ABSTRACT
Iron homeostasis is of critical importance to living organisms. Drosophila melanogaster has emerged as an excellent model to study iron homeostasis, while the regulatory mechanism of iron metabolism remains poorly understood. Herein, we accidently found that knockdown of juvenile hormone (JH) acid methyltransferase (Jhamt) specifically in the fat body, a key rate-limiting enzyme for JH synthesis, led to iron accumulation locally, resulting in serious loss and dysfunction of fat body. Jhamt knockdown-induced phenotypes were mitigated by iron deprivation, antioxidant and Ferrostatin-1, a well-known inhibitor of ferroptosis, suggesting ferroptosis was involved in Jhamt knockdown-induced defects in the fat body. Further study demonstrated that upregulation of Tsf1 and Malvolio (Mvl, homolog of mammalian DMT1), two iron importers, accounted for Jhamt knockdown-induced iron accumulation and dysfunction of the fat body. Mechanistically, Kr-h1, a key transcription factor of JH, acts downstream of Jhamt inhibiting Tsf1 and Mvl transcriptionally. In summary, the findings indicated that fat body-derived Jhamt is required for the development of Drosophila by maintaining iron homeostasis in the fat body, providing unique insight into the regulatory mechanisms of iron metabolism in Drosophila.
Subject(s)
Drosophila Proteins , Drosophila melanogaster , Fat Body , Homeostasis , Iron , Methyltransferases , Animals , Drosophila melanogaster/metabolism , Iron/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Fat Body/metabolism , Methyltransferases/metabolism , Methyltransferases/genetics , Juvenile Hormones/metabolism , Ferroptosis/physiology , Kruppel-Like Transcription FactorsABSTRACT
Antimicrobial blue light (aBL) is utilized as a new approach to inhibit the growth of Staphylococcus aureus (S. aureus). Mediated by the endogenous chromophore, aBL possesses the similar photokilling property with aPDI (antimicrobial photodynamic inactivation), however, their mechanistic discrepancies in triggering the death of staphylococcal cells are not yet understood. Here, we describe the use of a 460-nm-LED to curb the viability of S. aureus. According to the results, the bacterial survival was sharply decreased when blue light was applied, reaching a maximum of 4.11 ± 0.04 log10 units. Moreover, the membrane integrity was damaged by aBL, causing the leakage of intracellular DNA. Transcriptomic analysis indicates the divergent gene expression upon either aBL or aPDI, with pathways such as transport, DNA repair, expression regulation and porphyrin massively affected by aBL. Among the commonly regulated genes, LrgA was underpinned on account of its involvement with biofilm formation and protein transport. By comparing the wildtype with the LrgA-overexpressing (LrgA+) strain, the survival rate, membrane penetration, surface structure and biofilm formation were, to a varying degree, improved for LrgA+, which may suggest that LrgA plays essential roles in modulating the responsiveness of S. aureus. Besides, LrgA may function through regulating the expression of autolysis-related systems. Finally, LrgA overexpression did not attenuate but aggravate the impairment induced by aPDI, showcasing a distinct responsive strategy from aBL. Taken together, this study unveils a unique molecular alteration for the aBL-mediated inactivation, providing the basis of utilizing blue light to reduce the harm brought by S. aureus.
Subject(s)
Bacterial Proteins , Biofilms , Blue Light , Staphylococcus aureus , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Biofilms/drug effects , Biofilms/radiation effects , Gene Expression Regulation, Bacterial/radiation effects , Gene Expression Regulation, Bacterial/drug effects , Microbial Viability/radiation effects , Microbial Viability/drug effects , Porphyrins/chemistry , Porphyrins/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/radiation effects , Staphylococcus aureus/genetics , Staphylococcus aureus/physiology , Transcription, Genetic/radiation effects , Transcription, Genetic/drug effectsABSTRACT
OBJECTIVE: High-risk human papillomavirus (HR-HPV) infection is the chief cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. The Erhuang suppository (EHS) is a traditional Chinese medicine (TCM) prepared from realgar (As2S2), Coptidis rhizoma, alumen, and borneolum syntheticum and has been used for antiviral and antitumor purposes. However, whether EHS can efficiently alleviate HR-HPV infection remains unclear. This study was conducted to evaluate the efficacy of EHS for the treatment of persistent HR-HPV infection in the uterine cervix. METHODS: In this study, we evaluated the therapeutic efficacy of EHS in a randomized controlled clinical trial with a 3-month follow-up. Totally, 70 patients with persistent HR-HPV infection were randomly assigned to receive intravaginal administration of EHS or placebo. HPV DNA, ThinPrep cytologic test (TCT), colposcopy, and safety evaluation were carried out after treatment. Microarray analysis was performed to compare transcriptome profiles before and after EHS treatment. A K14-HPV16 mouse model was generated to confirm the efficiency of EHS. RESULTS: After 3 months, 74.3% (26/35) of the patients in the treatment group were HPV negative, compared to 6.9% (2/29) in the placebo group. High-throughput microarrays revealed distinct transcriptome profiles after treatment. The differentially expressed genes were significantly enriched in complement activation, immune response, and apoptotic processes. The K14-HPV16 mouse model also validated the remarkable efficacy of EHS. CONCLUSION: This study demonstrated that EHS is effective against HR-HPV infection and cervical lesions. Additionally, no obvious systemic toxicity was observed in patients during the trial. The superior efficacy and safety of EHS demonstrated its considerable value as a potential cost-effective drug for the treatment of HPV infection and HPV-related cervical diseases.
Subject(s)
Cervix Uteri , Drugs, Chinese Herbal , Papillomavirus Infections , Transcriptome , Humans , Female , Papillomavirus Infections/drug therapy , Papillomavirus Infections/genetics , Papillomavirus Infections/virology , Adult , Suppositories , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/administration & dosage , Cervix Uteri/drug effects , Cervix Uteri/virology , Cervix Uteri/pathology , Transcriptome/drug effects , Animals , Medicine, Chinese Traditional , Middle Aged , Mice , Uterine Cervical Dysplasia/drug therapy , Uterine Cervical Dysplasia/genetics , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/virologyABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.
Subject(s)
Brain , Disease Models, Animal , Prenatal Exposure Delayed Effects , Animals , Mice , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/genetics , Female , Pregnancy , Brain/drug effects , Brain/metabolism , Autistic Disorder/genetics , Autistic Disorder/chemically induced , Autistic Disorder/metabolism , DNA Methylation/drug effects , DNA Methylation/genetics , Behavior, Animal/drug effects , Male , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/chemically induced , Autism Spectrum Disorder/metabolism , Pyrenes/toxicity , Mice, Inbred C57BLABSTRACT
Lead (Pb) is one of the most common heavy metal pollutants that possesses multi-organ toxicity. For decades, great efforts have been devoted to investigate the damage of Pb to kidney, liver, bone, blood cells and the central nervous system (CNS). For the common, dietary exposure is the main avenue of Pb, but our knowledge of Pb toxicity in gastrointestinal tract (GIT) remains quite insufficient. Importantly, emerging evidence has documented that gastrointestinal disorders affect other distal organs like brain and liver though gut-brain axis or gut-liver axis, respectively. This review focuses on the recent understanding of intestinal toxicity of Pb exposure, including structural and functional damages. We also review the influence and mechanism of intestinal toxicity on other distal organs, mainly concentrated on brain and liver. At last, we summarize the bioactive substances that reported to alleviate Pb toxicity, providing potential dietary intervention strategies to prevent or attenuate Pb toxicity.
Subject(s)
Environmental Pollutants , Lead , Lead/toxicity , Humans , Environmental Pollutants/toxicity , Intestines/drug effects , Liver/drug effects , Animals , Brain/drug effectsABSTRACT
Human beings are routinely exposed to chronic and low dose of Bisphenols (BPs) due to their widely pervasiveness in the environment. BPs hold similar chemical structures to 17ß-estradiol (E2) and thyroid hormone, thus posing threats to human health by rendering the endocrine system dysfunctional. Among BPs, Bisphenol-A (BPA) is the best-known and extensively studied endocrine disrupting compound (EDC). BPA possesses multisystem toxicity, including reproductive toxicity, neurotoxicity, hepatoxicity and nephrotoxicity. Particularly, the central nervous system (CNS), especially the developing one, is vulnerable to BPA exposure. This review describes our current knowledge of BPA toxicity and the related molecular mechanisms, with an emphasis on the role of Wnt signaling in the related processes. We also discuss the role of oxidative stress, endocrine signaling and epigenetics in the regulation of Wnt signaling by BPA exposure. In summary, dysfunction of Wnt signaling plays a key role in BPA toxicity and thus can be a potential target to alleviate EDCs induced damage to organisms.
Subject(s)
Benzhydryl Compounds , Endocrine Disruptors , Phenols , Wnt Signaling Pathway , Phenols/toxicity , Benzhydryl Compounds/toxicity , Humans , Endocrine Disruptors/toxicity , Wnt Signaling Pathway/drug effects , Animals , Environmental Exposure/adverse effects , Environmental Pollutants/toxicity , Oxidative Stress/drug effectsABSTRACT
The influence of starch granule surface proteins (SGSPs) and starch granule-associated proteins (SGAPs) on bread retrogradation was investigated in a reconstituted dough system. The removal of both SGSPs and SGAPs resulted in poor bread qualities, decreasing specific volume and crumb porosity, leading to more baking loss and compact crumb structure. Particularly, removing SGSPs was effective in promoting the bread retrogradation. After 7 days of storage, the hardness of bread without SGSPs showed an increase of 353.34 g than the bread without SGAPs. Proton population and relaxation times exhibited that the absence of SGSPs significantly decreased the content of bound water from 11.51 % to 7.03 %, indicating lower water-holding capacity due to the loosen gelling structure. Compared to the control group, bread without SGSPs accelerated the starch recrystallinity by a reduction in soluble starch content, thereby increasing the retrogradation enthalpy and relative crystallinity through promoting the molecular reassociation in starch.
Subject(s)
Bread , Water , Starch/chemistry , Thermodynamics , HardnessABSTRACT
Understanding the mechanisms for oocyte maturation and optimizing the protocols for in vitro maturation (IVM) are greatly important for improving developmental potential of IVM oocytes. The miRNAs expressed in cumulus cells (CCs) play important roles in oocyte maturation and may be used as markers for selection of competent oocytes/embryos. Although a recent study from our group identified several new CCs-expressed miRNAs that regulate cumulus expansion (CE) and CC apoptosis (CCA) in mouse oocytes, validation of these findings and further investigation of mechanisms of action in other model species was essential before wider applications. By using both in vitro and in vivo pig oocyte models with significant differences in CE, CCA and developmental potential, the present study validated that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes. We demonstrated that miR-149 and miR-31 targeted SMAD family member 6 (SMAD6) and transforming growth factor ß2 (TGFB2), respectively, in the transforming growth factor-ß (TGF-ß) signaling. Furthermore, both miR-149 and miR-31 increased CE and decreased CCA via activating SMAD family member 2 (SMAD2) and increasing the expression of SMAD2 and SMAD family member 4. In conclusion, the present results show that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes by activating the TGF-ß signaling, suggesting that they might be used as markers for pig oocyte quality.
Subject(s)
Cumulus Cells , In Vitro Oocyte Maturation Techniques , MicroRNAs , Oocytes , Animals , Female , Cumulus Cells/physiology , In Vitro Oocyte Maturation Techniques/veterinary , In Vitro Oocyte Maturation Techniques/methods , MicroRNAs/genetics , MicroRNAs/metabolism , Oocytes/physiology , Swine , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta/metabolismABSTRACT
The retrogradation behaviors of five damaged wheat starches (DS) after milling 0, 30, 60, 90, and 120 min with different water contents (33, 50, 60 %) were evaluated. Milling treatment increased DS content and developed an agglomeration of small particles. After 7 days of storage, the recrystallinity and long-range ordered structure of starch pastes were increased with the contents of DS and water. This process led to a lower setback viscosity and poor leaching of amylose. LF-NMR indicated a conversion from tightly bound water and free water to weakly bound water. During storage, DS12 with 60 % water content had the highest retrogradation tendency where the retrogradation enthalpy increased by 1.5 J/g and 2.2 J/g compared with DS0 with 60 % and DS12 with 33 % water content. DS with higher water content promoted the water mobility and made the starch molecular chains migrated conveniently. These changes facilitated the recrystallinity process during retrogradation period.
ABSTRACT
Bisphenol A (BPA) has been implicated in cognitive impairment. Icariin is the main active ingredient extracted from Epimedium Herb with protective function of nervous system. However, the potential therapeutic effects of Icariin on spatial memory deficits induced by developmental BPA exposure in Sprague-Dawley rats have not been investigated. This study investigated the therapeutic effect of Icariin (10 mg/kg/day, from postnatal day (PND) 21 to PND 60 by gavage) on spatial memory deficits in rat induced by developmental BPA exposure (1 mg/kg/day, from embryonic to PND 60), demonstrating that Icariin can markedly improve spatial memory in BPA-exposed rat. Furthermore, intra-gastric administration of Icariin could attenuate abnormal hippocampal cell dispersion and loss, improved the dendritic spine density and Nissl bodies. Moreover, Icariin reversed BPA induced reduction of frequency of miniature excitatory postsynaptic currents(mEPSC) and decrease of Vesicular glutamate transporter 1(VGlut1). Collectively, Icariin could effectively rescue BPA-induced spatial memory impairment in male rats by preventing cell loss and reduction of dendritic spines in the hippocampus. In addition, we also found that VGlut1 is a critical target in the repair of BPA-induced spatial memory by Icariin. Thus, Icariin may be a promising therapeutic agent to attenuate BPA-induced spatial memory deficits.
Subject(s)
Flavonoids , Hippocampus , Phenols , Spatial Memory , Rats , Animals , Male , Rats, Sprague-Dawley , Benzhydryl Compounds/toxicity , Memory Disorders/chemically induced , Memory Disorders/prevention & control , Maze LearningABSTRACT
Ferroptosis, a new type of cell death accompanied by iron accumulation and lipid peroxidation, is implicated in the pathology of Parkinson's disease (PD), which is a prevalent neurodegenerative disorder that primarily occurred in the elderly population. Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea with known neuroprotective effects in PD patients. But whether EGCG-mediated neuroprotection against PD involves regulation of ferroptosis has not been elucidated. In this study, we established a PD model using PINK1 mutant Drosophila. Iron accumulation, lipid peroxidation and decreased activity of GPX, were detected in the brains of PD flies. Additionally, phenotypes of PD, including behavioral defects and dopaminergic neurons loss, were ameliorated by ferroptosis inhibitor ferrostatin-1 (Fer-1). Notably, the increased iron level, lipid peroxidation and decreased GPX activity in the brains of PD flies were relieved by EGCG. We found that EGCG exerted neuroprotection mainly by restoring iron homeostasis in the PD flies. EGCG inhibited iron influx by suppressing Malvolio (Mvl) expression and simultaneously promoted the upregulation of ferritin, the intracellular iron storage protein, leading to a reduction in free iron ions. Additionally, EGCG downregulated the expression of Duox and Nox, two NADPH oxidases that produce reactive oxygen species (ROS) and increased SOD enzyme activity. Finally, modulation of intracellular iron levels or regulation of oxidative stress by genetic means exerted great influence on PD phenotypes. As such, the results demonstrated that ferroptosis has a role in the established PD model. Altogether, EGCG has therapeutic potentials for treating PD by targeting the ferroptosis pathway, providing new strategies for the prevention and treatment of PD and other neurodegenerative diseases.
Subject(s)
Drosophila Proteins , Ferroptosis , Neurodegenerative Diseases , Parkinson Disease , Aged , Animals , Humans , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Parkinson Disease/pathology , Drosophila/metabolism , Iron/metabolism , Protein Serine-Threonine Kinases , Drosophila Proteins/geneticsABSTRACT
Kaempferol (Kam) is a flavonoid antioxidant found in fruits and vegetables, which was discovered as neuroprotective antioxidants. Lead (Pb), an environmental pollution, could induce learning and memory deficits. Nevertheless, little is known about the mechanisms underlying Kam actions in Pb-induced learning and memory deficits. In this study, we investigated the effects of Kam on Pb-induced cognitive deficits. Pb-exposed rats were treated with 50 mg/kg Kam from postnatal day (PND) 30 to PND 60. Then, Y-maze and Morris water maze have been used to detect the spatial memory in all groups of rats. Hematoxylin and eosin (HE) staining and Nissl staining were used to analyze the neuronal structure damages. The results found Kam treatment improved the learning and memory ability and alleviated hippocampal neuronal pathological damages. Besides, Kam could significantly reverse the synaptic transmission related protein expression including PSD95 and NMDAR2B. Further research found that Kam downregulated autophagy markers, P62, ATG5, Beclin1, and LC3-II. Furthermore, 3-MA, autophagy inhibitor, increased the levels of NMDAR2B and PSD95 in Pb-induced PC12 cells, indicating Kam alleviated Pb-induced neurotoxicity through inhibiting autophagy activation. Our results showed that Kam could ameliorate Pb-induced cognitive impairments and neuronal damages by decreasing Pb-induced excess autophagy accumulation.
Subject(s)
Cognitive Dysfunction , Lead , Rats , Animals , Lead/toxicity , Maze Learning , Kaempferols/pharmacology , Kaempferols/therapeutic use , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Memory Disorders/chemically induced , Antioxidants/pharmacology , AutophagyABSTRACT
Lead (Pb) is an environmental neurotoxic metal. Chronic Pb exposure causes behavioral changes in humans and rodents, such as dysfunctional learning and memory. Nevertheless, it is not clear whether Pb exposure disrupts the neural circuit. Thus, here we aim at investigating the effects the chronic Pb exposure on neural-behavioral and neural circuits in mice from prenatal to postnatal day (PND) 63. Pregnant mice and their male offspring were treated with Pb (150 ppm) until postnatal day 63. In this study, several behavior tests and Golgi-Cox staining methods were used to assess spatial memory ability and synaptogenesis. Virus-based tracing systems and immunohistochemistry assays were used to test the relevance of chronic Pb exposure with disrupted neural circuits. The behavioral experiments and Golgi-Cox staining results showed that Pb exposure impaired spatial memory and spine density in mice. The virus tracing results revealed that the Entorhinal cortex (EC) neurons could be directly projected to Cornuammonis 1 (CA1) and Dentate gyrus (DG), forming a critical circuit inhibited, in either a direct or indirect way, by Pb invasion. In addition, excitatory neural input from ECï¼labeled with CaMKIIï¼to CA1 and DG was significantly attenuated by Pb exposure. In conclusion, our data indicated that Pb significantly impaired the excitatory connections from EC to the hippocampus (CA1 and DG), providing a novel neuro-circuitry basis for Pb neurotoxicity.
Subject(s)
Hippocampus , Lead , Pregnancy , Female , Humans , Mice , Animals , Male , Lead/toxicity , Nervous System , Spatial Memory , NeuronsABSTRACT
Chicken embryo development is a dynamic process. However, no detailed information is available about the protein abundance changes associated with the lipid mechanism and antioxidant enzyme activity during the egg embryo development. Thus, in the present study, an TMT-based proteomic approach was used to quantify protein abundance changes at different stages of chicken embryonic development. A total of 289 significantly differentially abundant hepatic proteins were quantified, of which 180 were upregulated and 109 were downregulated in the comparison of Day 20 with Day 12 in chicken embryos. Pathway analysis showed that metabolic pathways were the most highly enriched pathways, followed by arachidonic acid metabolism and steroid biosynthesis. Integration of proteomic-based studies profiling of three incubation stages revealed that the two compare groups (Day 12 vs Day 20 and Day 16 vs Day 20) shared some key differentially abundant proteins (DAPs), including LBFABP, FABP5, CYP4V2, PDCD4, LAL, APOA1, APOA4, SAA, FABP2, ACBSG2, FABP2, CYP51A1, and FBXO9. The STRING database and GO analysis results showed that there was close connectivity between APOA4, LBFABP, SERPINC1, APOA1, FGB, FGA, ANGPTL3 and these proteins were involved in the oxidation-reduction process, lipid transport, iron ion, heme, and lipid binding. Importantly, APOA4, FABP2, and CYP51A1 might be key factors to control fat deposition and antioxidant enzyme activity during chicken embryonic development. These findings will facilitate a better understanding of antioxidant and lipid mechanisms in chicken embryo and these DAPs can be further investigated as candidate markers to predict lipid deposition and the activity of antioxidant enzymes.
Subject(s)
Antioxidants , Chickens , Animals , Chick Embryo , Chickens/metabolism , Antioxidants/metabolism , Proteomics/methods , Liver/metabolism , Embryonic Development , LipidsABSTRACT
Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Lead (Pb) exposure impaired the development and the health of bones, which slows the growth of children. However, it is far from clear what exactly the effects of Pb on skeletal muscle development are. In this study, C2C12 cells are commonly used as an in vitro model of muscle regeneration due to their ability to transition from a proliferative phase into differentiated myofibers. The dose of 1, 5, and 10 µM Pb were adopted to study the toxicity of Pb on C2C12 proliferation and differentiation. First, the effects of Pb on cell viability were detected and the results demonstrated that 5 µM and 10 µM Pb exposure decreased cell viability, while 1 µM Pb exposure has no obvious effects on cell viability. Then, 1-10 µM Pb exposure seriously reduced the C2C12 myoblasts differentiation, with the decrease of myogenic differentiation marker genes expression, including Muscle creatine kinase (MCK), Myosin Heavy Chain 4 (MYH4), Myogenin (MYOG), Myogenic Differentiation (MYOD). What's more, it was found that the epigenetic modifier histone deacetylase-2 (HDAC2) was upregulated after Pb exposure on C2C12 myoblasts. Further studies conclusively showed knockdown of HDAC2 ameliorated Pb-damaged C2C12 myoblasts differentiation, indicating HDAC2 plays a vital role in the Pb-induced C2C12 myoblasts differentiation deficits. In summary, these results demonstrated that Pb exposure inhibited C2C12 myoblasts differentiation by regulating HDAC2.
Subject(s)
Lead , Myoblasts , Child , Humans , Lead/toxicity , Lead/metabolism , Cell Differentiation/genetics , Gene Expression , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolismABSTRACT
Exposure to Bisphenol A (BPA) has led to an increased risk of obesity and nonalcoholic fatty liver diseases (NAFLDs). However, it is as yet unclear if the damage caused by BPA is able to be repaired sufficiently after exposure has ceased. Therefore, this project aims to investigate the effects of BPA on the hepatic lipid metabolism function and its potential mechanisms in mice by comparing the BPA exposure model and the BPA exposure + cessation of drug treatment model. Herein, the male C57BL/6 mice were exposed in the dose of 50 µg/kg/day and 500 µg/kg/day BPA for 8 weeks, and then transferred to a standard chow diet for another 8 weeks to recover. Based on our previous RNA-seq study, we examined the expression patterns of some key genes. The results showed that the mice exposed to BPA manifested NAFLD features. Importantly, we also found that there was a significant expression reversion for SCD1, APOD, ANGPT4, PPARß, LPL and G0S2 between the exposure and recovery groups, especially for SCD1 and APOD (p < 0.01). Notably, BPA could significantly decrease the level of APOD protein (p < 0.01) whereas there was an extremely significant increase after the exposure ceased. Meanwhile, APOD over-expression suppressed TG accumulation in the AML12 cells. In conclusion, the damage caused by BPA is able to be repaired by the upregulation of APOD and exposure to BPA should be carefully examined in chronic liver metabolic disorders or diseases.
ABSTRACT
Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.
Subject(s)
Depression , Lead , Pregnancy , Female , Mice , Animals , Lead/toxicity , Depression/chemically induced , Mice, Inbred C57BL , Hippocampus , Anxiety/chemically induced , Dentate GyrusABSTRACT
BACKGROUND: In early life, sialic acid (SA) plays a crucial role in neurodevelopment and neuronal function. However, it remains unclear whether and how SA supplementation in early life promotes behavioral response to stress in adolescence. OBJECTIVES: This study aimed to examine the effects and mechanisms of SA on the antistress capability under challenging situations. METHODS: In this study, C57BL/6 mice were daily supplemented with 1 µL SA solution/g body weight at the dose of 10 mg/kg/d from postnatal day (PND) 5-45. The antistress behaviors, including open field, elevated plus maze, forced swimming test, and tail suspension test, were performed at PND 46, PND 48, PND 50, and PND 52 to detect the antistress ability of SA, respectively. RESULTS: Our results showed that SA-treated mice were more active in facing challenging situations. The fiber photometry experiment showed that SA promoted the excitatory neuronal response in the medial prefrontal cortex (mPFC), which was extensively interconnected to stress. Besides, electrophysiological results revealed SA enhanced synaptic transmission rather than neuronal excitability of mPFC excitatory neurons. It was also supported by the increasing spine density of mPFC excitatory neurons. At the molecular amount, the SA elevated the transmitter release-related proteins of mPFC, including Synapsin 1 and vesicular glutamate transporter 1 (VGlut 1). Furthermore, SA supplementation enhanced synaptic transmission mainly by altering the kinetics of synaptic transmission. CONCLUSIONS: The SA supplementation enhanced the response capability to stress under challenging situations, and the enhanced synaptic transmission of mPFC excitatory neurons may be the neurological basis of active response under challenging situations. In general, our findings suggested that SA supplementation in early life can promote stress resistance in adolescence.
Subject(s)
N-Acetylneuraminic Acid , Synaptic Transmission , Mice , Animals , N-Acetylneuraminic Acid/pharmacology , Mice, Inbred C57BL , Synaptic Transmission/physiology , Neurons/physiology , Prefrontal Cortex/physiologyABSTRACT
Bisphenol A (BPA), a widely used endocrine disruptor, has been implicated in cognitive impairment via epigenetic machinery. N6-methyl adenosine (m6A) has recently emerged as a new epigenetic factor that influences cognition, but the role of m6A in BPA induced cognitive deficits has not been explored yet. In this study, we found increased global m6A abundance accompanied with elevated expression of methyltransferase-like 3 (METTL3) in hippocampal neurons following BPA exposure. Inhibition of METTL3 activity by selective METTL3 inhibitor 2457 (STM) in cultured neurons abolished BPA induced m6A upregulation and abnormal synaptic transmission. Additionally, knockdown of METTL3 in hippocampus abrogated BPA induced learning and memory deficit in rats. Further study showed that m6A modification was enriched in mRNA of cholinergic receptor nicotinic alpha 4 subunit (Chrna4). Inhibition of METTL3 either by STM or shRNA restored BPA induced downregulation of Chrna4, suggesting that Chrna4 may be a potential target involved in BPA induced neurotoxicity that modified by m6A. Collectively, our findings demonstrated that METTL3 mediated m6A modification was involved in BPA induced cognitive deficit with Chrna4 as a potential target, which enriched our understanding of the role of epigenetics (RNA modifications) in BPA induced neurotoxicity and provided new insights into BPA or its substitutes induced damages in other organs.