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1.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800919

RESUMO

Trypsin inhibitors (TI), a common anti-nutritional factor in soybean, prevent animals' protein digestibility reducing animal growth performance. No commercial soybean cultivars with low or null concentration of TI are available. The availability of a high throughput genotyping assay will be beneficial to incorporate the low TI trait into elite breeding lines. The aim of this study is to develop and validate a breeder friendly Kompetitive Allele Specific PCR (KASP) assay linked to low Kunitz trypsin inhibitor (KTI) in soybean seeds. A total of 200 F3:5 lines derived from PI 547656 (low KTI) X Glenn (normal KTI) were genotyped using the BARCSoySNP6K_v2 Beadchip. F3:4 and F3:5 lines were grown in Blacksburg and Orange, Virginia in three years, respectively, and were measured for KTI content using a quantitative HPLC method. We identified three SNP markers tightly linked to the major QTL associated to low KTI in the mapping population. Based on these SNPs, we developed and validated the KASP assays in a set of 93 diverse germplasm accessions. The marker Gm08_44814503 has 86% selection efficiency for the accessions with low KTI and could be used in marker assisted breeding to facilitate the incorporation of low KTI content in soybean seeds.

2.
Opt Express ; 29(3): 3269-3283, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33770929

RESUMO

Distributed acoustic sensors (DASs) have the capability of registering faint vibrations with high spatial resolution along the sensing fiber. Advanced algorithms are important for DAS in many applications since they can help extract and classify the unique signatures of different types of vibration events. Deep convolutional neural networks (CNNs), which have powerful spectro-temporal feature learning capability, are well suited for event classification in DAS. Generally, these data-driven methods are highly dependent on the availability of large quantities of training data for learning a mapping from input to output. In this work, to fully utilize the collected information and maximize the power of CNNs, we propose a method to enlarge the useful dataset for CNNs from two aspects. First, we propose an intensity and phase stacked CNN (IP-CNN) to utilize both the intensity and phase information from a DAS with coherent detection. Second, we propose to use data augmentation to further increase the training dataset size. The influence of different data augmentation methods on the performance of the proposed CNN architecture is thoroughly investigated. The experimental results show that the proposed IP-CNN with data augmentation produces a classification accuracy of 88.2% on our DAS dataset with 1km sensing length. This indicates that the usage of both intensity and phase information together with the enlarged training dataset after data augmentation can greatly improve the classification accuracy, which is useful for DAS pattern recognition in real applications.

3.
Virol J ; 18(1): 46, 2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33639976

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and broke out as a global pandemic in late 2019. The acidic pH environment of endosomes is believed to be essential for SARS-CoV-2 to be able to enter cells and begin replication. However, the clinical use of endosomal acidification inhibitors, typically chloroquine, has been controversial with this respect. METHODS: In this study, RT-qPCR method was used to detect the SARS-CoV-2N gene to evaluate viral replication. The CCK-8 assay was also used to evaluate the cytotoxic effect of SARS-CoV-2. In situ hybridization was used to examine the distribution of the SARS-CoV-2 gene in lung tissues. Hematoxylin and eosin staining was also used to evaluate virus-associated pathological changes in lung tissues. RESULTS: In this study, analysis showed that endosomal acidification inhibitors, including chloroquine, bafilomycin A1 and NH4CL, significantly reduced the viral yields of SARS-CoV-2 in Vero E6, Huh-7 and 293T-ACE2 cells. Chloroquine and bafilomycin A1 also improved the viability and proliferation of Vero E6 cells after SARS-CoV-2 infection. Moreover, in the hACE2 transgenic mice model of SARS-CoV-2 infection, chloroquine and bafilomycin A1 reduced viral replication in lung tissues and alleviated viral pneumonia with reduced inflammatory exudation and infiltration in peribronchiolar and perivascular tissues, as well as improved structures of alveolar septum and pulmonary alveoli. CONCLUSIONS: Our research investigated the antiviral effects of endosomal acidification inhibitors against SARS-CoV-2 in several infection models and provides an experimental basis for further mechanistic studies and drug development.


Assuntos
Antivirais/farmacologia , /virologia , Endossomos/efeitos dos fármacos , /fisiologia , Replicação Viral/efeitos dos fármacos , Cloreto de Amônio/farmacologia , /metabolismo , Animais , /patologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/farmacologia , Endossomos/metabolismo , Feminino , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Pulmão/patologia , Macrolídeos/farmacologia , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Células Vero
4.
Cell Death Dis ; 12(2): 202, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608512

RESUMO

Ring1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell-cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

5.
Invest New Drugs ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534026

RESUMO

As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates' analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.

6.
J Cell Mol Med ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33305893

RESUMO

Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) can act as a tumour-specific promoter by triggering the expression of certain genes in tumour cells. This study aims to investigate the inhibitory effects and to explore the inhibitory pathway of a dual cancer-specific recombinant adenovirus (Ad-apoptin-hTERTp-E1a, Ad-VT) on breast cancer stem cells. Breast cancer cell spheres were obtained from MCF-7 cells through serum-free suspension culture. The cell spheres were detected by flow cytometry for CD44+ CD24- cell subsets. The stemness of MCF-7-CSC cells was confirmed by in vivo tumorigenesis experiments. The inhibitory effect of the recombinant adenoviruses on MCF-7-CSC cells was evaluated by CCK-8 assay. In addition, the stemness of adenovirus-infected MCF-7-CSC cells was analysed by testing the presence of CD44+ CD24- cell subsets. The ability of the recombinant adenovirus to induce MCF-7-CSC cell apoptosis was detected by staining JC-1, TMRM and Annexin V. Our results showed that a significantly higher proportion of the CD44+ CD24- cell subsets was present in MCF-7-CSC cells with a significantly increased expression of stem cell marker proteins. The MCF-7-CSC cells, whlist exhibited a strong tumorigenic ability with a certain degree of stemness in mice, were shown to be strongly inhibited by recombinant adenovirus Ad-VT through cell apoptosis. In addition, Ad-VT was shown to exert a killing effect on BCSCs. These results provide a new theoretical basis for the future treatment of breast cancer.

7.
Opt Lett ; 45(24): 6675-6678, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33325868

RESUMO

An ultrafast time-stretched swept source with a sweep rate of 400 MHz is demonstrated based on the buffering of a 100 MHz femtosecond laser pulse train. To the best of our knowledge, this is the highest sweep rate of swept sources for optical coherence tomography (OCT) that has been reported. With a 10 dB sweep range of ∼100nm, an axial resolution of 19 µm is obtained in the OCT. OCT imaging of high-speed rotating disks is demonstrated. A composite complex apodization method is proposed and demonstrated to enhance the signal to noise ratio in the OCT imaging.

8.
Med Sci Monit ; 26: e929638, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33190141

RESUMO

The Figure 2 and Figure 4C were incorrectly published in the article titled MicroRNA-125b down-regulation mediates endometrial cancer invasion by targeting ERBB2. Chao Shang, Yan-ming Lu, Li-rong Meng, Med Sci Monit 2012; 18(4): BR149-155. 10.12659/MSM.882617. The correct Figures are as follows.

9.
J Pak Med Assoc ; 70 [Special Issue](9): 84-87, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33177733

RESUMO

OBJECTIVE: To investigate the clinical efficacy of percutaneous vertebroplasty (PVP) on osteoporotic vertebral compression fracture and relevant issues. METHODS: The data of 80 patients with osteoporotic vertebral compression fracture admitted to Orthopaedics Department, Huanggang Central Hospital from September 2013 to September 2015 was selected for analysis. The data selection was done from December 2018 to February 2019 Under local anaesthesia and C-arm X-ray fluoroscopy, percutaneous kyphoplasty was performed by puncturing into unilateral (or bilateral) pedicle(s) percutaneously and fixing with bone cement. The degree of lower back pain and the recovery of vertebral height in patients were observed and recorded before surgery, 24 hours and 3 months after surgery. RESULTS: All of the 80 patients had a successful surgery. After 24 hours of surgery, 47 (58.75%) patients had no lower back pain, 33 (41.25%) had mild dull pain locally; 74 (92.50%) patients were able to have out-of-bed activity on Day1 after surgery, and 6 (7.50%) patients were able to have out-of-bed activity on Day 3 after surgery. The visual analogue scale (VAS) score and percentage of injured vertebra height to original vertebra height 24 hours and 3 months after surgery were significantly better than those before surgery (P<0.01). The VAS score 3 months after surgery was significantly superior to the VAS score 24 hours after surgery (P<0.01). Compared with 24 hours after surgery, the injured vertebra height was lost 3 months after surgery, but it was not statistically significant (P>0.05). There were no complications, such as infection, haematoma, spinal nerve injury and bone cement toxicosis. CONCLUSIONS: In the treatment of thoracolumbar osteoporotic vertebral compression fracture, PVP can effectively relieve pain, restore vertebral height partially and the efficacy is satisfactory.

10.
Smart Health (Amst) ; 182020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33043105

RESUMO

Depression is a serious mental health problem. Recently, researchers have proposed novel approaches that use sensing data collected passively on smartphones for automatic depression screening. While these studies have explored several types of sensing data (e.g., location, activity, conversation), none of them has leveraged Internet traffic of smartphones, which can be collected with little energy consumption and the data is insensitive to phone hardware. In this paper, we explore using coarse-grained meta-data of Internet traffic on smartphones for depression screening. We develop techniques to identify Internet usage sessions (i.e., time periods when a user is online) and extract a novel set of features based on usage sessions from the Internet traffic meta-data. Our results demonstrate that Internet usage features can reflect the different behavioral characteristics between depressed and non-depressed participants, confirming findings in psychological sciences, which have relied on surveys or questionnaires instead of real Internet traffic as in our study. Furthermore, we develop machine learning based prediction models that use these features to predict depression. Our evaluation shows that Internet usage features can be used for effective depression prediction, leading to F 1 score as high as 0.80.

11.
Cell Death Dis ; 11(10): 936, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127881

RESUMO

Blood-tumor barrier (BTB) presents a major obstacle to brain drug delivery. Therefore, it is urgent to enhance BTB permeability for the treatment of glioma. In this study, we demonstrated that MIAT, ZAK, and phosphorylated NFκB-p65 (p-NFκB-p65) were upregulated, while miR-140-3p was downregulated in glioma-exposed endothelial cells (GECs) of BTB compared with those in endothelial cells cocultured with astrocytes (ECs) of blood-brain barrier (BBB). MIAT inhibited miR-140-3p expression, increased the expression of ZAK, enhanced the ratio of p-NFκB-p65:NFκB-p65, and promoted the endothelial leakage of BTB. Our current study revealed that miR-140-3p was complementary to the ZAK 3'untranslated regions (3'-UTR), and luciferase activity of ZAK was inhibited by miR-140-3p in 293T cells. MiR-140-3p silencing resulted in an increase in BTB permeability by targeting ZAK, while overexpression of miR-140-3p had the opposite results in GECs of BTB. Overexpression of ZAK induced an increase in BTB permeability, and this effect was related to ZAK's ability to mediate phosphorylation of NFκB-p65. Conversely, ZAK silencing get opposite results in GECs of BTB. As a molecular sponge of miR-140-3p, MIAT attenuated its negative regulation of the target gene ZAK by adsorbing miR-140-3p. P-NFκB-p65 as a transcription factor negatively regulated the expression of TJ-associated proteins by means of chip assay and luciferase assay. Single or combined application of MIAT and miR-140-3p effectively promoted antitumor drug doxorubicin (Dox) across BTB to induce apoptosis of glioma cells. In summary, MIAT functioned as a miR-140-3p sponge to regulate the expression of its target gene ZAK, which contribution to phosphorylation of NFκB-p65 was associated with an increase in BTB permeability by down-regulating the expression of TJ associated proteins, thereby promoting Dox delivery across BTB. These results might provide a novel strategy and target for chemotherapy of glioma.

12.
Nanomaterials (Basel) ; 10(10)2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32992641

RESUMO

Hierarchical porous birnessite-MnO2-based nanostructure composite materials were prepared on a nickel foam substrate by a successive ionic layer adsorption and reaction method (SILAR). Following composition with reduced graphene oxide (rGO) and multiwall carbon nanotubes (MWCNTs), the as-obtained MnO2, MnO2/rGO and MnO2/rGO-MWCNT materials exhibited pore size distributions of 2-8 nm, 5-15 nm and 2-75 nm, respectively. For the MnO2/rGO-MWCNT material in particular, the addition of MWCNT and rGO enhanced the superb distribution of micropores, mesopores and macropores and greatly improved the electrochemical performance. The as-obtained MnO2/rGO-MWCNT/NF electrode showed a specific capacitance that reached as high as 416 F·g-1 at 1 A·g-1 in 1 M Na2SO4 aqueous electrolyte and also an excellent rate capability and high cycling stability, with a capacitance retention of 85.6% after 10,000 cycles. Electrochemical impedance spectroscopy (EIS) analyses showed a low resistance charge transfer resistance for the as-prepared MnO2/rGO-MWCNT/NF nanostructures. Therefore, MnO2/rGO-MWCNT/NF composites were successfully synthesized and displayed enhanced electrochemical performance as potential electrode materials for supercapacitors.

13.
Front Oncol ; 10: 1026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714864

RESUMO

Apoptin is a protein that specifically induces apoptosis in tumor cells. The anti-tumorigenic functions of Apoptin, including autophagy activation and its interaction with apoptosis, have not been precisely elucidated. Here we investigate the main pathways of apoptin-mediated killing of human liver cancer cells, as well as its putative role in autophagy and apoptosis. The anti-proliferative effect of apoptin in liver cancer cells was analyzed in vitro by crystal violet staining and MTS detection, and also in vivo using a tumor-based model. The main pathway related to apoptin-induced growth inhibition in vitro was evaluated by flow cytometry and fluorescence staining. The relationship between apoptosis and autophagy on apoptin-treating cells was analyzed using apoptosis and autophagy inhibitors, mitochondrial staining, Annexin V-FITC/PI flow detection, LC3 staining, and western blotting. The effect of ROS toward the apoptosis and autophagy of apoptin-treating cells was also evaluated by ROS detection, Annexin V-FITC/PI flow detection, LC3 staining, and western blotting. Inhibition of apoptosis in apoptin-treating liver cancer cells significantly reduced the autophagy levels in vitro. The overall inhibition increased from 12 h and the effect was most obvious at 48 h. Inhibition of autophagy could increase apoptin-induced apoptosis of cells in a time-dependent manner, reaching its peak at 24 h. Apoptin significantly alters ROS levels in liver cancer cells, and this effect is directly related to apoptosis and autophagy. ROS appears to be the key factor linking apoptin-induced autophagy and apoptosis through the mitochondria in liver cancer cells. Therefore, evaluating the interaction between apoptin-induced apoptosis and autophagy is a promising step for the development of alternate tumor therapies.

14.
Front Pharmacol ; 11: 986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695005

RESUMO

TSPO is mainly expressed in the mitochondrial outer membrane of microglia in the central nervous system, and its expression is greatly increased when microglia are activated. However, the role and mechanism of this protein in microglial activation is not well characterized. In this study, we investigated the role of TSPO in microglial activation by isolating primary microglia from TSPO knockout mice and constructing TSPO-knockdown microglial cell line. We found that TSPO deficiency significantly inhibited microglial activation induced by LPS or IL-4. Mechanistically, TSPO deficiency greatly decreased the mitochondrial membrane potential and ATP production. Moreover, an analysis of cellular energy metabolism showed that TSPO deficiency suppressed mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in microglial overall metabolic deficits. Together, our results reveal a crucial role of TSPO in microglial activation through the regulation of mitochondrial metabolism, thus providing a potential therapeutic target for neuroinflammation-related diseases of the central nervous system.

15.
ACS Appl Mater Interfaces ; 12(19): 21922-21935, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32324368

RESUMO

Mesoporous aluminosilicates are promising solid acid catalysts. They are also excellent supports for transition metal catalysts for various catalytic applications. Synthesis of mesoporous aluminosilicates with controllable particle size, morphology, and structure, as well as adjustable acidity and high hydrothermal stability, is very desirable. In this work, we demonstrate the scalable synthesis of Al-SBA-15 microspheres with controllable physicochemical properties by using the microfluidic jet-spray-drying technology. The productivity is up to ∼30 g of dried particles per nozzle per hour. The Al-SBA-15 microspheres possess uniform controllable micron sizes (27.5-70.2 µm), variable surface morphologies, excellent hydrothermal stability (in pure steam at 800 °C), high surface areas (385-464 m2/g), ordered mesopore sizes (5.4-5.8 nm), and desirable acid properties. The dependence of various properties, including particle size, morphology, porosity, pore size, acidity, and hydrothermal stability, of the obtained Al-SBA-15 microspheres on experimental parameters including precursor composition (Si/Al ratio and solid content) and processing conditions (drying and calcination temperatures) is established. A unique morphology transition from smooth to wrinkled microsphere triggered by control of the Si/Al ratio and solid content is observed. The particle formation and morphology-evolution mechanism are discussed. The Al-SBA-15 microspheres exhibit high acid catalytic performance for aldol-condensation reaction between benzaldehyde and ethyl alcohol with a high benzaldehyde conversion (∼56.3%), a fast pseudo-first-order reaction rate (∼0.1344 h-1), and a high cyclic stability, superior to the commercial zeolite acid (H-ZSM-5). Several influencing factors on the catalytic performance of the obtained Al-SBA-15 microspheres are also studied.

16.
Med Sci Monit ; 26: e924162, 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32277069

RESUMO

The authors informed the journal that an error occurred in their manuscript. The authors selected the wrong figure when uploading it due to the similarity of figures. They found this error when they were periodically sorting the experimental data and contacted the journal. This change does not affect the final results and conclusion. Reference: 1. Dalong Xie, Chao Shang, Hui Zhang, Yan Guo, Xiaojie Tong: Upregulation of miR-9 Target CBX7 Regulates Invasion Ability of Bladder Transitional Cell Carcinoma. Med Sci Monit 2015; 21: 225-230. DOI: 10.12659/MSM.893232.

17.
Opt Express ; 28(3): 2699-2713, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32121952

RESUMO

ϕ-OTDR perturbation detection applications demand optimal precision of the perturbation location. Strategies for improving both signal-to-noise (SNR) and precision of the perturbation location in a laboratory environment may fail when applying to a very long fiber under test (FUT) in real-field environments. With this deployment, meaningful energy points representing the response of a certain perturbation can be located at random locations of the fiber other than the original location of the perturbation. These random locations are referred to as the ghost energy points that confuse the system to mistakenly consider the location of these points as the original perturbation location. We present in this paper a novel space-time scanning (ST-scan) method that segregates the ghost energy point locations from those of the real perturbation so that the original perturbation location estimation is improved.

18.
Front Oncol ; 10: 229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158698

RESUMO

Oncolytic virotherapy is emerging as an important agent in cancer treatment. In a previous study, we designed and constructed Ad-Apoptin-hTERTp-E1a (Ad-VT), a dual cancer-selective anti-tumor recombinant adenovirus. In this study, crystal violet staining and WST-1 assays showed that Ad-VT has a significant tumor killing effect in a time and dose dependent manner. The combination of Ad-VT (10 MOI) and gemcitabine (10 nM) significantly inhibited NCI-H226 cells, but did not increase the killing effect of gemcitabine on human normal bronchial epithelial cells BEAS-2B. Hoechst, JC-1 and Annexin V experiments demonstrated that the combination of Ad-VT and gemcitabine mainly inhibited NCI-H226 cell proliferation by inducing apoptosis (mitochondrial pathway). The combination also significantly inhibited the migration and invasion abilities of NCI-H226 cells. In vivo, Ad-VT in combination with low-dose gemcitabine could effectively inhibit tumor growth and prolong survival of mice. Ad-VT has the characteristics of tumor-selective replication and killing, in vitro and in vivo. The combined application of Ad-VT and gemcitabine has a synergistic effect, which can increase the anti-tumor effect and reduce the toxicity of chemotherapy drugs, indicating that Ad-VT has a potential clinical value in the treatment of lung squamous cell carcinoma.

19.
J Psychopharmacol ; 34(4): 441-451, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913078

RESUMO

BACKGROUND: Fast-acting and cognitive-enhancing antidepressants are desperately needed. Activation of translocator protein (18 kDa, TSPO) is a novel strategy for developing potential antidepressants, but there are no data available on the onset time of TSPO ligands. This study aimed to investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand, in TSPO knock-out (KO) mice. METHODS: TSPO wild-type (WT) and KO mice were subjected to a six-week chronic unpredicted stress (CUS) paradigm. Then, the mice were treated with AC-5216 and tested with depressive and cognitive behaviours. RESULTS: A single dose of AC-5216 (0.3 mg/kg) exerted anxiolytic- and antidepressant-like actions in TSPO WT mice. Moreover, in chronically stressed WT mice, two to four days of AC-5216 treatment (0.3 mg/kg, once per day) produced fast-onset antidepressant-like effects in the novelty-suppressed feeding and sucrose preference tests, as well as memory-enhancing effects in the novel object recognition test. In addition, a rapid (with five days of treatment) restoration of serum corticosterone levels and prefrontal cortex (PFC) allopregnanolone levels was found. Further studies showed that in these stress-exposed WT mice, AC-5216 significantly increased the levels of mTOR signalling-related proteins (mBDNF, p-mTOR, PSD-95, synapsin-1, GluR1), as well as the total dendritic length and branching points of pyramidal neurons in the PFC. CONCLUSIONS: These results suggest that TSPO mediates the fast-onset antidepressant-like and memory-enhancing effects of AC-5216, possibly through the rapid activation of mTOR signalling and restoration of dendritic complexity in the PFC.

20.
Behav Brain Res ; 379: 112320, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31669345

RESUMO

There is a serious need for fast-acting drugs to treat post-traumatic stress disorder (PTSD). Our previous studies revealed that YL-IPA08, a novel small-molecule TSPO agonist, exerted significant anti-PTSD effects in various animal models. However, the onset time of YL-IPA08 and its underlying mechanisms remain unclear. In the present study, we first investigated the time course of YL-IPA08 compared to selective serotonin reuptake inhibitors (SSRIs) in the well-known time-dependent sensitization model of PTSD. YL-IPA08 required only 2-4 days of treatment to take effect in behavioural models of PTSD, whereas sertraline required 7-8 days. Furthermore, the mechanism study revealed that YL-IPA08 elicited anti-PTSD-like effects associated with increased GABA levels and allopregnanolone efflux in the hippocampus and prefrontal cortex and increased corticosterone levels in the serum after only 5 days of treatment, whereas sertraline required 9 days. Our results demonstrate that YL-IPA08 can exert fast-onset anti-PTSD-like effects, and its mechanisms may be related to the increased GABA levels, allopregnanolone efflux and the hypothalamic-pituitary-adrenal (HPA) axis function.

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