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1.
Micron ; 144: 103028, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33647773

RESUMO

The microstructure and hardness of case-hardened steel were investigated after carburizing and austenitizing at 820-900 °C, and oil quenching and tempering at 180 °C. The carburized case had a multiphase microstructure consisting of martensite, carbides, and retained austenite, and the maximum content of the retained austenite was 30%; the particle size range was 2-3 µm. The nano-hardness decreased from about 12 GPa near the surface to about 7 GPa in the core, and the microhardness decreased from 800 HV0.2 to 450 HV0.2. The in-depth distribution of the microhardness and nano-hardness showed a similar trend, and the ratio of nano-hardness to microhardness was about 15. The results were attributed to the fine particle size of the retained austenite and its even distribution in the martensite matrix and it could not lower the nano-hardness. The nano-hardness was relatively low in areas of the retained austenite (about 5.5 GPa), and pop-in effects were observed, indicating the phase transformation of the retained austenite during nanoindentation loading.

2.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33649839

RESUMO

Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high­throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride­induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin­3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC­LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF­ß1­induced expression of α­smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.

3.
Dig Liver Dis ; 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33563583

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer. Extracellular vesicles (EV)-mediated microRNA (miRNA) delivery is critical in cancer metastasis. We aimed to identify the mechanism of HCC cell-derived EVs-mediated miR-3129 in HCC. METHODS: After EVs isolation and identification, miR-3129 expression in plasma EVs was evaluated and its diagnostic efficiency was analyzed. miR-3129 inhibitor was transfected into HepG2 and SMMC7721 cells, and cell malignant episodes were assessed. HCC cells were incubated with EVs from MHCC-97H cells and transfected with miR-3129 inhibitor and/or TXNIP. The nude mice were injected with MHCC-97H cells-EV or MHCC-97H cells-EV/miR-3129 inhibitor, and HCC growth and metastasis were assessed. RESULTS: miR-3129 was highly expressed in plasma EVs from HCC patients, which was the essential diagnostic biomarker for HCC. miR-3129 downregulation inhibited the malignant episodes of HCC cells. MHCC-97H cell-EVs were absorbed by HCC cells and transferred miR-3129 to HCC cells. EVs-carried miR-3129 promoted malignant episodes of HCC cells, which were weakened by miR-3129 inhibition in EVs. miR-3129 targeted TXNIP. TXNIP overexpression averted the effect of EVs-carried miR-3129 in HCC. In vivo, MHCC-97H cell-EVs transferred miR-3129 to facilitate HCC growth and metastasis. CONCLUSION: MHCC-97H cell-EVs transferred miR-3129 to promote HCC metastasis by targeting TXNIP.

4.
5.
Methods ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33549725

RESUMO

RNA molecules play critical roles in cellular functions at the level of gene expression and regulation. The intricate 3D structures and the functional roles of RNAs make RNA molecules ideal targets for therapeutic drugs. The rational design of RNA-targeted drug requires accurate modeling of RNA-ligand interactions. Recently a new computational tool, RLDOCK, was developed to predict ligand binding sites and binding poses. Using an iterative multiscale sampling and search algorithm and a energy-based evaluation of ligand poses, the method enables efficient and accurate predictions for RNA-ligand interactions. Here we present a detailed illustration of the computational procedure for the practical implementation of the RLDOCK method. Using Flavin mononucleotide (FMN) docking to F. nucleatum FMN riboswitch as an example, we illustrate the computational protocol for RLDOCK-based prediction of RNA- ligand interactions. The RLDOCK software is freely accessible at http://https://github.com/Vfold-RNA/RLDOCK.

6.
Rejuvenation Res ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607932

RESUMO

Umbilical cord mesenchymal stem cells (UCMSCs) have been identified as a potentially ideal cell type for use in regenerative therapeutic contexts owing to their excellent paracrine secretory abilities and other desirable properties. Previous work has shown that stem cell-derived exosomes can effective reduce skin aging, but few studies have specifically focused on the role of UCMSC-derived exosomes in this context. In the present study, we isolated exosomes derived from UCMSCs grown in a 3D culture system and explored their ability to modulate the photo-aging of HaCaT keratinocytes. Cell viability and proliferation was assessed via CCK8 assay, whereas wound healing and transwell assays were used to assess cell migratory capabilities. UVB irradiation (60mJ/cm2) was used to induce photo-aging of HaCaT cells. TUNEL and SA-ß-Gal staining were used to explore HaCaT cell apoptosis and senescence respectively, while qPCR was used to assess the expression of relevant genes at the mRNA level. We found that UCMSC-derived exosomes were able to enhance normal HaCaT cell proliferation and migration, while also inhibiting UVB-induced damage to these cells. These exosomes also reduced HaCaT cell apoptosis and senescence, increasing collagen type I expression and reducing matrix metalloproteinase (MMP1) expression in photo-aged HaCaT cells. Together, these findings indicate that UCMSC-derived exosomes have the potential to be used therapeutically to suppress skin aging.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33608141

RESUMO

INTRODUCTION: Patients with severe periodontitis typically present with pathologic tooth migration. To improve esthetics and masticatory function, orthodontic treatment is required. Research on periodontal orthodontic treatment has been sparse, particularly from the microbial perspective. Hence, we analyzed the microbial and clinical changes in patients with well-controlled periodontitis in the early stage of orthodontic treatment. METHODS: Ten patients with well-controlled periodontitis were asked to collect saliva before and 1 and 3 months after appliance placement (T0, T1, and T2, respectively) and underwent clinical examinations before and 1, 3, and 6 months after appliance placement (T0, T1, T2, and T3, respectively). The microbial community of saliva was analyzed by 16S rRNA gene sequencing. Gingival index, the plaque index, and the probing pocket depth were clinically assessed. RESULTS: The plaque index significantly increased from T0 to T1 and decreased at T2 and T3. The probing pocket depth and gingival index increased slightly at T2, but not significantly, in both the high-risk site and low-risk site. The alpha and beta diversity increased at T1. The microbial community structure was similar at T0 and T2. The relative abundance of core genera and periodontal pathogens was stable during the initial 3 months of orthodontic treatment. CONCLUSIONS: The orthodontic appliance promoted plaque accumulation and altered the microbial community of patients with well-controlled periodontitis during the first month of orthodontic treatment. The microbial community returned to the basal composition at 3 months after appliance placement, and the periodontal inflammation during the 6-months orthodontic treatment was under control.

8.
Nutrients ; 13(2)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530505

RESUMO

Astaxanthin (AX) is a carotenoid that exerts potent antioxidant activity and acts in the lipid bilayer. This study aimed to investigate the effects of AX on muscle-atrophy-mediated disturbance of mitochondria, which have a lipid bilayer. Tail suspension was used to establish a muscle-atrophied mouse model. AX diet fed to tail-suspension mice prevented loss of muscle weight, inhibited the decrease of myofiber size, and restrained the increase of hydrogen peroxide (H2O2) production in the soleus muscle. Additionally, AX improved downregulation of mitochondrial respiratory chain complexes I and III in the soleus muscle after tail suspension. Meanwhile, AX promoted mitochondrial biogenesis by upregulating the expressions of adenosine 5'-monophosphate-activated protein kinase (AMPK) α-1, peroxisome proliferator-activated receptor (PPAR)-γ, and creatine kinase in mitochondrial (Ckmt) 2 in the soleus muscle of tail-suspension mice. To confirm the AX phenotype in the soleus muscle, we examined its effects on mitochondria using Sol8 myotubes derived from the soleus muscle. We found that AX was preferentially detected in the mitochondrial fraction; it significantly suppressed mitochondrial reactive oxygen species (ROS) production in Sol8 myotubes. Moreover, AX inhibited the activation of caspase 3 via inhibiting the release of cytochrome c into the cytosol in antimycin A-treated Sol8 myotubes. These results suggested that AX protected the functional stability of mitochondria, alleviated mitochondrial oxidative stress and mitochondria-mediated apoptosis, and thus, prevented muscle atrophy.

9.
Sleep Med Rev ; 58: 101436, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33571887

RESUMO

Sleep disturbances are highly prevalent in pregnancy and are frequently overlooked as a potential cause of significant morbidity. The association between sleep disturbances and pregnancy outcomes remains largely controversial and needs to be clarified to guide management. To evaluate the association between sleep disturbances and maternal complications and adverse fetal outcomes, we performed a systematic search of PubMed, Embase and Web of Science for English-language articles published from inception to March 6, 2020, including observational studies of pregnant women with and without sleep disturbances assessing the risk of obstetric complications in the antenatal, intrapartum or postnatal period, and neonatal complications. Data extraction was completed independently by two reviewers. We utilized the Newcastle-Ottawa Scales to assess the methodological quality of included studies and random-effect models to pool the associations. A total of 120 studies with 58,123,250 pregnant women were included. Sleep disturbances were assessed, including poor sleep quality, extreme sleep duration, insomnia symptoms, restless legs syndrome, subjective sleep-disordered breathing and diagnosed obstructive sleep apnea. Significant associations were found between sleep disturbances in pregnancy and a variety of maternal complications and adverse fetal outcomes. Overall sleep disturbances were significantly associated with pre-eclampsia (odds ratio = 2.80, 95% confidence interval: 2.38-3.30), gestational hypertension (1.74, 1.54-1.97), gestational diabetes mellitus (1.59, 1.45-1.76), cesarean section (1.47, 1.31-1.64), preterm birth (1.38, 1.26-1.51), large for gestational age (1.40, 1.11-1.77), and stillbirth (1.25, 1.08-1.45), but not small for gestational age (1.03, 0.92-1.16), or low birth weight (1.27, 0.98-1.64). Sleep disturbances were related to higher morbidities in pregnant women who are 30 y or older and overweight before pregnancy. The findings indicate that sleep disturbances, which are easily ignored and treatable for both pregnant women and clinical services, deserve more attention from health care providers during prenatal counseling and health care services.

10.
Forensic Sci Int Genet ; 52: 102483, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33610949

RESUMO

mRNA markers provide a very promising method for the identification of human body fluids or tissues in the context of forensic investigations. Previous studies have shown that different body fluids can be distinguished from each other according to their specific mRNA biomarkers. In this study, we evaluated eight semen-specific mRNA markers (KLK3, NKX3-1, CKB, KLK2, PRAC1, SEMG1, TGM4, and SORD) that encompass 12 coding single nucleotide polymorphisms (cSNPs) to identify the semen contributor in a mixed stain. Five highly specific and sensitive mRNA markers for blood, menstrual blood, saliva, vaginal secretions, and skin were also incorporated into the PCR system as body fluid-positive controls. Reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR and SNaPshot mini-sequencing assays were established for the identification of semen-specific mRNA. The amplicon size ranged from 133 to 337 bp. The semen-specific system was examined against blood, menstrual blood, saliva, vaginal secretions, and skin swabs. The eight mRNA biomarkers were semen-specific and could be successfully typed in laboratory-generated mixtures composed of different body fluids supplemented with 1 ng of semen cDNA. This system possessed a high sensitivity that ranged from 1:10-1:100 for detecting trace amounts of semen in semen-containing body fluid mixtures. Additionally, our results demonstrated that the cSNPs polymorphisms included in the mRNA markers were concordant with genomic DNA (gDNA). Despite the presence of other body fluids, the system exhibited high sensitivity and specificity to the semen in the mixture. In future studies, we will add other cSNPs from the semen-specific genes using massively parallel sequencing to further improve our system.

11.
J Craniofac Surg ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33538448

RESUMO

BACKGROUND: Although infantile hemangiomas (IHs) are usually self-limiting, residual elevated appearance may remain. Topical beta-blockers are effective in superficial IHs management, while intralesionally injected diprospan is effective at treating deep, localized IHs. A single application of topical timolol or injected diprospan has obvious limitations. Therefore, for elevated, localized mixed IHs, we applied topical timolol combined with intralesionally injected diprospan, using their respective advantages to maximize benefits. PURPOSE: To evaluate the clinical efficacy and safety of topical timolol combined with intralesionally injected diprospan for the treatment of elevated, localized mixed IHs and identify the optimal injection time. METHODS: Infants with elevated, localized mixed IHs in the proliferative phase were treated with injected diprospan combined with topical timolol between March 2018 and March 2020. The injection was administered only when the tumor surface was higher than that of the surrounding tissue. The patients were asked to return every 4 weeks for a treatment response evaluation, and complications were recorded. RESULTS: Thirty-six patients with elevated, localized mixed IHs (thickness >3 mm on Doppler ultrasound) were recruited. The mean age at treatment initiation was 3.58 ±â€Š1.50 months (range: 1.00-6.00 months). The follow-up period ranged from 9 to 24 months. Considering the size of the IH at the end of treatment, regression was observed in 31 (86.1%) cases, stabilization was observed in 5 (13.9%) cases, and no treatment failure was observed. All the IHs improved in color and height after treatment. CONCLUSION: Topical timolol combined with intralesionally injected diprospan is an effective and safe treatment for elevated, localized mixed IH. The injection is needed only when we forecast the elevated tissue may remain after regression.

12.
Mol Psychiatry ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542468

RESUMO

Pandemics have become more frequent and more complex during the twenty-first century. Posttraumatic stress disorder (PTSD) following pandemics is a significant public health concern. We sought to provide a reliable estimate of the worldwide prevalence of PTSD after large-scale pandemics as well as associated risk factors, by a systematic review and meta-analysis. We systematically searched the MedLine, Embase, PsycINFO, Web of Science, CNKI, WanFang, medRxiv, and bioRxiv databases to identify studies that were published from the inception up to August 23, 2020, and reported the prevalence of PTSD after pandemics including sudden acute respiratory syndrome (SARS), H1N1, Poliomyelitis, Ebola, Zika, Nipah, Middle Eastern respiratory syndrome coronavirus (MERS-CoV), H5N1, and coronavirus disease 2019 (COVID-19). A total of 88 studies were included in the analysis, with 77 having prevalence information and 70 having risk factors information. The overall pooled prevalence of post-pandemic PTSD across all populations was 22.6% (95% confidence interval (CI): 19.9-25.4%, I2: 99.7%). Healthcare workers had the highest prevalence of PTSD (26.9%; 95% CI: 20.3-33.6%), followed by infected cases (23.8%: 16.6-31.0%), and the general public (19.3%: 15.3-23.2%). However, the heterogeneity of study findings indicates that results should be interpreted cautiously. Risk factors including individual, family, and societal factors, pandemic-related factors, and specific factors in healthcare workers and patients for post-pandemic PTSD were summarized and discussed in this systematic review. Long-term monitoring and early interventions should be implemented to improve post-pandemic mental health and long-term recovery.

13.
J Chem Theory Comput ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33560836

RESUMO

Modeling structures and functions of large ribonucleic acid (RNAs) especially with complicated topologies is highly challenging due to the inefficiency of large conformational sampling and the presence of complicated tertiary interactions. To address this problem, one highly promising approach is coarse-grained modeling. Here, following an iterative simulated reference state approach to decipher the correlations between different structural parameters, we developed a potent coarse-grained RNA model named as IsRNA1 for RNA studies. Molecular dynamics simulations in the IsRNA1 can predict the native structures of small RNAs from a sequence and fold medium-sized RNAs into near-native tertiary structures with the assistance of secondary structure constraints. A large-scale benchmark test on RNA 3D structure prediction shows that IsRNA1 exhibits improved performance for relatively large RNAs of complicated topologies, such as large stem-loop structures and structures containing long-range tertiary interactions. The advantages of IsRNA1 include the consideration of the correlations between the different structural variables, the appropriate characterization of canonical base-pairing and base-stacking interactions, and the better sampling for the backbone conformations. Moreover, a blind screening protocol was developed based on IsRNA1 to identify good structural models from a pool of candidates without prior knowledge of the native structures.

14.
RNA Biol ; : 1-11, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586616

RESUMO

Nucleotide modification in RNA controls a bevy of biological processes, including RNA degradation, gene expression, and gene editing. In turn, misregulation of modified nucleotides is associated with a host of chronic diseases and disorders. However, the molecular mechanisms driving these processes remain poorly understood. To partially address this knowledge gap, we used alchemical and temperature replica exchange molecular dynamics (TREMD) simulations on an RNA duplex and an analogous hairpin to probe the structural effects of modified and/or mutant nucleotides. The simulations successfully predict the modification/mutation-induced relative free energy change for complementary duplex formation, and structural analyses highlight mechanisms driving stability changes. Furthermore, TREMD simulations for a hairpin-forming RNA with and without modification provide reliable estimations of the energy landscape. Illuminating the impact of methylated and/or mutated nucleotides on the structure-function relationship and the folding energy landscape, the simulations provide insights into modification-induced alterations to the folding mechanics of the hairpin. The results here may be biologically significant as hairpins are widespread structure motifs that play critical roles in gene expression and regulation. Specifically, the tetraloop of the probed hairpin is phylogenetically abundant, and the stem mirrors a miRNA seed region whose modification has been implicated in epilepsy pathogenesis.

15.
Carbohydr Polym ; 258: 117596, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33593530

RESUMO

Osteosarcoma is the most common primary sarcoma of bone. The use of Chitooligosaccharide (COS) as a drug carrier is an emerging new strategy for cancer therapy. However, the application of COS in osteosarcoma has not been reported. Here, we investigated the influence of COS on osteosarcoma, and suggested the underlying mechanism. Initially, we obtained COS with a low-degree-polymerized (DP = 2-6) by enzymatic hydrolysis. Using these COS materials, in vitro assays showed that COS elicited the anti-tumor activity against osteosarcoma cells. We found that COS had significant effects on cell growth, metastasis inhibition, apoptosis and autophagy induction, and triggered pro-apoptosis autophagy through p53/mTOR signaling pathway in osteosarcoma cells. In addition, the COS also inhibited tumor growth and metastasis in an osteosarcoma xenograft model in vivo. Finally, we showed that COS could increase sensitivity to chemotherapy of cisplatin in vitro. Thus, we provide experimental evidence to demonstrate that COS has anti-tumor effect on osteosarcoma, and COS can be a new potential therapeutic candidate for the treatment of osteosarcoma.

16.
Spectrochim Acta A Mol Biomol Spectrosc ; 252: 119542, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33581574

RESUMO

Recent studies have shown that bacteria can also undergo apoptosis, which has gradually attracted researchers' attention. Cisplatin is a first-line drug to treat several cancers, but it can damage beneficial bacteria. Hence it is very important to explore the damage mechanism of cisplatin on beneficial bacteria. In this study, Lactobacillus paracasei, one kind of beneficial bacteria, was used as the model to investigate cisplatin damage. Conventional detection showed that cisplatin induced the apoptosis of Lactobacillus paracasei. Then Fourier transform infrared (FTIR) microspectroscopy was used to detect biomacromolecular changes in Lactobacillus paracasei apoptosis, and the following results were obtained: ① Second derivative IR spectra showed the changes of DNA, proteins, polysaccharides and lipids; ② Peak-area ratios suggested the changes of the protein and lipid structure and the decrease of DNA content; ③ Principal component analysis (PCA) further revealed significant changes in the DNA and protein content/structure. This study may have a new insight into the adverse reaction mechanism of cisplatin on Lactobacillus, moreover, it suggests that FTIR microspectroscopy may be a useful supplementary tool for investigating bacterial apoptosis.

17.
J Nat Prod ; 84(2): 247-258, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33533247

RESUMO

Sixteen new sesquiterpene lactones (1-16) along with 13 known analogues (17-29) were isolated from the whole plants of Centipeda minima. The structures of 1-16 were delineated by the combination of NMR spectroscopic experiments, HRESIMS, single-crystal X-ray diffraction analyses, and ECD spectra. Compounds 23-26 showed potent cytotoxicity against Hela, HCT-116, and HepG2 cells with IC50 values of 0.8-2.6, 0.4-3.3, and 1.1-2.6 µM, respectively. Compounds 8, 15, and 24 exhibited significant inhibitory activity on the production of nitric oxide in the lipopolysaccharide-activated RAW 264.7 mouse macrophage cell line, with IC50 values ranging from 0.1 to 0.2 µM.

18.
J Phys Chem B ; 125(4): 1156-1166, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33497570

RESUMO

Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemical probing provides local RNA flexibility information at single-nucleotide resolution. In general, SHAPE is thought of as a secondary structure (2D) technology, but we find evidence that robust tertiary structure (3D) information is contained in SHAPE data. Here, we report a new model that achieves a higher correlation between SHAPE data and native RNA 3D structures than the previous 3D structure-SHAPE relationship model. Furthermore, we demonstrate that the new model improves our ability to discern between SHAPE-compatible and -incompatible structures on model decoys. After identifying sequence-dependent bias in SHAPE experiments, we propose a mechanism driving sequence-dependent bias in SHAPE experiments, using replica-exchange umbrella sampling simulations to confirm that the SHAPE sequence bias is largely explained by the stability of the unreacted SHAPE reagent in the binding pocket. Taken together, this work represents multiple practical advances in our mechanistic and predictive understanding of SHAPE technology.

19.
Food Funct ; 12(4): 1672-1687, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33496711

RESUMO

Alcoholic liver diseases (ALDs) impose a substantial health burden on many countries. Bioactive peptides isolated from people, marine organisms, animals and plants have shown hepatoprotective effects on animal and hepatocyte models. In this study, an LO2 cell model of ethanol-induced liver injury in vitro was constructed. We investigated the hepatoprotective effects of the three-spot seahorse bioactive peptide (SBP) PAGPRGPA (Pro-Ala-Gly-Pro-Arg-Gly-Pro-Ala; 721.39 Da) and characterised the underlying metabolic pathways and biomarkers through a nontargeted metabolomics approach. We found that ethanol-induced oxidative stress impaired the cellular antioxidant system, leading to an imbalance in cellular homeostasis. However, SBP with a certain antioxidant activity inhibited reactive oxygen species (ROS) production, excessive intracellular Ca2+ level and abnormal apoptosis. It also restored the superoxide dismutase (SOD) and glutathione (GSH) levels and attenuated ethanol-induced oxidative damage and inflammation. SBP suppressed the activation of mitogen-activated protein kinase (MAPK) in ethanol-stimulated LO2 cells. It also regulated the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway to protect LO2 cells from oxidative damage by promoting the expression of antioxidant enzymes, such as heme oxygenase-1 (HO-1). Furthermore, the metabolomics approach demonstrated nine different biomarkers and six metabolic pathways. In summary, the hepatoprotective mechanisms of SBP in vitro, which can be attributed to the upregulation of antioxidant substances and amino acid metabolism, attenuate ethanol-induced oxidative stress.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33514875

RESUMO

Impaired glutamate homeostasis is a key characteristic of the neurobiology of drug addiction in rodent models and contributes to the vulnerability to relapse to drug seeking. Although disrupted astrocytic and presynaptic regulation of glutamate release has been considered to constitute with impaired glutamate homeostasis in rodent model of drug relapse, the involvement of endocannabinoids (eCBs) in this neurobiological process has remained largely unknown. Here, using cocaine self-administration in rats, we investigated the role of endocannabinoids in impaired glutamate homeostasis in the core of nucleus accumbens (NAcore), which was indicated by augmentation of spontaneous synaptic glutamate release, downregulation of metabotropic glutamate receptor 2/3 (mGluR2/3), and mGluR5-mediated astrocytic glutamate release. We found that the endocannabinoid, anandamide (AEA), rather than 2-arachidonoylglycerol elicited glutamate release through presynaptic transient receptor potential vanilloid 1 (TRPV1) and astrocytic cannabinoid type-1 receptors (CB1Rs) in the NAcore of saline-yoked rats. In rats with a history of cocaine self-administration and extinction training, AEA failed to alter synaptic glutamate release in the NAcore, whereas CB1R-mediated astrocytic glutamate release by AEA remained functional. In order to induce increased astrocytic glutamate release via exogenous AEA, (R)-methanandamide (methAEA, a metabolically stable form of AEA) was chronically infused in the NAcore via osmotic pumps during extinction training. Restoration of mGluR2/3 function and mGluR5-mediated astrocytic glutamate release was observed after chronic methAEA infusion. Additionally, priming or cue-induced reinstatement of cocaine seeking was inhibited in methAEA-infused rats. These results demonstrate that enhancing endocannabinoid signaling is a potential pathway to restore glutamate homeostasis and may represent a promising therapeutic strategy for preventing cocaine relapse.

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