Docking Target Research Articles

Ayurveda and Siddha systems polyherbal formulations to treat COVID-19 caused by SARS-CoV-2 and brief insight on application of Molecular Docking and SWISS Target prediction tools to study efficacy of active molecules

Ayurveda and Siddha systems are the two ancient medical systems originated in India more than 4000 years ago had given many formulary and treatment methods against influenza like infections. Kabasura churan from Siddha system and Maha sudharshan churan from the Ayurvedic system are the two major formulations along with many other individual herbs mentioned in the texts to treat Influenza like infections. Kabasura churan and Maha Sudarshan churan both have antipyretic, analgesic and anti-inflammatory effects. Both formulations were prepared according to Siddha and Ayurvedic texts. Herbs mentioned in both formulations like Turmeric, Tulsi (Basil), Kalmegh (Andrographis), Black Pepper, Liquorice (Mulethi), and Dronapushpi (Leucas) etc., had direct antiviral effect. Herbs like Aswagandha, Ginger, Guduchi (Tinospora), Kulanjan (Galangal) etc., had immunomodulatory and anti-inflammatory effect. Active compounds from different herbs were selected to study their antiviral activity through molecular docking algorithm. Application of modern of tools like Bioinformatics and Highthroughput screening methods can predict the efficacy of the ancient documented formulations and can be compared as per their literature. Compounds like curcumin, Glycyrrhizin, Ursolic acid, Quercetin, Andrographolide, Coumarins etc. were showed polyspecific activity like inhibition of Spike protein, Furin, Main Protease (Mpro) and Papain like Proteases (PLpro). Thus we propose use of Kabasura churan and Maha Sudharshan churan as alternative complementary medicine as a palliative treatment against COVID-19 caused by SARS-CoV-2 by conducting proper Randomized Clinical Trials

Thymoquinone-chemotherapeutic combinations: new regimen to combat cancer and cancer stem cells.

Cancer is a worldwide disease that causes millions of cases of mortality and morbidity. The major problem associated with the cancer is its resistance to conventional therapy and a high relapse rate. The use of chemotherapy to treat cancer began at the start of the twentieth century with attempts to control cancer. In time advance, many cancer chemotherapeutic agents have been developed for cancer treatment with different mechanisms of action including the alkylating agents, antimetabolites, antimicrotubule, topoisomerase inhibitors, and cytotoxic antibiotics, all of which have toxic effects toward normal cells in the body. Here, we reviewed chemotherapeutics' anticancer role potentiation and safety by thymoquinone (TQ) alone or in combination with the most common therapeutic drugs. Our search was done through PubMed, Science Direct, Springer Link, Taylor & Francis Online, Wiley Online Library, Nature publication group, SAGE Journals, and Web of Science databases. We recognized that TQ-chemotherapeutics combination increased chemo-modulation to the anticancer effect of different chemotherapeutics and protected the normal body cells from the toxic injuries that are induced by chemotherapeutics based on its antioxidant power. Moreover, the current study investigates the possible combinatory effect of TQ and chemotherapeutics to control cancer stem cells through molecular docking targeting of wingless/integrated (Wnt) and Hedgehog (Hh). We found that TQ modulates the Wnt and Hh pathways, by binding with tankyrase-2 and smoothened 7TM receptor, respectively, more efficiently than most chemotherapeutics drugs, while methotrexate showed high-binding affinity compared with TQ. Therefore, we encourage researchers to investigate the chemo-modulatory potential and protective effects of TQ in combination with chemotherapeutics for either cancer or cancer stem cell treatment.

In Silico Screening Anticancer of Six Triterpenoids toward miR-494 and TNF-α Targets

Hepatocellular carcinoma (HCC) accounts for up to 90% of all primary liver cancers worldwide. Cinobufagin is recognized to inhibit miR-494 as the HCC target. Increased expression of TNF-α results in an inadequate response to liver anticancer drugs. The models in this study were cinobufagin, cycloartenol, and ethyl acetate fractions of Ganoderma lucidum, 2–5. Seven docking targets in this study were Akt, ERK1, ERK2, PI3K, TNF-α, TNFR1, and TNFR2. Cycloartenol and compound 4 comply with Veber’s rules, Lipinski’s rule of 5, and demonstrate moderate toxicity. The action implies a potential docking target since it produces bond affinities with the compound 2–5 that agree with the IC50 in the literature, which is based on in vitro experiments. Akt as a receptor target is AZD5363. Cycloartenol shows a low ability to inhibit Akt. Conversely, compound 4 inhibits the Akt better than that of cycloartenol, although it is not as good as cinobufagin and AZD5363. Therefore, compound 4, a triterpenoid with a basic framework of lanostane has the potential to be an anticancer candidate for the liver.

Studies on effects of umbelliferon derivatives against periodontal bacteria; antibiofilm, inhibition of quorum sensing and molecular docking analysis

ObjectiveUmbelliferon derivatives are exclusively found in plants of Ferula spp. that are commonly used in curing various health concerns related to oral cavity. Diabetic patient are especially effected with periodontitis and allied complications. MethodWe investigated various compounds isolated from Ferula narthex exudate against clinical strains obtained from diabetic patients with periodontitis. Further antibiofilm, antiquorum sensing and molecular docking studies and ADMET analysis were performed. ResultsThe docking target included 2Q0J, 2UV0, 3QP5 and 3QP1. HYDE affinity assessment was performed for the first 30 top ranking docked conformations within these active sites.The binding free energy ΔG, FlexX docking score and the most favorable poses for all the compounds were determined. During in vitro analysis, feselol presented high inhibition of Pseudomonas aeruginosa (MIC 0.01 mg/mL, MBC 0.02 mg/mL). Similarly, Feselol presented significant inhibition against clinical strain S. epidermidis (MIC 0.087 mg/mL, MBC 0.174 mg/mL) and S. aureus (MIC 0.087 mg/mL, MBC 0.087 mg/mL) preceded by 10′-R-acetyl-karatavacinol against S. epidermidis (MIC 0.56 mg/mL, MBC 0.56 mg/mL) and S. aureus (MIC 0.28 mg/mL, MBC 0.28 mg/mL). During antibiofilm inhibition assay, 10′ R-acetyl-karatavacinol showed significant inhibition (54% at a final concentration 0.45 mg/mL), whereas slight antiquorum sensing activity was recorded. ConclusionsThe umbelliferon derivatives have significant inhibition of clinical isolates and moderate antibiofilm potential.

Interaction of the synthesized anticancer compound of the methyl-glycine 1,10-phenanthroline platinum nitrate with human serum albumin and human hemoglobin proteins by spectroscopy methods and molecular docking

In the present study, the interaction of the novel synthesized platinum complex named methyl-glycine 1,10-phenanthroline platinum nitrate product with two most crucial blood carrier proteins of hemoglobin (Hb) and human serum albumin (HSA) has been investigated. Notably, structural alternation ability of the above anticancer compound was assessed at various temperatures through multispectroscopic techniques such as far-UV circular dichroism (CD) and fluorescence with the participation of the molecular docking targeting Hb and HSA in the systems of the medicine delivery. Fluctuations in the inherent fluorescence intensities of the proteins in consequence of the Pt(II) complex binding represented statics of the quenching system. It should be mentioned that thermodynamic and binding parameters have been calculated through the analysis of the outcomes of the quenching and outcomes of van’t Hoff equation for the two proteins. Theoretical and experimental findings pointed out that the leading force for the Pt(II) complex interaction was electrostatic for HSA and hydrophobic interactions for Hb. Moreover, fluorescence experiments discovered that one binding site would be available because of the Pt(II) complex binding in the two proteins accompanied by a negative Gibbs free energy value. Additionally, the far-UV CD outputs suggested that the Pt(II) complex would cause some variations in the regular secondary and tertiary structures of the HSA as the remarkable going down in the α helical contents of proteins structures at different temperatures equal to 25 °C and 37 °C; however, any noteworthy modifications have not been seen in the respective structures of Hb. However, the interaction between the newly made-up medicine (Pt(II) complex) and the two most crucial blood carrier proteins of the Hb and HSA made a notable shifting in the structures and conformations of the proteins via many fluctuations in the secondary and tertiary structures of the two proteins. Hence, such researches of designing the novel metal anticancer medicines may gather useful data for exploring the more suitable path in the face-off with severe disorders like various cancers through inventing and developing metal medical compounds that are more advantageous and have fewer consequences.

The Atypical Protein Kinase C Small Molecule Inhibitor ζ-Stat, and Its Effects on Invasion Through Decreases in PKC-ζ Protein Expression

Ovarian cancer is estimated to reach 22,530 diagnoses and cause 13,980 cancer deaths per year. The most common histology diagnosed of ovarian cancer is epithelial ovarian carcinomas (EOC). An aggressive epithelial subtype is clear cell ovarian carcinoma (CCOC) and is characterized as a non-serous ovarian cancer. Protein kinase C (PKC) is an enzymatic family of proteins that have been found to be a component in cancer progression, tissue invasion, and metastasis. The atypical PKC (aPKC) isoforms, PKC-ι and PKC-ζ, have been suggested to participate in the increased proliferation of ovarian cancers. Previous studies have indicated that novel aPKC inhibitors ICA-1S and ζ-Stat decreased the migratory behaviors of colorectal cancer cells and were selective for PKC-ι/λ and PKC-ζ, respectively. The aims of this investigation were to further determine the binding mechanisms of ζ-Stat, expand on the tissue range of these compounds, investigate the therapeutic potential of ζ-Stat in CCOC, and to illustrate the disruption of invasion via the PKC-ζ signaling cascade. The methods utilized were molecular docking and virtual target screening, Western blot analysis, end-point PCR, GST pull down, cell viability and invasion and migration assays. We discovered that the small molecule inhibitor, ζ-Stat, is a prospective drug candidate to investigate as a novel potential treatment for CCOC. We also found that the PKC-ζ/Ect2/Rac1 activation pathway was decreased by ζ-Stat, which in turn decreased invasive behavior of CCOC.

Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type.

By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC of 7.2 M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.

Protein Docking Refinement with Systematic Conformational Search - Application to Models Inside the Docking Funnel

Structural refinement of modeled protein-protein complexes is an essential step in protein docking. Such refinement becomes increasingly challenging when the interacting proteins undergo significant conformational changes upon binding (unbound/bound interface RMSD>3 Å). We developed a flexible interface refinement protocol and benchmarked it on a set of top 100 docking models, which are inside the docking funnel (C-alpha ligand interface RMSD ≤ 10 Å [1]), generated for binary protein-protein complexes from the Dockground X-ray unbound set 4.0 (http://dockground.compbio.ku.edu). The refinement of the docking models was performed by a systematic local conformational search using previously developed Atom-Atom Contact Energy (AACE18) [2]. The average numbers of models of acceptable or better quality (according to CAPRI criteria [3]) in top-10 refined structures were 4.2, 3.0, and 1.7, for easy (unbound/bound interface RMSD ≤ 1.5 Å), medium (1.5 - 2.2 Å) and difficult (> 2.2 Å) docking targets, respectively. The results showed that the procedure performs better than other widely used refined protocols benchmarked on the same set of protein-protein complexes. 1. Hunjan et al. Proteins, 2008, 72: 344-352. 2. Anishchenko et al. Biophys. J., 2018, 115: 809-821. 3. Mendez et al. Proteins, 2003, 52: 51-67.

To Elucidate the Inhibition of Excessive Autophagy of Rhodiola crenulata on Exhaustive Exercise-Induced Skeletal Muscle Injury by Combined Network Pharmacology and Molecular Docking.

Autophagy can remodel skeletal muscle in response to exercise. However, excessive autophagy can have adverse effects on skeletal muscle. Although Rhodiola crenulata (R. crenulata) is thought to regulate autophagy, its active ingredients and mechanisms of action remain unclear. In this study, molecular docking and network pharmacology were used to screen for autophagy-related targets of R. crenulata. Subsequently, protein-protein interaction (PPI) analysis was used to find the relationships between the inverse docking targets and autophagy-related targets and therefore highlight the key targets. And then the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database was recruited to explain the functions and enrichment pathways of the target proteins. Finally, the potential targets were validated by immunohistochemistry of a mouse model of exhaustive exercise-induced skeletal muscle injury. We found a network of 15 major constituents of R. crenulata with 30 autophagy-related and 105 inverse-docking targets by molecular docking and network pharmacology. The results of PPI analysis indicated that 16 inverse-docking targets interacted 8 autophagy-related proteins. Further pathway analysis showed that R. crenulata could regulate exercise-induced skeletal muscle autophagy through mammalian target of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Forkhead box protein O (FoxO). The results of our animal experiments indicated that R. crenulata could suppress the expression of Ubiquitin-like protein ATG12 (ATG12), Beclin-1 (BECN1), and Serine/threonine-protein kinase ULK1 (ULK1), while increasing the expression of MTOR, NAD-dependent protein deacetylase sirtuin-1 (SIRT1), and Microtubule-associated protein tau (MAPT). In conclusion, this study demonstrated that R. crenulata may protect skeletal muscle injury induced by exhaustive exercise via regulating the mTOR, AMPK, and FoxO singling pathway.

Phenols fragment of Veronica ciliata Fisch. ameliorate free radical-induced nonalcoholic fatty liver disease by mediating PI3K/Akt signaling pathway

Ethnopharmacological relevanceVeronica ciliata Fisch. is used in numerous of Tibetan medicine prescriptions because of its hepatoprotective effect. Aims of this studyHere, we aimed to investigate the hepatoprotective effect and mechanism of phenolic fraction (PF) of V. ciliata Fisch. on liver injury induced by free radical. Materials and methodsBRL 3A cells were pre-treated with PF and luteolin (Lut) following tert-butyl hydroperoxide (t-BHP) treatment. The cell viability, lactate dehydrogenase (LDH) levels, reactive oxygen species (ROS) generation, apoptosis, cell cycle and autophagy were analyzed. Apoptotic, inflammatory, and autophagy,- related proteins were analyzed using Western blotting. The combination of molecular docking and drug affinity targeting experiments (DARTS) were first utilized to analysis the target protein of Lut. ResultsPF effectively suppressed t-BHP-induced apoptosis caused by mitochondrial dysfunction, which were associated with inhibiting ROS generation. Further investigation indicated that PF significantly suppressed apoptosis, inflammation, and autophagy by regulating the expression of related proteins. The results of molecular docking and drug affinity targeting experiments (DARTS) revealed that PI3K was the target protein of PF and Lut. Further studies have shown that PF relieved liver injury induced by t-BHP via suppressing phosphorylated expression of PI3K. ConclusionOur results indicate that PF effectively protect against hepatotoxicity induced by t-BHP through inhibiting the abnormal activation of PI3K-Akt signaling pathway and highlight the health benefits of PF regarding oxidative stress, proving it to be an important source of bioactive compounds associated with Nonalcoholic fatty liver disease (NAFLD).

Chemical profiling of Callicarpa nudiflora and its effective compounds identification by compound-target network analysis

Callicarpa nudiflora, belonging to the family Verbenaceae, is widely used to treat inflammation caused by bacterial infection.However, the underlying active substances of C. nudiflora against inflammation remains obscure. In this work, an ultra high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight mass spectrometry method was developed to characterize the ingredients in C. nudiflora, and a validated UHPLC coupled with triple quadrupole tandem mass spectrometry method was applied to quantify major components. As a result, a total of 96 chemical compounds were identified in C. nudiflora, and 26 compounds of them were further quantified in 34 batches of C. nudiflora. Based on the identified components from C. nudiflora, a compound-target network for the anti-inflammation effect was constructed by reverse docking target prediction, disease associated genes screening in DisGeNET and the protein-protein interaction from STRING. The compound-target network showed that C. nudiflora might exert anti-inflammation effect on the target of complement 3 and 5 in the pathway of cells and molecules involved in local acute inflammatory response, and 16 effective candidate compounds were found such as catalpol, acteoside, rutin, etc. This study provided an opportunity to deepen the understanding of the chemical composition and the potential anti-inflammatory mechanism of C. nudiflora.

Development of cardiotoxicity model using ligand-centric and receptor-centric descriptors

Background: Bioinformatics and statistical analysis have been employed to develop a classification model to distinguish toxic and non-toxic molecules. Aims: The primary objective of this study is to enumerate the cut-off values of various physico-chemical (ligand-centric) and target interaction (receptor-centric) descriptors which forms the basis for classifying cardiotoxic and non-toxic molecules. We also sought correlation of molecular docking, absorption, distribution, metabolism, excretion, and toxicology (ADMET) parameters, Lipinski rules, physico-chemical parameters, etc. of human cardiotoxicity drugs. Methods: A training and test set of 91 compounds were applied to linear discriminant analysis (LDA) using 2D and 3D descriptors as discriminating variables representing various molecular modeling parameters to identify which function of descriptor type is responsible for cardiotoxicity. Internal validation was performed using the leave-one-out cross-validation methodology ensuing in good results, assuring the stability of the discriminant function (DF). Results: The values of the statistical parameters Fisher Discriminant Analysis (FDA) and Wilk’s λ for the DF showed reliable statistical significance, as long as the success rate in the prediction for both the training and the test set attained more than 93% accuracy, 87.50% sensitivity and 94.74% specificity. Conclusion: The predictive model was built using a hybrid approach using organ-specific targets for docking and ADMET properties for the FDA (Food and Drug Administration) approved and withdrawn drugs. Classifiers were developed by linear discriminant analysis and the cut-off was enumerated by receiver operating characteristic curve (ROC) analysis to achieve reliable specificity and sensitivity.

Cross-docking benchmark for automated pose and ranking prediction of ligand binding.

Significant efforts have been devoted in the last decade to improving molecular docking techniques to predict both accurate binding poses and ranking affinities. Some shortcomings in the field are the limited number of standard methods for measuring docking success and the availability of widely accepted standard data sets for use as benchmarks in comparing different docking algorithms throughout the field. In order to address these issues, we have created a Cross-Docking Benchmark server. The server is a versatile cross-docking data set containing 4,399 protein-ligand complexes across 95 protein targets intended to serve as benchmark set and gold standard for state-of-the-art pose and ranking prediction in easy, medium, hard, or very hard docking targets. The benchmark along with a customizable cross-docking data set generation tool is available at http://disco.csb.pitt.edu. We further demonstrate the potential uses of the server in questions outside of basic benchmarking such as the selection of the ideal docking reference structure.

Template‐based modeling of diverse protein interactions in CAPRI rounds 38‐45

Structures of proteins complexed with other proteins, peptides, or ligands are essential for investigation of molecular mechanisms. However, the experimental structures of protein complexes of interest are often not available. Therefore, computational methods are widely used to predict these structures, and, of those methods, template-based modeling is the most successful. In the rounds 38-45 of the Critical Assessment of PRediction of Interactions (CAPRI), we applied template-based modeling for 9 of 11 protein-protein and protein-peptide interaction targets, resulting in medium and high-quality models for six targets. For the protein-oligosaccharide docking targets, we used constraints derived from template structures, and generated models of at least acceptable quality for most of the targets. Apparently, high flexibility of oligosaccharide molecules was the main cause preventing us from obtaining models of higher quality. We also participated in the CAPRI scoring challenge, the goal of which was to identify the highest quality models from a large pool of decoys. In this experiment, we tested VoroMQA, a scoring method based on interatomic contact areas. The results showed VoroMQA to be quite effective in scoring strongly binding and obligatory protein complexes, but less successful in the case of transient interactions. We extensively used manual intervention in both CAPRI modeling and scoring experiments. This oftentimes allowed us to select the correct templates from available alternatives and to limit the search space during the model scoring.

Novel membrane peptidase inhibitory peptides with activity against angiotensin converting enzyme and dipeptidyl peptidase IV identified from hen eggs

Abstract Angiotensin converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) are important membrane peptidases. The inhibition of ACE and DPP-IV enzymes has become a key therapeutic target for the treatment of hypertension and diabetes. This study was conducted to discover membrane peptidase inhibitory peptides that inhibit ACE and DPP-IV. Egg proteins were cleaved by pepsin and trypsin in silico. The potential activity, solubility, absorption, distribution, metabolism, excretion, and toxicity of the peptides were then predicted online. Finally, ACE and DPP-IV were applied as molecular docking targets for the potential peptides. After simulating gastrointestinal digestion, the IC50 values of ADF, MIR, and FGR against ACE activity were 27.75 ± 0.90 mM, 24.97 ± 0.80 mM, and 66.98 ± 1.40 μM, against DPP-IV activity were 16.83 mM, 4.86 mM, and 46.22 mM, respectively. The ACE and DPP-IV inhibitory peptides identified from hen egg proteins can be used as functional food ingredients for controlling hypertension and diabetes.

Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.

Cover Picture: Virtual Screening Based on Ensemble Docking Targeting Wild‐Type p53 for Anticancer Drug Discovery (C&B 7/2019)

Cover Picture: Virtual Screening Based on Ensemble Docking Targeting Wild‐Type p53 for Anticancer Drug Discovery (C&B 7/2019)

Role of UHRF1 in malignancy and its function as a therapeutic target for molecular docking towards the SRA domain.

The figure describes the location of UHRF1 (Ubiquitin-like with containing PHD and RING Finger domains 1) gene, mRNA and protein synthesis in the tumor cell and its structural domains with a focus on the docking of Naphthazarin on the SRA domain of UHRF1, resulting in reduction of tumor size.

Fluoxetine suppresses inflammatory reaction in microglia under OGD/R challenge via modulation of NF-κB signaling.

We aimed to investigate the anti-inflammatory role of fluoxetine, a selective serotonin reuptake inhibitor, in microglia (MG) and the mechanisms under oxygen glucose deprivation/reoxygenation (OGD/R). An OGD/R model on BV-2 cells was used for the study of microglia under ischemia/reperfusion injury in ischemic stroke. Lentiviral transfection was applied to knock down IκB-α. Enzyme-linked immunosorbent assay (ELISA) was used for detecting levels of TNF-α, IL-1β, and IL-6, and real-time PCR was used to assess the expression of IκB-α protein. Western blotting was applied to analyze NF-κB-signaling related proteins and Cell Counting Kit-8 (CCK-8) was used for assessing cell viability. Molecular docking and drug affinity responsive target stability (DARTS) assay were used for the detection of the interaction between IκB-α and fluoxetine. We found that fluoxetine decreased the levels of TNF-α, IL-1β, and IL-6 in supernatant as well as NF-κB subunits p65 and p50 in BV-2 cells under OGD/R. Fluoxetine significantly increased the level of IκB-α through the inhibition of IκB-α ubiquitylation and promoted the bonding of IκB-α and fluoxetine in BV-2 cells under OGD/R. Knocking down IκB-α attenuated the decreasing effect of TNF-α, IL-1β, and IL-6 as well as p65 and p50 in BV-2 cells under OGD/R led to by fluoxetine. In conclusion, our present study demonstrated the anti-inflammatory role of fluoxetine and its mechanisms related to the modulation of NF-κB-related signaling in MG under ischemia/reperfusion challenge.

Launch and Recovery of an Autonomous Underwater Vehicle From a Station-Keeping Unmanned Surface Vehicle

In-water tests of automated launch and recovery (L&R) of a Hydroid REMUS 100 autonomous underwater vehicle (AUV) from a station-keeping 16-ft wave adaptive modular vehicle unmanned surface vehicle (USV) have been conducted to determine the feasibility of developed concepts of operation. The USV is a catamaran with a custom-configured propulsion system that enables it to maintain position and heading on the surface. AUV launch is accomplished through lowering the AUV from the USV top tray to the water surface and releasing it. Recovery is initiated through requiring the AUV to navigate toward an acoustic homing beacon on a taut line suspended from the USV. The taut line serves as docking target and as a connecting link between the two vehicles during L&R. During these operations, the USV approximately keeps station on the water surface. Once the docking is complete, the USV moves forward, towing the AUV as it is extracted onboard the USV via a customized winch mechanism. It was found that for appropriate environmental conditions, L&R of the AUV from a station-keeping USV is an effective alternative to the mobile L&R method using the same vehicles, with the same launch and recovery system.