Biomedical subjects

Ayumu Yoshikawa

Publications and source records attributed to Ayumu Yoshikawa.

7 recordsLinked to original sources

PubMed2006

Hesr1 knockout mice exhibit behavioral alterations through the dopaminergic nervous system.

The basic helix-loop-helix (bHLH) transcriptional factor Hesr1 gene (hairy and enhancer of split-related 1, also called Hey1/HRT1/CHF2/HERP2) has been identified and characterized as a member of the subfamily of hairy/Enhancer of split, and shown to be involved in cardiovascular and neural development. We report that HESR1 binds directly to a part of the 3' non-coding region of the human dopamine transporter (DAT1) gene and represses the endogenous DAT1 gene in HEK293 cells. To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis. Several dopamine-related genes, such as DAT, dopamine receptors D1, D2, D4, and D5, were significantly upregulated. Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests. These results indicate that the HESR1 gene is related to neuropsychiatric disorders and behavioral traits through the dopaminergic nervous system.

Analysis of Variance↗

PubMed2006

Berberine alters the processing of Alzheimer's amyloid precursor protein to decrease Abeta secretion.

Berberine is an isoquinoline alkaloid isolated from Coptidis rhizoma, a major herb widely used in Chinese herbal medicine. Berberine's biological activity includes antidiarrheal, antimicrobial, and anti-inflammatory effects. Recent findings show that berberine prevents neuronal damage due to ischemia or oxidative stress and that it might act as a novel cholesterol-lowering compound. The accumulation of amyloid-beta peptide (Abeta) derived from amyloid precursor protein (APP) is a triggering event leading to the pathological cascade of Alzheimer's disease (AD); therefore the inhibition of Abeta production should be a rational therapeutic strategy in the prevention and treatment of AD. Here, we report that berberine reduces Abeta levels by modulating APP processing in human neuroglioma H4 cells stably expressing Swedish-type of APP at the range of berberine concentration without cellular toxicity. Our results indicate that berberine would be a promising candidate for the treatment of AD.

Amyloid beta-Peptides↗

PubMed2006

Lignan compounds and 4,4'-dihydroxybiphenyl protect C2C12 cells against damage from oxidative stress.

Lignan compounds are known to have various biological activities, especially antioxidative effects. We investigated whether lignan compounds show antioxidative activity in myoblast C2C12 cells. Among 14 lignan compounds investigated, two lignans containing two phenolic functional groups, namely Gomisin J and GR-12, prevented hydrogen peroxide (H(2)O(2))-induced cell death. A simple compound, 4,4'-dihydroxybiphenyl, which was found to be a common component of Gomisin J and GR-12, also largely prevented H(2)O(2)-induced cell death and almost completely prevented H(2)O(2)-induced increases in p38 MAPK phosphorylation. Our present results provide a useful in vitro system for clarifying the molecular mechanisms of lignan-mediated antioxidative effects and evaluating lead molecules toward the development of therapeutic drugs.

Animals↗

PubMed2005

Arginine residue 155 in the second intracellular loop plays a critical role in rat melanin-concentrating hormone receptor 1 activation.

Melanin-concentrating hormone (MCH) receptor 1 (MCH1R) is a class A G protein-coupled receptor. The MCH system has been linked to a variety of physiological functions, including the regulation of feeding and energy metabolism. We recently reported the importance of a dibasic motif in the membrane-proximal C-terminal region for MCH1R function. Here we reveal that an Arg residue in intracellular loop 2 of MCH1R plays a critical role in receptor function. We analyzed the roles of two distinct motifs, BBXXB and BXBB (in which B is a basic residue and X is a nonbasic residue), located in the three intracellular loops of MCH1R. Triple-substitution mutants of intracellular loops 1 and 3 could still activate calcium mobilization, albeit with lower efficacy or potency. However, mutations in intracellular loop 2 led to a complete loss of induction of signal transduction without changing the high affinity constant (Kd) value. By analyzing a series of single-substitution mutants, a point mutation of Arg155 in intracellular loop 2 was found to be responsible for the signaling pathway elicited by MCH. In addition, substitution at positions corresponding to Arg155 in human MCH receptor 2 and rat somatostatin receptor 2 also markedly abolished their ligand-induced signaling capacities, indicating that this Arg is a recognition determinant in several G protein-coupled receptors.

Amino Acid Sequence↗

PubMed2005

Denervation enhances the expression of SHPS-1 in rat skeletal muscle.

SHPS-1 (Src homology 2 domain containing protein tyrosine phosphatase substrate 1) is a transmembrane glycoprotein containing three immunoglobulin-like motifs in its extracellular domain and immunoreceptor tyrosine-based inhibitory motifs (ITIM) that interact with SHP-2 (Src homology 2 domain containing protein tyrosine phosphatase-2) in its cytoplasmic region. SHPS-1 is highly expressed in brain, but at much lower levels in skeletal muscle. In this study, we found that the level of the SHPS-1 mRNA increases in rat skeletal muscle after denervation. Western blot analysis also confirmed the increase of SHPS-1 in denervated muscle. Moreover, it was found that the glycosylation of SHPS-1 is N-linked in a muscle-specific manner, and that this is altered upon innervation or denervation. Immunohistochemistry revealed SHPS-1 immunoreactivity at neuromuscular junctions (NMJs) under innervation, whereas immunoreactivity was observed extrasynaptically in muscle fibers after denervation. Our results indicate that the expression, glycosylation, and localization of SHPS-1 are strongly regulated by the nervous system, and that SHPS-1 may play an important role in denervated skeletal muscle.

Animals↗

PubMed2003

Expression of ARPP-16/19 in rat denervated skeletal muscle.

It is known that denervation of rat skeletal muscle causes atrophy and this is often adopted as a model for human muscle atrophy. To understand the molecular changes that occur, it is important to identify the profiles of differential gene expression. In the present study, we investigated differentially expressed genes in denervated muscle using DNA microarrays with printed genes preferentially expressed in skeletal muscle. We found that several genes are differentially expressed. Of these genes, ARPP-16/19 (cAMP-regulated phosphoprotein 16/19) is selectively enhanced after denervation. The expression of ARPP-16/19 in denervated muscles starts to increase from two days after denervation surgery. On the other hand, the expression of ARPP-16/19 does not change in hind-limb suspended muscles, such as EDL and soleus muscles. These results suggest that the increase in ARPP-16/19 mRNA expression is regulated by unknown factor(s) secreted from nerves, and not by electrical muscle activity.

Animals↗

PubMed2002

The first molecular evidence that autophagy relates rimmed vacuole formation in chloroquine myopathy.

Chloroquine myopathy is a drug poisoning disease involving rimmed vacuole formation. By Western blot analysis, we investigated posttranslational modification of LC3 in cultured cells with a high concentration of chloroquine, and found that the autophagosome membrane-bound form of LC3 increased dose-dependently. We also constructed a disease model by excessive chloroquine injection into rats and unusual immunohistochemical alteration was chased using anti-LC3 antibodies. With chloroquine treatment, muscle atrophy occurred predominantly in soleus muscle and unusual autophagosomes were accumulated. Therefore, we concluded that autophagy plays an important role in rimmed vacuole formation in certain muscular atrophies.

Animals↗