anti-AD Activity Research Articles

Analyses of mRNA Profiling through RNA Sequencing on a SAMP8 Mouse Model in Response to Ginsenoside Rg1 and Rb1 Treatment

Ginsenoside Rg1 and Rb1 are the major ingredients in two medicines called QiShengLi (Z20027165) and QiShengJing (Z20027164) approved by China. These ingredients are believed to mitigate forgetfulness. Numerous studies have confirmed that GRg1 and GRb1 offer protection against Alzheimer's disease (AD), and our morris water maze (MWM) experiment also indicated that GRg1 and GRb1 may attenuate memory deficits in the 7-month-old SAMP8 mice; however, comprehensive understanding of their roles in AD remains limited. This study systematically explored the mechanism at the genome level of the anti-AD effects of GRg1 and GRb1 in a senescence-accelerated mouse prone 8 (SAMP8) model through deep RNA sequencing. A total of 74,885 mRNA transcripts were obtained. Expression analysis showed that 1,780 mRNA transcripts were differentially expressed in SAMP8 mice compared with the SAMP8+GRg1 mice. Moreover, 1,066 significantly dysregulated mRNA transcripts were identified between SAMP8 and SAMP8+GRb1 mice. Analyses according to gene ontology and the Kyoto Encyclopedia of Genes and Genomes revealed that oral administration of GRg1 and GRb1 improved the learning performance of the SAMP8 mouse model from various aspects, such as nervous system development and mitogen-activated protein kinase signaling pathway. The most probable AD-related transcriptional responses after medication were predicted and discussed in detail. This study is the first to provide a systematic dissection of mRNA profiling in SAMP8 mouse brain in response to GRg1 and GRb1 treatment. We explained their efficacy thoroughly from the source (gene-level explanation). The findings serve as a theoretical basis for the exploration of GRg1 and GRb1 as functional drugs with anti-AD activity.

Anti-Alzheimer’s disease activity of compounds from the root bark of Morus alba L.

The inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays important roles in prevention and treatment of Alzheimer's disease (AD). Among the individual parts of Morus alba L. including root bark, branches, leaves, and fruits, the root bark showed the most potent enzyme inhibitory activities. Therefore, the aim of this study was to evaluate the anti-AD activity of the M. alba root bark and its isolate compounds, including mulberrofuran G (1), albanol B (2), and kuwanon G (3) via inhibition of AChE, BChE, and BACE1. Compounds 1 and 2 showed strong AChE- and BChE-inhibitory activities; 1-3 showed significant BACE1 inhibitory activity. Based on the kinetic study with AChE and BChE, 2 and 3 showed noncompetitive-type inhibition; 1 showed mixed-type inhibition. Moreover, 1-3 showed mixed-type inhibition against BACE1. The molecular docking simulations of 1-3 demonstrated negative binding energies, indicating a high affinity to AChE and BACE1. The hydroxyl group of 1-3 formed hydrogen bond with the amino acid residues located at AChE and BACE1. Consequently, these results indicate that the root bark of M. alba and its active compounds might be promising candidates for preventive and therapeutic agents for AD.

Assessment of Anti-atopic Dermatitis Activity of Oroxylum indicum Extract Incorporated Cream

Aims: The search for plant-based treatments against atopic dermatitis (AD), a relapsing dermatological condition with high prevalence in tropical regions, has always been attracting special attention. Among many folk remedies for AD, Oroxylum indicum Linn (Bignoniaceae) is a commonly used medicinal plant whose effectiveness has not yet been scientifically reported. This study thus aimed to investigate the anti-AD activity of ethyl acetate extract from the bark of Oroxylum indicum. Methodology: Five cream formulations containing Oroxylum indicum ethyl acetate bark extract in different concentrations (0%, 1.25%, 2.5%, 3.75%, and 5%) were topically applied onto the dorsal skin of 2,4-dinitrochlorobenzene-sensitized BALB/C mice once a day during 6 weeks. Phosphate-Buffered Saline (PBS) and Protopic (Tacrolimus 0.1%) were used as negative and positive control, respectively. All mice were subjected to the assessment of AD-like symptoms including the development of eczematous skin lesions, intensity of pruritus and histological alterations. Results: The plant extract at 5% was significantly effective in suppressing the dermatitis scores by 23.26% (n=6, p<0.001) and scratching frequency by 34.86% (n=6, p<0.001) compared to the negative control while markedly reducing the signs of parakeratosis, hyperplasia, spongiosis, acanthosis, as well as the epidermal and dermal thickness in immunized mice. Conclusion: These results confirmed the inhibitory effect of Oroxylum indicum on the advance of AD at 5% when incorporated into a cream formulation and revealed the plant’s therapeutic potential in the approach to disease treatment. However, more studies on the immunosuppressive mechanism of the extract and the interplaying roles of main phytocomponents should ultimately support the utilization of this valuable medicinal plant.

The Identification of Biochanin A as a Potent and Selective β-Site App-Cleaving Enzyme 1 (Bace1) Inhibitor

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the enzyme involved in the abnormal production of the amyloidogenic peptide Aβ, one of the major causes of histological hallmarks of Alzheimer’s disease (AD). Thus, BACE1 represents a key target protein in the development of new potential target for the prevention and treatment of AD. In this study, in vitro anti-AD activity of biochanin A, a dietary isoflavone found in legumes and most notably red clover, were evaluated via human recombinant BACE1 inhibition assay, as well as enzyme kinetic and molecular docking predictions. Enzyme-based assays revealed that biochanin A exhibited a non-competitive inhibitory effect on BACE1 with an IC50 value of 28 μM and a Ki of 43 μM. In addition, docking simulation results demonstrated that ASN37, SER35, SER36, TRP76, and ARG128 residues of BACE1 interacted with biochanin A. Moreover, the binding energy of biochanin A was negative (−8.4 kcal/mol), indicating that it might potentiate a strong binding between the compound and the allosteric site of BACE1, resulting in further effective BACE1 inhibition. The present novel findings raise the possibility that biochanin A may be used as a preventative, developed into a therapeutic agent for AD, or both.

Structure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific Features in MHC Class I Recognition.

Adenoviruses (Ads) subvert MHC class I Ag presentation and impair host anti-Ad cellular activities. Specifically, the Ad-encoded E3-19K immunomodulatory protein targets MHC class I molecules for retention within the endoplasmic reticulum of infected cells. We report the x-ray crystal structure of the Ad type 4 (Ad4) E3-19K of species E bound to HLA-A2 at 2.64-Å resolution. Structural analysis shows that Ad4 E3-19K adopts a tertiary fold that is shared only with Ad2 E3-19K of species C. A comparative analysis of the Ad4 E3-19K/HLA-A2 structure with our x-ray structure of Ad2 E3-19K/HLA-A2 identifies species-specific features in HLA-A2 recognition. Our analysis also reveals common binding characteristics that explain the promiscuous, and yet high-affinity, association of E3-19K proteins with HLA-A and HLA-B molecules. We also provide structural insights into why E3-19K proteins do not associate with HLA-C molecules. Overall, our study provides new information about how E3-19K proteins selectively engage with MHC class I to abrogate Ag presentation and counteract activation of CD8(+) T cells. The significance of MHC class I Ag presentation for controlling viral infections, as well as the threats of viral infections in immunocompromised patients, underline our efforts to characterize viral immunoevasins, such as E3-19K.

Inhibitory activities of major anthraquinones and other constituents from Cassia obtusifolia against β-secretase and cholinesterases

Ethnopharmacological relevanceSemen Cassiae has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Alzheimer's disease (AD) models. Aim of the studyThe basic goal of this study was to evaluate the anti-AD activities of C. obtusifolia and its major constituents. Previously, the extract of C. obtusifolia seeds, was reported to have memory enhancing properties and anti-AD activity to ameliorate amyloid β-induced synaptic dysfunction. However, the responsible components of C. obtusifolia seeds in an AD are currently still unknown. In this study, we investigated the inhibitory effects of C. obtusifolia and its constituents against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) enzyme activity. Materials and methodsIn vitro cholinesterase enzyme assays by using AChE, BChE, and BACE1 were performed. We also scrutinized the potentials of Cassiae semen active component as BACE1 inhibitors via enzyme kinetics and molecular docking simulation. ResultsIn vitro enzyme assays demonstrated that C. obtusifolia and its major constituents have promising inhibitory potential against AChE, BChE, and BACE1. All Cassiae semen constituents exhibited potent inhibitory activities against AChE and BACE1 with IC50 values of 6.29–109µg/mL and 0.94–190µg/mL, whereas alaternin, questin, and toralactone gentiobioside exhibited significant inhibitory activities against BChE with IC50 values of 113.10–137.74µg/mL. Kinetic study revealed that alaternin noncompetitively inhibited, whereas cassiaside and emodin showed mixed-type inhibition against BACE1. Furthermore, molecular docking simulation results demonstrated that hydroxyl group of alaternin and emodin tightly interacted with the active site residues of BACE1 and their relevant binding energies (−6.62 and −6.89kcal/mol), indicating a higher affinity and tighter binding capacity of these compounds for the active site of BACE1. ConclusionThe findings of the present study suggest the potential of C. obtusifolia and its major constituents for use in the development of therapeutic or preventive agents for AD, especially through inhibition of AChE, BChE and BACE1 activities.

Cranberry extract supplementation exerts preventive effects through alleviating Aβ toxicity in Caenorhabditis elegans model of Alzheimer's disease

Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Aβ toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Aβ toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals.

Lycibarbarspermidines A-O, New Dicaffeoylspermidine Derivatives from Wolfberry, with Activities against Alzheimer's Disease and Oxidation.

Fifteen new dicaffeoylspermidine derivatives, lycibarbarspermidines A-O (1-15), were isolated from the fruit of Lycium barbarum (wolfberry). The structures were unambiguously determined by spectroscopic analyses and chemical methods. Dicaffeoylspermidine derivatives, a rare kind of plant secondary metabolites, are primarily distributed in the family of Solanaceae. Only six compounds were structurally identified, and all of them are acyclic aglycones. Compounds 1-15 are the first glycosidic products of dicaffeoylspermidine derivatives, and compounds 14-15 are the first cyclization products of dicaffeoylspermidine derivatives. Moreover, dicaffeoylspermidine derivatives were first isolated and identified from wolfberry. The short-term memory assay on a transgenic fly Alzheimer's disease (AD) model showed that 1-15 exhibited different levels of anti-AD activity. The oxygen radical absorbance capacity assay revealed that 1-15 all displayed antioxidant capacity. Both anti-AD and antioxidant functions are related to the effects of wolfberry. Therefore, dicaffeoylspermidine derivatives are considered beneficial constituents responsible for the antiaging, neuroprotective, anti-AD, and antioxidant effects of wolfberry.

Kinetics and molecular docking studies of fucosterol and fucoxanthin, BACE1 inhibitors from brown algae Undaria pinnatifida and Ecklonia stolonifera

Since the action of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is strongly correlated with the onset of Alzheimer's disease (AD), the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. In our ongoing research aimed at identifying anti-AD remedies derived from maritime plants, we evaluated the BACE1 inhibitory activities of fucosterol and fucoxanthin from Ecklonia stolonifera and Undaria pinnatifida. In vitro anti-AD activities were performed via BACE1 inhibition assays, as well as enzyme kinetic and molecular docking predictions. Based on enzyme-based assays, fucosterol and fucoxanthin showed noncompetitive and mixed-type inhibition, respectively, against BACE1. In addition, docking simulation results demonstrated that the Lys224 residue of BACE1 interacted with one hydroxyl group of fucosterol, while two additional BACE1 residues (Gly11 and Ala127) interacted with two hydroxyl groups of fucoxanthin. Moreover, the binding energy of fucosterol and fucoxanthin was negative (−10.1 and −7.0 kcal/mol), indicating that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of BACE1, resulting in more effective BACE1 inhibition. The results suggest that fucosterol and fucoxanthin may be used beneficially in the treatment of AD and provide potential guidelines for the design of new BACE1 inhibitors.

Anti-Alzheimer's disease potential of coumarins from Angelica decursiva and Artemisia capillaris and structure-activity analysis.

To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin). Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58,-6.25 and-6.37kcal/mol respectively). Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.

Combined experimental and simulation studies suggest a revised mode of action of the anti-Alzheimer disease drug NQ-Trp.

Inhibition of the aggregation of the monomeric peptide β-amyloid (Aβ) into oligomers is a widely studied therapeutic approach in Alzheimer's disease (AD). Many small molecules have been reported to work in this way, including 1,4-naphthoquinon-2-yl-L-tryptophan (NQ-Trp). NQ-Trp has been reported to inhibit aggregation, to rescue cells from Aβ toxicity, and showed complete phenotypic recovery in an in vivo AD model. In this work we investigated its molecular mechanism by using a combined approach of experimental and theoretical studies, and obtained converging results. NQ-Trp is a relatively weak inhibitor and the fluorescence data obtained by employing the fluorophore widely used to monitor aggregation into fibrils can be misinterpreted due to the inner filter effect. Simulations and NMR experiments showed that NQ-Trp has no specific "binding site"-type interaction with mono- and dimeric Aβ, which could explain its low inhibitory efficiency. This suggests that the reported anti-AD activity of NQ-Trp-type molecules in in vivo models has to involve another mechanism. This study has revealed the potential pitfalls in the development of aggregation inhibitors for amyloidogenic peptides, which are of general interest for all the molecules studied in the context of inhibiting the formation of toxic aggregates.

Role of nanomedicines in delivery of anti-acetylcholinesterase compounds to the brain in Alzheimer's disease.

Alzheimer's disease (AD) is a multifarious progressive neuro-degenerative state among elders. Potentiation of central cholinergic activity by using acetylcholinesterase inhibitors (AChEI) is considered as one of the major pharmacological means for the management of AD. Investigation in the past and the rest decades revealed that many drugs with anti-AD activity, including the AChEI have been discovered from natural and synthetic origin but getting success in their brain delivery is still limited. However, barriers like blood-brain barrier, blood-cerebrospinal fluid barrier and p-glycoproteins restrict the effective and safe drug delivery to the brain in patients with AD. Advancement in nanotechnology-based drug delivery systems over the last decade exemplifies the effective drug delivery and targeting to the brain with controlled rate in various diseases including AD. Till recently, diverse kinds of nanomedicines for targeting of the anti-AD drugs in brain are being studied. In this review, we have highlighted the recent progress in AChEI, challenges in their effective brain delivery (physicochemical properties and biological barriers) and possible nanotechnology-based strategies that can deliver drugs across the CNS barriers during AD.

BACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryos

The aim of the present study was to evaluate the comparative anti-Alzheimer's disease (AD) activities of different parts of Nelumbo nucifera (leaves, de-embryo seeds, embryos, rhizomes, and stamens) in order to determine the selectivity and efficient use of its individual components. Anti-AD activities of different parts of N. nucifera were evaluated via inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) along with scavenging activity on peroxynitrite (ONOO(-)). Among the evaluated parts of N. nucifera, the embryo extract exhibited significant inhibitory potential against BACE1 and BChE as well as scavenging activity against ONOO(-). Thus, the embryo extract was selected for detailed investigation on anti-AD activity using BACE1- and ChEs-inhibitory assays. Among the different solvent-soluble fractions, the dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol (n-BuOH) fractions showed promising ChEs and BACE1 inhibitory activities. Repeated column chromatography of the CH2Cl2, EtOAc and n-BuOH fractions yielded compounds 1-5, which were neferine (1), liensinine (2), vitexin (3), quercetin 3-O-glucoside (4) and northalifoline (5). Compound 2 exhibited potent inhibitory activities on BACE1, AChE, and BChE with respective IC50 values of 6.37 ± 0.13, 0.34 ± 0.02, and 9.96 ± 0.47 µM. Likewise, compound 1 showed potent inhibitory activities on BACE1, AChE, and BChE with IC50 values of 28.51 ± 4.04, 14.19 ± 1.46, and 37.18 ± 0.59 µM, respectively; the IC50 values of 3 were 19.25 ± 3.03, 16.62 ± 1.43, and 11.53 ± 2.21 µM, respectively. In conclusion, we identified potent ChEs- and BACE1-inhibitory activities of N. nucifera as well as its isolated constituents, which may be further explored to develop therapeutic and preventive agents for AD and oxidative stress related diseases.

Evaluation of anti-atopic dermatitis activity of Hypsizigus marmoreus extract.

Hypsizigus marmoreus is an edible mushroom that is cultivated worldwide. In this study, we investigated antiinflammatory activities of H. marmoreus extract on atopic dermatitis (AD)-like symptoms. Ethanol extract of H. marmoreus (HMEE) was administrated in powder to BALB/c mice in which AD was induced by 1-chloro 2, 4, 6-trinitrobenzene [picryl-chloride, (PCL)]. The dermatitis severity score and the thickness of the epidermis were significantly decreased following daily intake of HMEE powder (1 g/kg/day) for 5 weeks compared with a PCL-treated group. The mRNA expression of proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and interferon-gamma (IFN-γ), was significantly attenuated in the dorsal skin of the HMEE-fed mouse group compared with the PCL-treated mouse group. In addition, in concanavalin A-stimulated and lipopolysaccharide-stimulated mouse splenocytes and macrophages, levels of IL-1β and IFN-γ production were attenuated following the addition of HMEE. Interestingly, the administration of HMEE to mouse splenocytes stimulated the production of an antiinflammatory cytokine, IL-4. However, increases in the levels of proinflammatory cytokines and nitric oxide were attenuated by treating the mouse splenocytes, mouse macrophages, and Raw 264.7 cell line with HMEE. These results strongly suggest that HMEE exhibits anti-AD activity via the regulation of inflammatory responses.

The effects of C-glycosylation of luteolin on its antioxidant, anti-Alzheimer's disease, anti-diabetic, and anti-inflammatory activities.

To investigate the effect of C-glycosylation at different positions of luteolin, the structure-activity relationships of luteolin and a pair of isomeric C-glycosylated derivatives orientin and isoorientin, were evaluated. We investigated the effects of C-glycosylation on the antioxidant, anti-Alzheimer's disease (AD), anti-diabetic and anti-inflammatory effects of luteolin and its two C-glycosides via in vitro assays of peroxynitrite (ONOO(-)), total reactive oxygen species (ROS), nitric oxide (NO), 1,1-diphenyl-2-picrylhydraxyl (DPPH), aldose reductase, protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor cleaving enzyme 1 (BACE1), and cellular assays of NO production and inducible nitric oxide synthase (iNOS)/cyclooxygenase-2 expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Of the three compounds, isoorientin showed the highest scavenging activity against DPPH, NO, and ONOO(-), while luteolin was the most potent inhibitor of ROS generation. In addition, luteolin showed the most potent anti-AD activity as determined by its inhibition of AChE, BChE, and BACE1. With respect to anti-diabetic effects, luteolin exerted the strongest inhibitory activity against PTP1B and rat lens aldose reductase. Luteolin also inhibited NO production and iNOS protein expression in LPS-stimulated macrophages, while orientin and isoorientin were inactive at the same concentrations. The effects of C-glycosylation at different positions of luteolin may be closely linked to the intensity and modulation of antioxidant, anti-AD, anti-diabetic, and anti-inflammatory effects of luteolin and its C-glycosylated derivatives.

Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues

The aggregation of the 42-residue amyloid β-protein (Aβ42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aβ42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Aβ42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the Aβ42-taxifolin adduct was suggested by mass spectrometry, Aβ42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of Aβ42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Aβ42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-Aβ42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Aβ42 as well as Aβ42. Furthermore, interaction of (+)-taxifolin with the β-sheet region in Aβ42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Aβ42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of Aβ42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.

Crystal structure of adenovirus E3-19K protein bound to HLA-A2 reveals mechanism for immunomodulation

Event Abstract Back to Event Crystal structure of adenovirus E3-19K protein bound to HLA-A2 reveals mechanism for immunomodulation Lenong Li1, Marlene Bouvier1* and Yasameen Muzahim1 1 University of Illinois at Chicago, College of Medicine, Microbiology and Immunology, United States The cell-surface presentation of viral antigens by MHC class I molecules is critical for eliminating host infected cells. In turn, viruses have evolved various strategies to interfere with antigen processing and presentation. The adenovirus (Ad) E3-19K protein binds to and retains MHC class I molecules in the endoplasmic reticulum (ER), thereby suppressing anti-Ad activities of CD8+ T-cells. E3-19K is a type I transmembrane glycoprotein that comprises a N-terminus ER-lumenal domain, a transmembrane domain, and a C-terminus cytosolic tail. The ER-lumenal domain of E3-19K associates with the ER-lumenal domain of MHC I, while the dilysine motif in the cytosolic tail of E3-19K provides the signal for localization of the E3-19K/MHC I complex in the ER. We will describe a novel rescue refolding strategy that allowed formation of the Ad serotype 2 (Ad2) E3-19K/HLA-A2 complex, from which we recently grew crystals diffracting to 1.95 Å resolution. Ad2 E3-19K binds to the N-terminus of the HLA-A2 groove, contacting the α1-, α2-, and α3-domains and β2m. Ad2 E3-19K has a unique structure comprised of a large N-terminal domain, formed by two partially overlapping β-sheets arranged in a V-shape, a C-terminal α-helix and tail. The structure reveals determinants in E3-19K and HLA-A2 that are important for complex formation; conservation of some of these determinants in E3-19K of different Ad species and MHC I of different HLA loci suggests a universal binding mode for all E3-19K proteins. Our structure offers explanations for the mechanism by which E3-19K modulates antiviral cellular immunity. Acknowledgements Supported by NIH grants R01 AI045070-12 and R56 AI102468-01. References Li, L., Muzahim, Y., and Bouvier, M. (2012) Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation. Nat. Struc. Molec. Biol. 19: 1176-1181. Keywords: MHC I, Antigen Presentation, adenovirus, viral immune evasion mechanisms, structural immunology Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Host-pathogen interactions Citation: Li L, Bouvier M and Muzahim Y (2013). Crystal structure of adenovirus E3-19K protein bound to HLA-A2 reveals mechanism for immunomodulation. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00955 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Marlene Bouvier, University of Illinois at Chicago, College of Medicine, Microbiology and Immunology, Chicago, Illinois, 60612, United States, mbouvier@uic.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lenong Li Marlene Bouvier Yasameen Muzahim Google Lenong Li Marlene Bouvier Yasameen Muzahim Google Scholar Lenong Li Marlene Bouvier Yasameen Muzahim PubMed Lenong Li Marlene Bouvier Yasameen Muzahim Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A rapid and sensitive detection of ferritin at a nanomolar level and disruption of amyloid β fibrils using fluorescent conjugated polymer

Enhanced levels of toxic metals, especially iron, from the labile iron pool in the brain are primarily responsible for the pathogenesis of several neurological disorders, such as Alzheimer's disease (AD). These metals are a major source for generating highly toxic reactive oxygen species (ROS), accelerating amyloid β (Aβ) peptide aggregation in the brains of AD patients. Aβ has high affinity for iron, resulting in its accumulation and localization in brain plaques enhancing neurotoxic H2O2, oxidative stress and free radical formation. Hence, controlling neurotoxicity would also involve regulation of the redox-active metals present, along with the Aβ. Non toxic conjugated polymer (CP) poly(1,4-bis-(8-(8-hydroxyquinoline)-octyloxy)-benzene) (PHQ) binds iron containing heme and non-heme proteins, such as ferritin, at nanomolar levels with the highest known selectivity (a Stern–Volmer constant (Ksv) value of 0.84 × 107 M−1) in cerebrospinal fluid (CSF) and has been utilized to interact with the bound iron, including non-heme ferritin, in the Aβ protofibril aggregates and diminish their accumulation. The anti-AD activity of PHQ was confirmed via in vitro control studies by doping CSF of healthy individuals (H-CSF) with Aβ(1–40) with and without iron using a Thioflavin-T (ThT) binding assay test and electron microscopy analysis. This conceptually new strategy to clear the cerebral deposits using a CP allows the toxic aggregated Aβ peptide fibrils present in the CSF to be successfully disrupted under physiological conditions.

A novel organogermanium protected atopic dermatitis induced by oxazolone

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that is often associated with other atopic diseases, such as asthma and allergic rhinitis. Although topical steroids have widely been prescribed for patients with AD, skin abnormalities are frequently observed after prolonged steroid treatment. In this study, a novel water-soluble organogermanium compound (Ge-Vit) was prepared because organogermanium is a known INF-γ inducer. The Ge-Vit treatment decreased the basal TEWL and IgE production and attenuated the disruption of the skin barrier function in a murine model of chronic contact dermatitis. The histological examination further supported the anti-AD activities. These results suggested that Ge-Vit can be a useful drug candidate for treating atopic dermatitis.

Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer’s disease rescue factor Humanin

Humanin (HN) inhibits Alzheimer’s disease (AD)-relevant neuronal death and dysfunction, by interacting with a receptor (s) involving ciliary neurotrophic factor receptor α (CNTFR), WSX-1, and gp130. It remains unknown whether this complex is the sole HN receptor that mediates HN-induced anti-AD activity. We here report that an alternatively spliced WSX-1 isoform, encoding an extracellular 270-amino-acid region of WSX-1 with cytokine-binding regions (named soluble WSX-1; sWSX-1), is expressed in neuronal cells lacking function of full-length WSX-1 and enables HN to rescue AD-relevant death. This result suggests that CNTFR/soluble WSX-1/gp130 behaves as an alternative functional HN receptor.