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The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits.

ABSTRACT: Prenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this review, we highlight research examining the most prevalent drugs of abuse and their effects on brain development with a focus on endoplasmic reticulum stress and oxidative stress signaling pathways. A thorough exploration of drug-induced cellular stress mechanisms during prenatal brain development may provide insight into therapeutic interventions to combat effects of prenatal drug exposure.

SUBMITTER: Tsai SA

PROVIDER: S-EPMC6430408 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits.

Tsai S-Y A SA Bendriem Raphael M RM Lee Chun-Ting D CD

Neurobiology of stress 20181227

Prenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this re ...[more]

PMID: 30937351

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Project description:Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) in the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2? (eIF2?). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.

Project description:BackgroundIn Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. The therapeutic mechanisms of DD in pancreatic fibrosis are unclear.AimThis study aimed to investigate the regulatory mechanisms of DD on oxidative stress and endoplasmic reticulum stress in CP.Materials and methodsExperimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. The western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. The pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. The interactions between TCM components and Keap-1 were investigated by molecular docking modeling.ResultsThe pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1.ConclusionsThese results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways.

Project description:Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose-exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance. Graphical abstract.

Dataset Information

The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits.

Publications

The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits.

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