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The utilization of Cobalt (Co) has surged due to it is critical role in renewable energy technologies and other high-tech applications. Concurrently, the potential health risks associated with Co exposure have raised concerns. Previous studies, including our own, have shown that Co can impair learn and memory functions as an epigenetic hazard, even at low concentrations. In this study, we explore the mechanisms of Co-induced ferroptosis in neurodegenerative damage both in vivo and in vitro, focusing on the epigenetic regulation by N6-methyladenosine (m6A) demethylase alkB homolog 5 (ALKBH5). We identify heme oxygenase-1 (HO-1) as a direct target gene of ALKBH5, playing a crucial role in mitigating Co-induced ferroptosis. ALKBH5 deficiency affects the post-transcriptional regulation of HO-1 through m6A modification, which in turn influences mRNA's stability, intracellular distribution, and alternative splicing, thereby enhancing susceptibility to Co-induced ferroptosis. Additionally, we discuss the potential involvement of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in regulating alternative splicing of HO-1 mRNA, potentially mediated by m6A modifications. This study provides new epigenetic insights into the post-transcriptional regulatory mechanisms involved in Co-induced ferroptosis and highlights the broader implications of environmental hazards in neurodegenerative damage.
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BACKGROUND: Unfavourable lipid and glucose levels may play a crucial role in the pathogenesis of gestational diabetes mellitus (GDM). However, there is a lack of prospective studies on the relationship between lipid profiles, lipid ratios and GDM during pregnancy. AIMS: To prospectively investigate the relationship between lipid profile and lipid ratios in early and mid-pregnancy and their pattern of change from early to mid-pregnancy and the risk of GDM. METHODS: This nested case-control study was based on maternal and child healthcare hospitals from Fujian Province, China. We included pregnant women who delivered in the hospital from January 2021 to June 2023. Lipid profiles (TC, TG, ApoA1, ApoB, HDL-c, LDL-c) and fasting glucose were measured before 14 weeks of gestation and between 20 and 28 weeks of gestation, and lipid ratios (triglyceride glucose index, TG/HDL-c and TC/HDL-c) was constructed. Logistic regression was used to assess the relationship between lipid profile, lipid ratios and GDM. RESULTS: Of 1586 pregnant women, 741 were diagnosed with GDM. After adjusting for potential confounders, TG, ApoA1, ApoB, LDL-c, triglyceride glucose index, TG/HDL-c, and TC/HDL-c in early pregnancy were positively associated with the risk of GDM (odds ratios [95% CI] for extreme interquartile comparisons were 2.040 (1.468-2.843), 1.506 (1.091-2.082), 1.529 (1.110-2.107), 1.504 (1.086-2.086), 1.952 (1.398-2.731), 2.127 (1.526-2.971), and 2.370 (1.700-3.312), all trend P < 0.05). HDL-c was negatively associated with the risk of GDM (0.639: 0.459-0.889, trend P all less than 0.05). Similarly, in mid-pregnancy, lower levels of HDL-c, higher levels of triglyceride glucose index, TG/HDL-c ratio, and TC/HDL-c ratio were associated with increased risk of GDM (all trends P < 0.05). Stably high levels (both ≥ median for early and mid-pregnancy) of triglyceride glucose index, TG/HDL-c and TC/HDL-c were associated with increased risk of GDM (OR [95% CI]: 2.369 (1.438-3.940), 1.588 (1.077-2.341), 1.921 (1.309-2.829), respectively). The opposite was true for HDL-c, where stable high levels were negatively associated with GDM risk (OR [95% CI]: 0.599 (0.405-0.883)). CONCLUSION: Increases in triglyceride glucose index, TG/HDL-c ratio, and TC/HDL-c ratio in early and mid-pregnancy, as well as their stable high levels from early to mid-pregnancy, are associated with a higher risk of GDM. In contrast, increased levels of HDL-c, both in early and mid-pregnancy, and their stable high levels from early to mid-pregnancy were associated with a lower risk of GDM. That highlighted their possible clinical relevance in identifying those at high risk of GDM.
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Diabetes Gestacional , Lipídeos , Humanos , Feminino , Diabetes Gestacional/sangue , Diabetes Gestacional/epidemiologia , Gravidez , Adulto , Estudos de Casos e Controles , China/epidemiologia , Lipídeos/sangue , Estudos Prospectivos , Glicemia/análise , Fatores de Risco , Triglicerídeos/sangueRESUMO
Bilirubin-induced brain damage is a serious clinical consequence of hyperbilirubinemia, yet the underlying molecular mechanisms remain largely unknown. Ferroptosis, an iron-dependent cell death, is characterized by iron overload and lipid peroxidation. Here, we report a novel regulatory mechanism of demethylase AlkB homolog 5 (ALKBH5) in acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis in hyperbilirubinemia. Hyperdifferential PC12 cells and newborn Sprague-Dawley rats were used to establish in vitro and in vivo hyperbilirubinemia models, respectively. Proteomics, coupled with bioinformatics analysis, first suggested the important role of ferroptosis in hyperbilirubinemia-induced brain damage. In vitro experiments showed that ferroptosis is activated in hyperbilirubinemia, and ferroptosis inhibitors (desferrioxamine and ferrostatin-1) treatment effectively alleviates hyperbilirubinemia-induced oxidative damage. Notably, we observed that the ferroptosis in hyperbilirubinemia was regulated by m6A modification through the downregulation of ALKBH5 expression. MeRIP-seq and RIP-seq showed that ALKBH5 may trigger hyperbilirubinemia ferroptosis by stabilizing ACSL4 mRNA via m6A modification. Further, hyperbilirubinemia-induced oxidative damage was alleviated through ACSL4 genetic knockdown or rosiglitazone-mediated chemical repression but was exacerbated by ACSL4 overexpression. Mechanistically, ALKBH5 promotes ACSL4 mRNA stability and ferroptosis by combining the 669 and 2015 m6A modified sites within 3' UTR of ACSL4 mRNA. Our findings unveil a novel molecular mechanism of ferroptosis and suggest that m6A-dependent ferroptosis could be an underlying clinical target for the therapy of hyperbilirubinemia.
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Homólogo AlkB 5 da RNA Desmetilase , Coenzima A Ligases , Ferroptose , Estabilidade de RNA , Ratos Sprague-Dawley , Animais , Ferroptose/genética , Ratos , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Células PC12 , Cicloexilaminas/farmacologia , Humanos , Desferroxamina/farmacologia , Estresse Oxidativo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Fenilenodiaminas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Modelos Animais de Doenças , Peroxidação de LipídeosRESUMO
Parkinson's disease (PD) is a prevalent neurodegenerative disease and approximately one third of patients with PD are estimated to experience depression. Paraquat (PQ) is the most widely used herbicide worldwide and PQ exposure is reported to induce PD with depression. However, the specific brain region and neural networks underlying the etiology of depression in PD, especially in the PQ-induced model, have not yet been elucidated. Here, we report that the VGluT2-positive glutamatergic neurons in the paraventricular thalamic nucleus (PVT) promote depression in the PQ-induced PD mouse model. Our results show that PVTVGluT2 neurons are activated by PQ and their activation increases the susceptibility to depression in PD mice. Conversely, inhibition of PVTVGluT2 neurons reversed the depressive-behavioral changes induced by PQ. Similar to the effects of intervention the soma of PVTVGluT2 neurons, stimulation of their projections into the central amygdaloid nucleus (CeA) also strongly influenced depression in PD mice. PQ induced malfunctioning of the glutamate system and changes in the dendritic and synaptic morphology in the CeA through its role on PVTVGluT2 neuronal activation. In summary, our results demonstrate that PVTVGluT2 neurons are key neuronal subtypes for depression in PQ-induced PD and promote depression processes through the PVTVGluT2-CeA pathway.
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Núcleos da Linha Média do Tálamo , Neurônios , Paraquat , Proteína Vesicular 2 de Transporte de Glutamato , Animais , Paraquat/toxicidade , Masculino , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Neurônios/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Camundongos Endogâmicos C57BL , Herbicidas/toxicidade , Camundongos , Doença de Parkinson/metabolismoRESUMO
The exact mechanisms underlying the initiation and exacerbation of Parkinson's disease (PD) by paraquat remain unclear. We have revealed that exosomes mediate neurotoxicity induced by low dose paraquat exposure by transmitting intercellular signaling. Exposure to 40 µM paraquat promoted exosome release from mouse microglia cells (BV2) in vitro. Paraquat exposure at 100 µM caused degeneration of mouse dopaminergic MN9D cells and inhibited microglia exosome uptake by fluorescently labeling exosomes. We established an incubation model for exosomes and dopaminergic neuron cells under PQ treatment. The results indicated that microglial exosomes alleviated degeneration, increasing proliferation and PD-related protein expression of dopaminergic neurons; however, paraquat reversed this effect. Then, through exosome high-throughput sequencing and qRT-PCR experiments, miR-92a-3p and miR-24-3p were observed to transfer from exosomes to dopaminergic neurons, inhibited by paraquat. The specificity of miR-92a-3p and miR-24-3p was verified in PD patients exosomes, indicating the potential diagnostic value of the exosomal miRNAs in paraquat-induced PD. These results suggest glia-neuron communication in paraquat-induced neurodegeneration and may identify stable paraquat-mediated PD biomarkers, offering clues for early recognition and prevention of pesticide-induced degenerative diseases.
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Biomarcadores , Neurônios Dopaminérgicos , Exossomos , MicroRNAs , Microglia , Paraquat , Doença de Parkinson , Paraquat/toxicidade , Exossomos/metabolismo , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Biomarcadores/metabolismo , Neuroproteção/efeitos dos fármacos , Humanos , Linhagem CelularRESUMO
Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases, and approximately one third of patients with PD are estimated to have depression. Paraquat (PQ) exposure is an important environmental risk factor for PD. In this study, we established a mouse model of PQ-induced PD with depression to comprehensively investigate cellular heterogeneity and the mechanisms underlying the progression of depression in the context of PD. We utilized single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of individual cells from model mice and characterize the gene expression profiles in each differentially expressed cell type. We identified a specific glutamatergic neuron cluster responsible for the development of heterogeneous depression-associated changes and established a comprehensive gene expression atlas. Furthermore, functional enrichment and cell trajectory analyses revealed that the mechanisms underlying the progression of PD with depression were associated with specific glutamatergic neurons. Together, our findings provide a valuable resource for deciphering the cellular heterogeneity of PD with depression. The suggested connection between intrinsic transcriptional states of neurons and the progression of depression can provide insight into potential biomarkers and specific targets for anti-depression treatment in patients with PD. SYNOPSIS: Our results obtained using model mice confirm the core effects of PQ exposure on glutamatergic neurons and their potential role in the development of PD with depression.
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Paraquat , Doença de Parkinson , Humanos , Animais , Camundongos , Paraquat/toxicidade , Doença de Parkinson/genética , Depressão/induzido quimicamente , Depressão/genética , Perfilação da Expressão Gênica , RNARESUMO
With the evidence emerging that abnormal expression of long noncoding RNAs (lncRNAs) are involved in onset of Parkinson's disease (PD), the role of NR_030777 contributing to this disease is of great interest. We recently found that a novel lncRNA "NR_030777" demonstrates protective effects on PQ-induced neurodegeneration. However, the underlying molecular mechanisms of NR_030777 in the regulation of mitochondrial fission and mitophagy involved in PQ-induced neuronal damage remain to be explored. NR_030777 brain conditional overexpressing mice as well as in vitro primary neuronal cells from cerebral cortex and Neuro2a cells were adopted. Immunofluorescence, Immunohistochemistry, qRT-PCR and Western blotting were used to evaluate the expression levels of RNA and proteins. RNA immunoprecipitation and RNA pulldown experiment were used to evaluate the interaction of NR_030777 with its target proteins. NR_030777 and mitophagy were increased, and tyrosine hydroxylase (TH) levels recovered after NR_030777 overexpression upon PQ treatment. The overexpression and knockdown of NR_030777 unveiled that NR_030777 positively regulated mitophagy such as the upregulation of LC3B-II:I, ATG12-ATG5, p62 and NBR1. Moreover, the application of mdivi-1, a DRP-1 inhibitor, in combination with NR_030777 genetic modified cells unveiled that NR_030777 promoted DRP1-mediated mitochondrial fission and mitophagy. Furthermore, NR_030777 were directly bound to CDK1 to increase p-DRP1 levels at the Ser616 site, leading to mitochondrial fission and mitophagy. On the other hand, NR_030777 acted directly on ATG12 within the ATG12-ATG5 complex in the 800-1400 nt region to modulate the membrane formation. Accordingly, NR_030777 deficiency in neuron cells compromised cell mitophagy. Finally, the above findings were confirmed using NR_030777-overexpressing mice. NR_030777 exerted a protective effect on PQ-exposed mice by enhancing mitophagy. Our data provide the first scientific evidence for the precise invention of PQ-induced PD. Our findings further propose a breakthrough for understanding the regulatory relationship between NR_030777, CDK1, ATG12 and mitophagy in PQ-induced PD.
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Proteína Quinase CDC2 , Dinâmica Mitocondrial , Mitofagia , Doença de Parkinson , RNA Longo não Codificante , Animais , Camundongos , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Paraquat/toxicidade , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
The pollution of heavy metals (HMs) in the environment is a significant global environmental issue, characterized by its extensive distribution, severe contamination, and profound ecological impacts. Excessive exposure to heavy metal pollutants can damage the nervous system. However, the mechanisms underlying the neurotoxicity of most heavy metals are not completely understood. Epigenetics is defined as a heritable change in gene function that can influence gene and subsequent protein expression levels without altering the DNA sequence. Growing evidence indicates that heavy metals can induce neurotoxic effects by triggering epigenetic changes and disrupting the epigenome. Compared with genetic changes, epigenetic alterations are more easily reversible. Epigenetic reprogramming techniques, drugs, and certain nutrients targeting specific epigenetic mechanisms involved in gene expression regulation are emerging as potential preventive or therapeutic tools for diseases. Therefore, this review provides a comprehensive overview of epigenetic modifications encompassing DNA/RNA methylation, histone modifications, and non-coding RNAs in the nervous system, elucidating their association with various heavy metal exposures. These primarily include manganese (Mn), mercury (Hg), lead (Pb), cobalt (Co), cadmium (Cd), nickel (Ni), sliver (Ag), toxic metalloids arsenic (As), and etc. The potential epigenetic mechanisms in the etiology, precision prevention, and target therapy of various neurodevelopmental disorders or different neurodegenerative diseases are emphasized. In addition, the current gaps in research and future areas of study are discussed. From a perspective on epigenetics, this review offers novel insights for prevention and treatment of neurotoxicity induced by heavy metal pollutants.
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Intoxicação por Arsênico , Poluentes Ambientais , Mercúrio , Metais Pesados , Humanos , Poluentes Ambientais/toxicidade , Poluentes Ambientais/análise , Metais Pesados/análise , Mercúrio/análise , Cádmio/análise , Epigênese Genética , Monitoramento Ambiental/métodos , Medição de RiscoRESUMO
BACKGROUND: As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell-cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiO2NPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation. RESULTS: After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation. CONCLUSION: Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity.
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Estruturas da Membrana Celular , Nanotubos de Carbono , Nanotubos , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Nanotubos de Carbono/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Neuroglia/metabolismo , Trifosfato de Adenosina , ApoptoseRESUMO
Triclosan (TCS) is an antimicrobial compound incorporated into more than 2000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, thereby raising concerns about its impact on human health and environmental pollution. Here, we demonstrated that 20 weeks' exposure of TCS drove the development of glucose intolerance by inducing compositional and functional alterations in intestinal microbiota in rats. Fecal-transplantation experiments corroborated the involvement of gut microbiota in TCS-induced glucose-tolerance impairment. 16S rRNA gene-sequencing analysis of cecal contents showed that TCS disrupted the gut microbiota composition in rats and increased the ratio of Firmicutes to Bacteroidetes. Cecal metabolomic analyses detected that TCS altered host metabolic pathways that are linked to host glucose and amino acid metabolism, particularly branched-chain amino acid (BCAA) biosynthesis. BCAA measurement confirmed the increase in serum BCAAs in rats exposed to TCS. Western blot and immunostaining results further confirmed that elevated BCAAs stimulated mTOR, a nutrient-sensing complex, and following IRS-1 serine phosphorylation, resulted in insulin resistance and glucose intolerance. These results suggested that TCS may induce glucose metabolism imbalance by regulating BCAA concentration by remodeling the gut microbiota.
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Microbioma Gastrointestinal , Intolerância à Glucose , Triclosan , Humanos , Ratos , Animais , Intolerância à Glucose/induzido quimicamente , Triclosan/toxicidade , RNA Ribossômico 16S/genética , GlucoseRESUMO
Introduction: Research on the trajectory of dietary patterns and changes in obesity has been inconclusive. Methods: This study described the dietary intake and adiposity trajectories of Chinese adults and assessed the association between dietary trajectories and changes in body mass index (BMI) and waist-to-hip ratio (WHR). We used data from 3, 643 adults who participated in the China Health and Nutrition Survey from 1997 to 2015. Detailed dietary data were collected by conducting three consecutive 24-h recalls. Multitrajectories of diet scores were identified by a group-based multitrajectory method. We described the change in BMI and WHR using group-based trajectory modeling. We assessed the associations between dietary trajectories and changes in people with obesity using a logistic regression model. Results: Our study revealed four trajectories of low-carbohydrate (LCD) and low-fat diet (LFD) scores. Three adiposity trajectories were identified according to the baseline level and developmental trend of BMI and WHR. Compared with the reference group, which was characterized by sustained healthy dietary habits with healthy diet scores at baseline and sustained maintenance of healthy diet scores, the other three diet trajectories had a higher risk of falling into the adverse adiposity trajectory. Discussion: Maintaining a healthy LCD and LFD can markedly decrease the risk of adiposity.
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Padrões Dietéticos , Obesidade , Adulto , Humanos , Estudos de Coortes , Obesidade/epidemiologia , Dieta , Índice de Massa CorporalRESUMO
Ferroptosis is driven by irondependent accumulation of lipid hydroperoxides, and hemolytic hyperbilirubinemia causes accumulation of unconjugated bilirubin and iron. The present study aimed to assess the role of ferroptosis in hemolytic hyperbilirubinemiainduced brain damage (HHIBD). Rats were randomly divided into the control, phenylhydrazine (PHZ) and deferoxamine (DFO) + PHZ groups, with 12 rats in each group. Ferroptosisassociated biochemical and protein indicators were measured in the brain tissue of rats. We also performed tandem mass taglabeled proteomic analysis. The levels of iron and malondialdehyde were significantly higher and levels of glutathione (GSH) and superoxide dismutase activity significantly lower in the brain tissues of the PHZ group compared with those in the control group. HHIBD also resulted in significant increases in the expression of the ferroptosisrelated proteins acylCoA synthetase longchain family member 4, ferritin heavy chain 1 and transferrin receptor and divalent metal transporter 1, as well as a significant reduction in the expression of ferroptosis suppressor protein 1. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the differentially expressed proteins of rat brain tissues between the control and PHZ groups were significantly involved in ferroptosis, GSH metabolism and fatty acid biosynthesis pathways. Pretreatment with DFO induced antioxidant activity and alleviated lipid peroxidationmediated HHIBD. In addition, PC12 cells treated with ferric ammonium citrate showed shrinking mitochondria, high mitochondrial membrane density, and increased lipid reactive oxygen species and intracellular ferrous iron, which were antagonized by pretreatment with ferrostatin1 or DFO, which was reversed by pretreatment with ferrostatin1 or DFO. The present study demonstrated that ferroptosis is involved in HHIBD and provided novel insights into candidate proteins that are potentially involved in ferroptosis in the brain during hemolytic hyperbilirubinemia.
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Lesões Encefálicas , Ferroptose , Ratos , Animais , Proteômica , Apoptose , Ferro/metabolismo , Hiperbilirrubinemia , Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Hemólise , Glutationa/metabolismo , LipídeosRESUMO
OBJECTIVE: Our present study utilized case-control research to explore the relationship between specific circRNAs and pediatric obesity through a literature review and bioinformatics and to predict their possible biological functions, providing ideas for epigenetic mechanism studies of pediatric obesity. METHODS: CircRNAs related to pediatric obesity were preliminarily screened by a literature review and qRT-PCR. CircRNA expression in children with obesity (n = 75) and control individuals (n = 75) was confirmed with qRT-PCR in a case-control study. This was followed by bioinformatics analyses, such as GO analysis, KEGG pathway analysis, and ceRNA network construction. Multivariate logistic regression was utilized to analyze the effects of circRNAs on obesity. A receiver operating characteristic (ROC) curve was also drawn to explore the clinical application value of circRNAs in pediatric obesity. RESULTS: Has_circ_0046367 and hsa_circ_0000284 were separately validated to be statistically downregulated and upregulated, respectively, in the peripheral blood mononuclear cells of children with obesity and revealed as independent indicators of increased CHD risk [hsa_circ_0046367 (OR = 0.681, 95% CI: 0.480 ~ 0.967) and hsa_circ_0000284 (OR = 1.218, 95% CI: 1.041 ~ 1.424)]. The area under the ROC curve in the combined analysis of hsa_circ_0046367 and hsa_circ_0000284 was 0.706 (95% CI: 0.623 ~ 0.789). Enrichment analyses revealed that these circRNAs were actively involved in neural plasticity mechanisms, cell secretion and signal regulation. CONCLUSION: The present research revealed that low expression of hsa_circ_0046367 and high expression of hsa_circ_0000284 are risk factors for pediatric obesity and that neural plasticity mechanisms are closely related to obesity.
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Obesidade Infantil , RNA Circular , Criança , Humanos , RNA Circular/genética , Obesidade Infantil/genética , Estudos de Casos e Controles , Leucócitos Mononucleares , Biologia ComputacionalRESUMO
BACKGROUND/AIM: Chronic obstructive pulmonary disease (COPD) has become a prominent healthcare issue in recent years. Cigarette smoking (CS) and fine particulate matter (PM2.5) are important causative factors for COPD. This study assessed the aberrant lncRNA profiles in the tissue of rats with COPD caused by CS or PM2.5 Materials and Methods: A COPD rat model was developed using CS (CSM) or PM2.5 (PMM), and lung tissue RNA was extracted. The Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) were used to investigate the correlations between the distinct lncRNAs and mRNA pathways. A coding-non-coding gene co-expression network (CNC) was constructed by establishing connections between differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) associated with mitochondrial dysfunction and the inflammatory response. RESULTS: A quantitative real-time reverse transcription PCR (qRT-PCR) experiment was performed to verify the expression of the particular lncRNAs. Microarray analysis of lung tissue from the COPD model revealed that 123 and 444 lncRNAs were substantially raised and reduced in PMM vs. the control group (Ctrl), respectively, as were 621 and 1,178 mRNAs. Meanwhile, 81 and 340 lncRNAs were consistently raised and lowered in CSM vs. Ctrl, respectively, as were 408 and 931 mRNAs. GO enrichment and KEGG pathway analysis indicated that the COPD model was connected to inflammatory responses, mitochondrial dysfunction, and others. CONCLUSION: XR_340674, ENSRNOT00000089642, XR_597045, and XR_340651 were decreased, and XR_592469 was elevated. These lncRNAs were shown to be related to mitochondrial dysfunction in the lung tissue of animals exposed to CS or PM2.5.
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Doença Pulmonar Obstrutiva Crônica , RNA Longo não Codificante , Ratos , Animais , RNA Longo não Codificante/genética , Ratos Wistar , Doença Pulmonar Obstrutiva Crônica/genética , Material Particulado , Mitocôndrias/genética , Mitocôndrias/metabolismo , Perfilação da Expressão GênicaRESUMO
OBJECTIVE: Guided by the ecosystem theory model framework, we aimed to explore the influence of three ecological dimensions (social, family and psychological factors) on suicidal intention in people with severe mental illness (SMI). We hypothesized that three factors influence suicidal intention, and that psychological factors may play a mediating role in the influence of social and family factors on suicidal intention. METHODS: We collected 994 patients with SMI aged 18 and above from May 2021 to March 2022 in the Fourth Hospital of Fuzhou City. We used logistic regression to analyse the association between social, family, psychological factors and suicidal intention. Furthermore, we explored the mediating effects among the influencing factors. RESULTS: Younger male patients with schizophrenia were more likely to have suicidal intention due to psychosocial family factors (p < .05). Social factors (poor interpersonal relations, social retreat, social activities outside the home), family factors (parental functions, activities within the family, family functions), psychological factors (anxiety, depression, interest in the outside world, overt aggression, lack of accountability and planning) were all independent risk factors for suicidal intention in patients. Mediation analysis showed anxiety and depression mediated the role of social and family factors on suicidal intention (p < .05). CONCLUSION: Social, family and psychological factors were important risk factors for suicidal intention, with anxiety and depression being partial mediators for suicidal intention. Therefore, interventions that enhance family and social functioning and reduce anxiety and depression may be effective in reducing suicidal intention in SMI.
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Transtornos Mentais , Ideação Suicida , Humanos , Masculino , Intenção , Ecossistema , Ansiedade/psicologiaRESUMO
Paraquat (PQ) is an environmental poison that causes clinical symptoms similar to those of Parkinson's disease (PD) in vitro and in rodents. It can lead to the activation of microglia and apoptosis of dopaminergic neurons. However, the exact role and mechanism of microglial activation in PQ-induced neuronal degeneration remain unknown. Here, we isolated the microglia-derived exosomes exposed with 0 and 40 µM PQ, which were subsequently co-incubated with PQ-exposed neuronal cells to simulate intercellular communication. First, we found that exosomes released from microglia caused a change in neuronal cell vitality and reversed PQ-induced neuronal apoptosis. RNA sequencing data showed that these activated microglia-derived exosomes carried large amounts of circZNRF1. Moreover, a bioinformatics method was used to study the underlying mechanism of circZNRF1 in regulating PD, and miR-17-5p was predicted to be its target. Second, an increased Bcl2/Bax ratio could play an anti-apoptotic role. Bcl2 was predicted to be a downstream target of miR-17-5p. Our results showed that circZNRF1 plays an anti-apoptotic role by absorbing miR-17-5p and regulating the binding of Bcl2 after exosomes are internalized by dopaminergic neurons. In conclusion, we demonstrated a new intercellular communication mechanism between microglia and neurons, in which circZNRF1 plays a key role in protecting against PQ-induced neuronal apoptosis through miR-17-5p to regulate the biological process of PD. These findings may offer a novel approach to preventing and treating PD.
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MicroRNAs , Microglia , Paraquat/toxicidade , Neurônios Dopaminérgicos , Proteínas Proto-Oncogênicas c-bcl-2 , MicroRNAs/genéticaRESUMO
The widespread use of nanomaterials in daily life has led to increased concern about their potential neurotoxicity. Therefore, it is particularly important to establish a simple and reproducible assessment system. Representative nanomaterials, including cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiO2-NPs), and multiwall carbon nanotubes (MWCNTs), were compared in terms of their neurotoxicity and underlying mechanisms. In 0, 25, 50, and 75 µg/ml of these nanomaterials, the survival, locomotion behaviors, acetylcholinesterase (AchE) activity, reactive oxygen species production, and glutathione-S transferase 4 (Gst-4) activation in wildtype and transgenic Caenorhabditis elegans (C. elegans) were evaluated. All nanomaterials induced an imbalance in oxidative stress, decreased the ratio of survival, impaired locomotion behaviors, as well as reduced the activity of AchE in C. elegans. Interestingly, CoNPs and MWCNTs activated Gst-4, but not TiO2-NPs. The reactive oxygen species scavenger, N-acetyl-l-cysteine, alleviated oxidative stress and Gst-4 upregulation upon exposure to CoNPs and MWCNTs, and rescued the locomotion behaviors. MWCNTs caused the most severe damage, followed by CoNPs and TiO2-NPs. Furthermore, oxidative stress and subsequent activation of Gst-4 were involved in nanomaterials-induced neurotoxicity. Our study provides a comprehensive comparison of the neurotoxicity and mechanisms of typical nanomaterials, which could serve as a model for hazard assessment of environmental pollutants using C. elegans as an experimental model system.
Assuntos
Nanopartículas , Nanotubos de Carbono , Animais , Espécies Reativas de Oxigênio , Caenorhabditis elegans , Nanotubos de Carbono/toxicidade , Cobalto/toxicidade , Acetilcolinesterase , Estresse Oxidativo , Nanopartículas/toxicidadeRESUMO
BACKGROUND & AIMS: Although hyperuricemia is a known risk factor for coronary heart disease (CHD), little is known about the role of blood pressure in mediating this association. The purpose of this study is to investigate the role of blood pressure-related indicators and Thrombospondin 3 (THBS3) in the association between hyperuricemia and CHD. METHODS AND RESULTS: Our observational epidemiology study included 593 CHD cases and 760 controls from a residential stable sample. We also chose 43 new CHD patients and 43 controls to test the expression levels of THBS3 using ELISA kits. We used logistic regression models and mediating effect analysis to investigate the relationships between hyperuricemia and CHD, as well as the mediating role of blood pressure-related indicators and THBS3. In the general population (OR: 2.001 [95% CI: 1.528-2.622]), male population (OR: 1.591 [95% CI: 1.119-2.262]), and female population (OR: 2.813 [95% CI: 1.836-4.310]), hyperuricemia is an independent risk factor for CHD. In general, average systolic blood pressure (SBP) and average pulse pressure difference (PPD) mediated 3.35% and 4.59%, respectively, of the association between hyperuricemia and CHD, and 6.60% and 6.60% in women. However, in the male population, we have not yet found that blood pressure-related indicators had a significant mediating effect. Meanwhile, we found that THBS3 mediated 19.23% of the association between hyperuricemia and CHD. CONCLUSIONS: Average SBP, PPD, and THBS3 all play a role in the association of hyperuricemia and CHD. In the female population, similar mediating results in blood pressure-related indicators were observed.
Assuntos
Doença das Coronárias , Hiperuricemia , Humanos , Masculino , Feminino , Pressão Sanguínea/fisiologia , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiologia , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Abnormal methylation of N6-methyladenosine (m6A) is reportedly associated with central nervous system disorders. However, the role of m6A mRNA methylation in unconjugated bilirubin (UCB) neurotoxicity requires further research. METHODS: Rat pheochromocytoma PC12 cells treated with UCB were used as in vitro models. After the PC12 cells were treated with UCB (0, 12, 18, and 24 µM) for 24 h, the total RNA m6A levels were measured using an m6A RNA methylation quantification kit. The expression of m6A demethylases and methyltransferases was detected through western blotting. We determined the m6A mRNA methylation profile in PC12 cells exposed to UCB (0 and 18 µM) for 24 h using methylated RNA immunoprecipitation sequencing (MeRIP-seq). RESULTS: Compared with the control group, UCB (18 and 24 µM) treatment decreased the expression of the m6A demethylase ALKBH5 and increased the expression of the methyltransferases METTL3 and METTL14, which resulted in an increase in the total m6A levels in PC12 cells. Furthermore, 1533 m6A peaks were significantly elevated and 1331 peaks were reduced in the UCB (18 µM)-treated groups compared with those in the control group. Genes with differential m6A peaks were mainly enriched in protein processing in the endoplasmic reticulum, ubiquitin-mediated proteolysis, cell cycle, and endocytosis. Through combined analysis of the MeRIP-seq and RNA sequencing data, 129 genes with differentially methylated m6A peaks and differentially expressed mRNA levels were identified. CONCLUSION: Our study suggests that the modulation of m6A methylation modifications plays a significant role in UCB neurotoxicity.
Assuntos
Metiltransferases , RNA , Ratos , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células PC12 , Metiltransferases/genética , Metiltransferases/metabolismo , RNA/metabolismo , Adenosina/metabolismoRESUMO
OBJECTIVES: To determine whether longitudinal trajectories of nighttime sleep duration and daytime napping duration are related to subsequent multimorbidity risk. To explore whether daytime napping can compensate for negative effects of short nighttime sleep. METHODS: The current study included 5262 participants from China Health and Retirement Longitudinal Study. Self-reported nighttime sleep duration and daytime napping duration were collected from 2011 to 2015. The 4-year sleep duration trajectories were conducted by group-based trajectory modeling. The 14 medical conditions were defined by self-reported physician diagnoses. Multimorbidity was diagnosed as participants with 2 or more of the 14 chronic diseases after 2015. Associations between sleep trajectories and multimorbidity were assessed by Cox regression models. RESULTS: During 6.69 years of follow-up, we observed multimorbidity in 785 participants. Three nighttime sleep duration trajectories and three daytime napping duration trajectories were identified. Participants with persistent short nighttime sleep duration trajectory had the higher risk of multimorbidity (hazard ratio = 1.37, 95% confidence interval: 1.06-1.77), compared with those with persistent recommended nighttime sleep duration trajectory. Participants with persistent short nighttime sleep duration and persistent seldom daytime napping duration had the highest risk of multimorbidity (hazard ratio = 1.69, 95% confidence interval: 1.16-2.46). CONCLUSIONS: In this study, persistent short nighttime sleep duration trajectory was associated with subsequent multimorbidity risk. Daytime napping could compensate for the risk of insufficient night sleep.