidative damage caused to these cells. In conclusion, our findings demonstrate that CYP2E1 overexpression plays a crucial role in 2-CE induced oxidative damage of rat astrocytes, and that CYP2E1 expression is upregulated partially through the activation of the ERK1/2 and SP1 signaling pathways by ROS generated during CYP2E1-mediated 2-CE metabolism. This study provides novel information that can be used in elucidating the mechanism by which 1,2-DCE induces brain edema.
Asunto(s)
Astrocitos/efectos de los fármacos , Citocromo P-450 CYP2E1/metabolismo , Etilenclorhidrina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Astrocitos/enzimología , Astrocitos/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Técnica del Anticuerpo Fluorescente , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
Arsenic exposure through drinking water can impair the learning and memory ability of children in China and other countries. Synaptic plasticity plays a key role in the process of learning and memory. Alterations in the expression of presynaptic and postsynaptic proteins can be used to evaluate synaptic plasticity, and further to evaluate impairment in learning and memory ability. Thereby, the aim of this study was to explore the mechanisms underlying arsenic neurotoxicity by focusing on alterations in the hippocampal synapses of mouse offspring induced by developmental arsenite exposure. Mother mice and their offspring were exposed to 0, 25, 50 or 100 mg L-1 arsenite via drinking water from the first day of gestation until postnatal day (PND) 35. The spatial learning and memory ability of PND 35 mice was evaluated using a Morris water maze. The levels of speciated arsenicals in the brain of PND 7, 14, 21 and 35 mice were analyzed by hydride generation coupled with atomic absorption spectrophotometry. Synaptic structure and protein expression of postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the hippocampus of PND 7, 14, 21 and 35 mice were examined. The findings from this study disclosed that the spatial learning ability of mice could be impaired by exposure to 25 mg L-1 arsenite; however spatial memory ability could not be impaired until exposure to 100 mg L-1 arsenite. The thickness of the postsynaptic density (PSD) decreased, whereas the width of the synaptic cleft widened significantly in arsenite exposure groups. Moreover, protein expression of both PSD-95 and SYP decreased significantly in arsenite exposure groups. In conclusion, the results of this study demonstrated that developmental arsenite exposure could depress the expression of synaptic proteins, subsequently cause alteration in synaptic structures, and finally contribute to arsenite-induced deficits in spatial learning and memory ability in mouse offspring.
Asunto(s)
Arsenitos/toxicidad , Encéfalo/patología , Hipocampo/patología , Plasticidad Neuronal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/patología , Sinapsis/patología , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Memoria/efectos de los fármacos , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
2-Chloroethanol (2-CE) is one of the reactive metabolites of 1,2-DCE in vivo, which might contribute to brain edema formation induced by 1,2-dichloroethane (1,2-DCE) poisoning. Thus, the purpose of this study was to explore the roles of mitogen-activated protein kinase (MAPK) signal pathways in upregulation of matrix metalloproteinase-9 (MMP-9) in 2-CE exposed rat astrocytes. Expression of p38 MAPK (p38), extracellular signal regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and MMP-9 at both protein and gene levels in rat astrocytes were determined using western blot and real-time RT-PCR methods. The results showed that both protein and mRNA levels of MMP-9 in 2-CE exposed astrocytes significantly increased. Meanwhile, protein levels of phosphorylated p38 (p-p38), ERK1/2 (p-ERK1/2) and JNK1/2 (p-JNK1/2) in 2-CE exposed astrocytes also significantly increased. In addition, both protein and mRNA levels of MMP-9 significantly decreased in response to reduced protein levels of p-p38, p-ERK1/2 and p-JNK1/2 achieved by supplement with their specific inhibitors, indicating that activation of MAPK signal pathways might play an important role in upregulation of MMP-9 expression at the transcriptional level in 2-CE exposed astrocytes. Furthermore, since pretreatment of n-acetyl-l-cysteine (NAC), a powerful antioxidant amino acid, could attenuate the elevated levels of MMP-9, p-p38, p-ERK2 and p-JNK1/2 in 2-CE exposed astrocytes, activation of MAPK signal pathways in 2-CE exposed astrocytes could be mediated partially by reactive oxygen species (ROS), which was most likely generated in the metabolism of 2-CE.
RESUMEN
This study was to explore the mechanisms underlying 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of matrix metalloproteinase-2 (MMP-2) in rat astrocytes induced by 2-chloroethanol (2-CE), an intermediate metabolite of 1,2-DCE in vivo. Protein and mRNA levels of MMP-2, and the phosphorylated protein levels of p38 MAPK (p-p38), extracellular signal regulated protein kinase (p-ERK1/2) and c-Jun N-terminal kinase (p-JNK1/2) in astrocytes were examined by immunostaining, western blot or real-time RT-PCR analysis. Findings from this study disclosed that protein levels of MMP-2 were upregulated by 2-CE in astrocytes. Meanwhile, protein levels of p-p38, p-ERK1/2 and p-JNK1/2 were also increased apparently in the cells treated with 2-CE. Moreover, pretreatment of astrocytes with SB202190 (inhibitor of p38 MAPK), U0126 (inhibitor of ERK1/2) or SP600125 (inhibitor of JNK1/2) could suppress the upregulated expression of p-p38, p-ERK1/2, and p-JNK1/2. In response to suppressed protein levels of p-p38 and p-JNK1/2, the protein levels of MMP-2 also decreased significantly, indicating that activation of MAPK signal pathways were involved in the mechanisms underlying 2-CE-induced upregulation of MMP-2 expression.