Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.

Early onset diagnosis in Alzheimer's disease patients via amyloid-ß oligomers-sensing probe in cerebrospinal fluid.

Amyloid-ß (Aß) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aß oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aß during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aß self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.

Benzo[d]imidazole-pyrrolo[1,2-a]pyrazine Hybrids Ameliorate Amyloid Aggregates in the Brain of Alzheimer Transgenic Mice.

Abnormal assembly of amyloid ß (Aß) in the brain is implicated in Alzheimer's disease (AD) and is associated with cognitive impairments. Since Aß accumulation occurs in advance of the onset of clinical symptoms, identifying preventable drug candidates regulating Aß accumulation is regarded as a promising approach in AD therapeutic. Herein, we synthesized eight Yonsei Institute of pharmaceutical sciences Alzheimer's Drug (YIAD) compounds based on 5-benzyl-6-phenylbenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine structures. Subsequently, YIAD-0203 and YIAD-0205 were selected as effective candidates via thioflavin T assays and gel electrophoresis. The potential therapeutic effect of YIAD-0203 and YIAD-0205 on Aß aggregates was investigated through an AD transgenic mouse model with five familial AD mutations (5XFAD) by oral gavage. Significant amounts of Aß plaque and oligomer reduction were observed in the hippocampus region of both 4.3-month-old (early stage of AD) and 6.0-month-old (mid stage of AD) YIAD-0205-treated 5XFAD mice brains when compared to the nontreated brains. The ability of YIAD-0205 to ameliorate Aß aggregates in the early and mid stages of AD progression supports the notion that YIAD-0205 could be utilized as a reliable scaffold for the development of preventive AD drug candidates.

Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques.

Amyloid-ß (Aß) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aß drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aß peptidomimetics that exploit the self-assembling nature of Aß and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aß, DAB, found to cross the BBB and solubilize Aß oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aß interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Effect of Vanadium Addition on the High-Temperature Friction Behavior in Nanostructured Al-Cr-V-N Films Prepared by UBMS.

In recent year, vanadium-doped tribological films have become available as possible candidates for self-lubrication at high temperatures. In this work, quaternary Al-Cr-V-N films were deposited onto silicon wafer and WC-Co substrates by an unbalanced magnetron sputtering using high purity (99.99%) CrAl2 and V targets with argon-nitrogen reactive gases. EPMA results revealed that vanadium atoms can incorporated from 0 to 13 at.% into the films. The maximum hardness value was ~32 GPa at vanadium content of 7.1 at.% in the Al-Cr-V-N films. The high-temperature tribometer was used to analysis the friction characteristics of the films with elevated temperature. As a result of the high temperature friction test after heating up to 700 °C, the average friction coefficient decreased from 0.62 to 0.35 with increasing of vanadium contents in the Al-Cr-V-N films. It is concluded that the reduction of the friction coefficient is attributed to the formation of V2O5, which is a Magnéli phase that acts as a lubrication at high temperature.

Multi-Functional Cr-Al-Ti-Si-N Nanocomposite Films Deposited on WC-Co Substrate for Cutting Tools.

Multi-functional quinary Cr-Al-Ti-Si-N thin films were deposited onto WC-Co substrates using a cathodic arc evaporation system. In this study, the influence of silicon contents on the microstructure, mechanical, tribological, and oxidation properties of Cr-Al-Ti-Si-N thin films were systematically investigated and correlated for application of cutting tools. Based on results from various analyses, the Cr-Al-Ti-Si-N films showed excellent properties including mechanical, tribological, oxidation and adhesion values compared with those of the Cr-Al-Ti-N film. The Cr-Al-Ti-Si-N films with a Si content of around 4.21 at.% exhibited the highest hardness of 45 GPa, very low friction coefficient of 0.38 at room temperature against an Inconel alloy ball and superior adhesion property (105 N). The Cr-Al-Ti-Si-N films also showed excellent oxidation resistance after annealing in the ambient air at 1000 °C. Therefore, the Cr-Al-Ti-Si(4.21 at.%)-N films could be help to improve the performance of machining and cutting tools with application of the films.

High Temperature Oxidation Behavior of Cr-Al-Si-N Nanocomposite Films Deposited by Filtered Arc Ion Plating Technique.

High temperature oxidation behavior of nanocomposite films is very important characteristics for application of machining and cutting tools. Quaternary Cr-Al-Si-N nanocomposite films with various compositions were deposited onto WC-Co and Si wafer substrates using a filtered arc ion plating technique. The composition of the films were controlled by different combinations of CrAl2 and Cr4Si composite target power in a reactive gas mixture of high purity Ar and N2 during depositions. The instrumental analyses revealed that the synthesized Cr-Al-Si-N films with Si content of 2.78 at.% were nanocomposites consisting of nano-sized crystallites (3-7 nm in dia.) and a thin layer of amorphous Si3N4 phases. The nanohardness of the Cr-Al-Si-N films exhibited the maximum values of ~42 GPa at a Si content of ~2.78 at.% due to the microstructural change to nanocomposite as well as solid-solution hardening. The Cr-Al-Si-N film shows superior result of oxidation resistance at 1050 °C for 30 min in air. Based on the XRD and GDOES analyses on the oxidized films, it could be revealed that the enrichment of Al (17.94 at.%) and Cr (26.24 at.%) elements in the film leads to form an Al2O3 and Cr2O3 layer on the Cr-Al-Si-N film surface. Therefore, in this study, the microstructural changes on the mechanical properties and oxidation behavior with various compositions in the Cr-Al-Si-N nanocomposite films were discussed and correlated with the deposition parameters.

Oxidation Behavior of Ti-Al-Si-N-O Nanocomposite Films Deposited by Filtered Arc Ion Plating Technique.

Oxidation behavior of nanocomposite films is very important characteristics for application of machining and cutting tools. In this study, Ti-Al-Si-N-O nanocomposite films were fabricated onto WC-Co and Si wafer substrates. The composition of the Ti-Al-Si-N-O films was analyzed by X-ray photo-electron spectroscope (XPS). Also X-ray diffactometer (XRD) analysis was conducted to investigate the crystallinity and phase transformation of the films. As a result of XRD, Ti-Al(18 at.%)-Si-N-O films showed the great oxidation resistance of 950 °C for 30 min in air. Based on glow discharge optical emission spectroscopy (GDOES) depth profiles, Ti-Al(18 at.%)- Si-N-O film annealed at 950 °C for 30 min shows formation of aluminum oxide layer on the film surface. On the other hand, Ti-Al(7.56 at.%)-Si-N-O film had a titanium oxide layer on the surface after annealing at 950 °C for 30 min.

Microstructure and Mechanical Properties of Functional Graded Ti-Al-Si-N-O Nanocomposite Films Deposited by Filtered Arc Ion Plating Technique.

Functional graded Ti-Al-Si-N-O nanocomposite films were deposited onto WC-Co substrate by a filtered arc ion plating system using TiAl and TiSi composite targets under N2/Ar atmosphere. XRD and XPS analyses revealed that the synthesized Ti-Al-Si-N-O films were nanocomposite consisting of nanosized (Ti, Al, Si)N crystallites embedded in an amorphous Si3N4/SiO2 matrix. The hardness of the Ti-Al-Si-N-O films exhibited the maximum hardness values of ~47 GPa at a Si content of ~5.63 at.% due to the microstructural change to a nanocomposite as well as the solid-solution hardening. Besides, Ti-Al-Si-N-O film with Si content of around 5.63 at.% also showed perfect adhesive strength value of 105.3 N. These excellent mechanical properties of Ti-Al-Si-N-O films could be help to improve the performance of machining tools and cutting tools with application of the film. A comparative study on microstructural characteristics among Ti-Al-Si-N-O films with various Si contents is reported in this paper.

Oxidation and Tribological Behavior of Ti-B-C-N-Si Nanocomposite Films Deposited by Pulsed Unbalanced Magnetron Sputtering.

Quinary Ti-B-C-N-Si nanocomposite films were deposited onto AISI 304 substrates using a pulsed d.c. magnetron sputtering system. The quinary Ti-B-C-N-Si (5 at.%) film showed excellent tribological and wear properties compared with those of the Ti-B-C-N films. The steady friction coefficient of 0.151 and a wear rate of 2 × 10-6 mm3N-1m-1 were measured for the Ti-B-C-N-Si films. The oxidation behavior of Ti-B-C-N-Si nanocomposite films was systematically investigated using X-ray diffraction (XRD), and thermal analyzer with differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). It is concluded that the addition of Si into the Ti-B-C-N film improved the tribological properties and oxidation resistance of the Ti-B-C-N-Si films. The improvements are due to the formation of an amorphous SiOx phase, which plays a major role in the self-lubricant tribo-layers and oxidation barrier on the film surface or in the grain boundaries, respectively.

Processing, structure, and properties of nanostructured multifunctional tribological coatings.

Nanostructured, nanocomposite binary (TiC-a:C), ternary (Cr-Al-N), quaternary (Ti-B-C-N) and quinternary (Ti-Si-B-C-N) multicomponent films have been deposited using unbalanced magnetron sputtering (UBMS) and closed field unbalanced magnetron sputtering (CFUBMS) from both elemental and composite targets. Approaches to control the film chemistry, volume fraction and size of the multicomponent species, and pulsed ion energy (ion flux) bombardment to tailor the structure and properties of the films for specific tribological applications, e.g., low friction coefficient and low wear rate, are emphasized. The synthesized films are characterized using X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), nanoindentation, and microtribometry. The relationships between processing parameters (pulsed ion energy and ion flux), thin film microstructure, mechanical and tribological properties are being investigated in terms of the nanocrystalline-nanocrystalline and nanocrystalline-amorphous composite thin film systems that are generated. In the Ti-Si-B-C-N films, nanocomposites of solid solutions, e.g., nanosized (Ti,C,N)B2 and Ti(C,N) crystallites are embedded in an amorphous TiSi2 and SiC matrix including some carbon, SiB4, BN, CN(x), TiO2 and B2O3 components. The Ti-Si-B-C-N coating with up to 150 W Si target power exhibited a hardness of about 35 GPa, a high H/E ratio of 0.095, and a low wear rate of from approximately 3 to approximately 10 x 10(-6) mm3/(Nm). In another aspect, using increased ion energy and ion flux, which are generated by pulsing the power of the target(s) in a closed field arrangement, to provide improved ion bombardment on tailoring the structure and properties of TiC-a:C and Cr-Al-N coatings are demonstrated. It was found that highly energetic species (up to hundreds eV) were found in the plasma by pulsing the power of the target(s) during magnetron sputtering. Applying higher pulse frequency and longer reverse time (lower duty cycle) will result in higher ion energy and ion flux in the plasma, which can be utilized to improve the film structure and properties. For example, optimum properties of the TiC-a:C coating were a hardness of 35 to 40 GPa and a COF of 0.2 to 0.22 for moderate maximum ion energies of 70 to 100 eV, and a super high hardness of 41 GPa and low wear rate of 3.41 x 10(-6) mm3N(-1) m(-1) was obtained for Cr-Al-N coatings deposited with a maximum ion energy of 122 eV. These conditions can be achieved by adjusting the pulsing parameters and target voltages. However, the pulsed ion energy together with the applied substrate bias are need to be carefully controlled in order to avoid excessive ion bombardment (e.g., the maximum ion energy is larger than 180 eV in the current study), which will responsible for an increase in point and line defects, and high residual stress in the crystalline structure.