Inhibitory Effects of Shikonin Dispersion, an Extract of Encapsulated in β-1,3-1,6 Glucan, on and Non-Mutans Streptococci.

Shikonin is extracted from the roots of , and shikonin extracts have been shown to have inhibitory effects on several bacteria. However, shikonin extracts are difficult to formulate because of their poor water solubility. In the present study, we prepared a shikonin dispersion, which was solubilized by the inclusion of β-1,3-1,6 glucan, and analysed the inhibitory effects of this dispersion on and non-mutans streptococci.

Inhibitory Effect of Adsorption of onto Scallop-Derived Hydroxyapatite.

Hydroxyapatite adsorbs various substances, but little is known about the effects on oral bacteria of adsorption onto hydroxyapatite derived from scallop shells. In the present study, we analyzed the effects of adsorption of onto scallop-derived hydroxyapatite. When scallop-derived hydroxyapatite was mixed with , a high proportion of the bacterial cells adsorbed onto the hydroxyapatite in a time-dependent manner.

In Vitro and In Vivo Antiglycation Effects of Connarus ruber Extract.

Accumulation of advanced glycation end products (AGEs) of the Maillard reaction has been implicated in the pathogenesis of diabetes and its complications. has been used as a folk remedy for several diseases, including diabetes; however, its underlying mechanism has not yet been investigated. This study investigated the effects of extract against glycation on collagen-linked AGEs and streptozotocin-induced diabetic rats (STZ-DM rats) .

Structural study of the recognition mechanism of tau antibody Tau2r3 with the key sequence (VQIINK) in tau aggregation.

One of the histopathological features of Alzheimer's disease (AD) is higher order neurofibrillary tangles formed by abnormally aggregated tau protein. The sequence VQIINK in the microtubule-binding domain of tau plays a key role in tau aggregation. Therefore, an aggregation inhibitor targeting the VQIINK region in tau may be an effective therapeutic agent for AD.

Transgenic rats expressing dominant negative BMAL1 showed circadian clock amplitude reduction and rapid recovery from jet lag.

The circadian rhythms are endogenous rhythms of about 24 h, and are driven by the circadian clock. The clock centre locates in the suprachiasmatic nucleus. Light signals from the retina shift the circadian rhythm in the suprachiasmatic nucleus, but there is a robust part of the suprachiasmatic nucleus that causes jet lag after an abrupt shift of the environmental lighting condition.

Crystal structure of the human tau PHF core domain VQIINK complexed with the Fab domain of monoclonal antibody Tau2r3.

Neurofibrillary tangles formed by abnormally aggregated tau protein are a histopathological feature of tauopathies. A tau aggregation inhibitor is a potential therapeutic agent for tauopathies. In this study, we prepared a monoclonal antibody for tau, monoclonal antibody to tau protein (Tau2r3), using as epitope the GGKVQIINKKLD peptide in the microtubule-binding domain of tau, the key region mediating tau aggregation.

Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity.

Four cyclic octapeptides were designed from ascidiacyclamide [cyclo(-Ile-Oxz-D-Val- Thz-) ] (ASC, 1) to investigate the effects of oxazoline (Oxz) and thiazole (Thz) rings on the structures and cytotoxicities of the peptides. cyclo(-Ile-Thz-D-Val-Oxz-) (2) had the same number of Oxz and Thz rings as ASC, but the ring positions were switched. cyclo(-Ile-Oxz-D-Val-Thz-Ile-Thz-D-Val-Thz-) (3) and cyclo(-Ile-Thz-D-Val-Oxz-Ile-Thz-D-Val-Thz-) (4) contained one Oxz and three Thz rings within the molecule.

Bortezomib Causes ER Stress-related Death of Acute Promyelocytic Leukemia Cells Through Excessive Accumulation of PML-RARA.

Background/aim: The success of proteasome inhibitors in therapy of multiple myeloma has led to their use for other malignancies. For the proteasome inhibitor bortezomib, combination therapies with histone deacetylase inhibitors, which up-regulate ubiquitin-proteasome system (UPS)-related enzymes, produce a beneficial effect. However, the mechanisms underlying the effect of bortezomib are not completely understood.

Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice.

Objective: Cellular inclusions of hyperphosphorylated tau are a hallmark of tauopathies, which are neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive immunization against hyperphosphorylated tau has been shown to attenuate phenotypes in model mice. We developed new monoclonal antibodies to hyperphosphorylated tau and sought high therapeutic efficacy for future clinical use.

Evaluation of radical scavenging properties of shikonin.

With the aim of developing effective anti-inflammatory drugs, we have been investigating the biochemical effects of shikonin of "Shikon" roots, which is a naphthoquinone with anti-inflammatory and antioxidative properties. Shikonin scavenged reactive oxygen species like hydroxyl radical, superoxide anion (O2 (•-)) and singlet oxygen in previous studies, but its reactivity with reactive oxygen species is not completely understood, and comparison with standard antioxidants is lacking. This study aimed elucidation of the reactivity of shikonin with nitric oxide radical and reactive oxygen species such as alkyl-oxy radical and O2 (•-).

CH-π interaction in VQIVYK sequence elucidated by NMR spectroscopy is essential for PHF formation of tau.

One of the histopathological features of Alzheimer's disease (AD) is higher order neurofibrillary tangles formed by abnormally aggregated tau protein. Investigation of the mechanism of tau aggregation is important for the clarifying the cause of AD and the development of therapeutic drugs. The microtubule-binding domain, which consists of repeats of similar amino acids (R1-R4) is thought to form the core component of paired helical filament (PHF).

Global analysis of phosphorylation of tau by the checkpoint kinases Chk1 and Chk2 in vitro.

Hyperphosphorylation of microtubule-associated protein tau is thought to contribute to Alzheimer's disease (AD) pathogenesis. We previously showed that DNA damage-activated cell cycle checkpoint kinases Chk1 and Chk2 phosphorylate tau at an AD-related site and enhance tau toxicity, suggesting potential roles of these kinases in AD. The purpose of this study is to systematically identify which sites in tau are directly phosphorylated by Chk1 and Chk2.

C-H ... π interplay between Ile308 and Tyr310 residues in the third repeat of microtubule binding domain is indispensable for self-assembly of three- and four-repeat tau.

Information on the structural scaffold for tau aggregation is important in developing a method of preventing Alzheimer's disease (AD). Tau contains a microtubule binding domain (MBD) consisting of three or four repeats of 31 and 32 similar residues in its C-terminal half. Although the key event in tau aggregation has been considered to be the formation of β-sheet structures from a short hexapeptide (306)VQIVYK(311) in the third repeat of MBD, its aggregation pathway to filament formation differs between the three- and four-repeated MBDs, owing to the intermolecular and intramolecular disulphide bond formations, respectively.

Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice.

Hepatocyte growth factor (HGF) and its receptor, c-Met, play pivotal roles in the nervous system during development and in disease states. However, the physiological roles of HGF in the adult brain are not well understood. In the present study, to assess its role in learning and memory function, we used transgenic mice that overexpress HGF in a neuron-specific manner (HGF-Tg) to deliver HGF into the brain without injury.

Phosphoproteome profiling using a fluorescent phosphosensor dye in two-dimensional polyacrylamide gel electrophoresis.

We validated the novel PhosphoQUANTI SolidBlue Complex (PQSC) dye for the sensitive fluorescent detection of phosphorylated proteins in polyacrylamide- and two-dimensional gel electrophoresis (PAGE and 2DE, respectively). PQSC can detect as little as 15.6 ng of ß-casein, a pentaphosphorylated protein, and 61.

Synaptotagmin1 synthesis induced by synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptors.

We have reported that systemic application of nicotinic agonists expresses a long-term potentiation (LTP)-like facilitation, a model of synaptic plasticity, in vivo in the mouse hippocampus. The present study conducted to clarify the involvement of synaptotagmin1 in synaptic plasticity by investigating the time-dependent change of the mRNA and protein levels of synaptotagmin1 during LTP-like facilitation in the mouse hippocampus. The mRNA expression of synaptotagmin1 increased during 2- to 8-h period by intraperitoneal application of nicotine (3mg/kg), returning to the basal level in 12-h.

Interplay between I308 and Y310 residues in the third repeat of microtubule-binding domain is essential for tau filament formation.

Investigation of the mechanism of tau polymerization is indispensable for finding inhibitory conditions or identifying compounds preventing the formation of paired helical filament or oligomers. Tau contains a microtubule-binding domain consisting of three or four repeats in its C-terminal half. It has been considered that the key event in tau polymerization is the formation of a β-sheet structure arising from a short hexapeptide (306)VQIVYK(311) in the third repeat of tau.

SJLB mice develop tauopathy-induced parkinsonism.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an inherited dementia caused by tauopathy. Recently, we established the N279K mutant human tau transgenic mice SJLB. Although SJLB mice show cognitive dysfunction with insoluble tau in the brain, it has remained unclear whether they show signs of parkinsonism.

Use of a phosphosensor dye in proteomic analysis of human mutant tau transgenic mice.

Recently, we have generated transgenic mice (designated as SJLB) carrying human N279K mutant tau, one of the tau mutations causing parkinsonism linked to chromosome 17 (FTDP-17). SJLB mice mimic some features of behavioral alterations and neuronal pathology of patients with Alzheimer's disease. To investigate how tau dysfunctions cause these features, we examined the expression and phosphorylation levels in SJLB mouse hippocampal proteins using a phosphosensor dye in two-dimensional poly acrylamide gel electrophoresis analysis and mass spectrometry.

Importance of Tyr310 residue in the third repeat of microtubule binding domain for filament formation of tau protein.

The inhibition of tau fibrillation is a potential therapeutic target for Alzheimer's and other neurodegenerative diseases. As a series of studies on inhibiting the transition of soluble monomeric tau into mature fibril, the effect of Tyr310 residue in the third repeat (R3) of the microtubule-binding domain (MBD) on the assembly of MBD was investigated using Tyr-substituted MBD mutants by fluorescence, circular dichroism spectroscopy and electron microscopy. Consequently, the importance of the Tyr residue located at position 310, not at other positions, was clearly shown.

Three-/four-repeat-dependent aggregation profile of tau microtubule-binding domain clarified by dynamic light scattering analysis.

The analysis of the self-assembly mechanism of the tau microtubule-binding domain (MBD) could provide the information needed to develop an effective method for the inhibition of the tau filament formation because of its core region that forms the filament. The MBD domain in the living body consists of similar three or four 31- to 32-residue repeats, namely 3RMBD (R134) and 4RMBD (R1234), respectively. The filament formation of the MBD has been mainly investigated by fluorescence spectroscopy utilizing the beta-sheet structure-binding signal sensor thioflavin.

Long-term potentiation-like facilitation through GABAA receptor blockade in the mouse dentate gyrus in vivo.

We have investigated the characteristics of a long-term potentiation (LTP)-like facilitation in vivo through GABAA receptor blockade in C57BL/6 and Alzheimer-model transgenic mice dentate gyrus. Bicuculline induced the 'LTP-like' facilitation in a dose-dependent manner. MK-801 inhibited the induction but not maintenance of 'LTP-like' facilitation through bicuculline.

Different inhibitory response of cyanidin and methylene blue for filament formation of tau microtubule-binding domain.

One of the priorities in Alzheimer research is to develop a compound that inhibits the filament formation of tau protein. Since the three- or four-repeat microtubule-binding domain (MBD) in tau protein plays an essential role in filament formation, the inhibitory behavior of cyanidin (Cy) and methylene blue (MB) with respect to heparin-induced filament formation of MBD in a neutral solution (pH 7.6) was characterized by fluorescence, circular dichroism, and electron microscopy measurements.

Linkage-dependent contribution of repeat peptides to self-aggregation of three- or four-repeat microtubule-binding domains in tau protein.

Although one of the priorities in Alzheimer's research is to clarify the filament formation mechanism for the tau protein, it is still unclear how it is transformed from a normal structure in a neuron. To examine the linkage-dependent contribution of each repeat peptide (R1-R4) to filament formation of the three- or four-repeat microtubule-binding domain (MBD) in the tau protein, four two-repeat peptides (R12, R13, R23 and R34) and two three-repeat peptides (R123 and R234) were prepared, and their in vitro self-aggregation was investigated by thioflavin S fluorescence and circular dichroism measurements, and by electron microscopy in neutral buffer (pH 7.6).