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961.
Zheng-Mei Xiong Kaori Kitagawa Yuji Nishiuchi Terutoshi Kimura Tomoyuki Nakamura Chiyoko Inagaki 《Life sciences》2009,84(5-6):132-138
AimsWe previously reported that the neurotoxicity of amyloid β protein (Aβ1–42, 10 nM) was blocked by an Aβ-derived tripeptide, Aβ32–34 (Ile-Gly-Leu, IGL), suggesting that IGL may be a lead compound in the design of Aβ antagonists. In the present study, three stable forms of IGL peptide with acetylation of its N-terminal and/or amidation of its C-terminal (acetyl-IGL, IGL-NH2 and acetyl-IGL-NH2) were synthesized and examined for their effects on Aβ-induced neurotoxicity.Main methodsPhosphatidylinositol 4-kinase type II (PI4KII) activity was measured using recombinant human PI4KIIα kinase and cell viability was assessed in primary cultured hippocampal neurons. To test effects in vivo, 1.5 μl of 100 nM Aβ and/or 100 nM acetyl-IGL was injected into the hippocampal CA1 region of right hemisphere in transgenic mice expressing V337M human tau protein. Four weeks later, behavior performance in the Morris water maze was tested and after another 2 weeks, sections of brain were prepared for immunohistochemistry.Key findingsAmong the three modified tripeptides, acetyl-IGL attenuated the Aβ-induced inhibition of PI4KII activity as well as enhancement of glutamate neurotoxicity in primary cultured rat hippocampal neurons. Injection of Aβ into the hippocampus of mice impaired spatial memory and increased the number of degenerating neurons in bilateral hippocampal regions. Co-injection of acetyl-IGL prevented the learning impairment as well as the neuronal degeneration induced by Aβ.SignificanceThese results suggest that a modified tripeptide, acetyl-IGL, may be effective in the treatment of Alzheimer's disease. 相似文献
962.
Yiping Zhu Kun Xiao Lanping Ma Bin Xiong Yan Fu Haiping Yu Wei Wang Xin Wang Dingyu Hu Hongli Peng Jingya Li Qi Gong Qian Chai Xican Tang Haiyan Zhang Jia Li Jingkang Shen 《Bioorganic & medicinal chemistry》2009,17(4):1600-1613
To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC50 = 0.567 μM; AChE: IC50 = 1.83 μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC50 = 98.7 nM) and mild protective effect against hydrogen peroxide (H2O2)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients. 相似文献
963.
964.
Jiang J Xia XB Xu HZ Xiong Y Song WT Xiong SQ Li Y 《Journal of cellular physiology》2009,218(1):66-74
Retinal neovascularization (NV) occurs in various ocular disorders including proliferative diabetic retinopathy, retinopathy of prematurity and secondary neovascular glaucoma, which often result in blindness. Vascular endothelial growth factor (VEGF) is an essential growth factor for angiogenesis, and is particularly regulated by hypoxia inducible factor-1alpha (HIF-1alpha) under hypoxic conditions. Therefore, HIF-1alpha and VEGF could provide targets for therapeutic intervention on retinal NV. In this study, we investigated the inhibitory effects of small interfering RNA (siRNA) targeting HIF-1alpha and VEGF on the expression of HIF-1alpha and VEGF in human umbilical vein endothelial cells (HUVEC) in vitro and on retinal NV in vivo. siRNA-expressing plasmids targeting human HIF-1alpha (HIF-1alpha siRNA) and human VEGF(165) (VEGF siRNA) were constructed. They were transfected and co-transfected to HUVEC and C57BL/6J mice of ischemic retinopathy model. HIF-1alpha siRNA and VEGF siRNA specifically downregulated HIF-1alpha and VEGF at both mRNA and protein levels in vitro and in vivo. Neovascular tufts and neovascular nuclei were decreased in gene therapy group compared to control hypoxia group. Co-transfection of HIF-1alpha siRNA and VEGF siRNA resulted in maximal effects on VEGF suppression in vitro and in vivo. It also manifested the maximal inhibitory effect on retinal NV. These results indicate that the application of HIF-1alpha siRNA and VEGF siRNA technology holds great potential as a novel therapeutic for retinal NV. 相似文献
965.
Min Chen Qian Chen Xue-Wen Cheng Ting-Jia Lu Han-Xing Liu Jie-Min Jia Chi Zhang Li Xu Zhi-Qi Xiong 《Journal of neurochemistry》2009,111(5):1094-1103
Deposition of ubiquitinated protein aggregates is a hallmark of neurodegeneration in both acute neural injuries, such as stroke, and chronic conditions, such as Parkinson's disease, but the underlying mechanisms are poorly understood. In the present study, we examined the role of Zn2+ in ischemia-induced impairment of the ubiquitin-proteasome system in the CA1 region of rat hippocampus after transient global ischemia. We found that scavenging endogenous Zn2+ reduced ischemia-induced ubiquitin conjugation and free ubiquitin depletion. Furthermore, exposure to zinc chloride increased ubiquitination and inhibited proteasomal enzyme activity in cultured hippocampal neurons in a concentration- and time-dependent manner. Further studies of the underlying mechanisms showed that Zn2+ -induced ubiquitination required p38 activation. These findings indicate that alterations in Zn2+ homeostasis impair the protein degradation pathway. 相似文献
966.
967.
Ming-hon Yau Yu Wang Karen S. L. Lam Jialiang Zhang Donghai Wu Aimin Xu 《The Journal of biological chemistry》2009,284(18):11942-11952
Lipoprotein lipase (LPL) is a principal enzyme responsible for the
clearance of chylomicrons and very low density lipoproteins from the
bloodstream. Two members of the Angptl (angiopoietin-like protein) family,
namely Angptl3 and Angptl4, have been shown to inhibit LPL activity in
vitro and in vivo. Here, we further investigated the structural
basis underlying the LPL inhibition by Angptl3 and Angptl4. By multiple
sequence alignment analysis, we have identified a highly conserved 12-amino
acid consensus motif that is present within the coiled-coil domain (CCD) of
both Angptl3 and Angptl4, but not other members of the Angptl family.
Substitution of the three polar amino acid residues (His46,
Gln50, and Gln53) within this motif with alanine
abolishes the inhibitory effect of Angptl4 on LPL in vitro and also
abrogates the ability of Angptl4 to elevate plasma triglyceride levels in
mice. The CCD of Angptl4 interacts with LPL and converts the catalytically
active dimers of LPL to its inactive monomers, whereas the mutant protein with
the three polar amino acids being replaced by alanine loses such a property.
Furthermore, a synthetic peptide consisting of the 12-amino acid consensus
motif is sufficient to inhibit LPL activity, although the potency is
much lower than the recombinant CCD of Angptl4. In summary, our data suggest
that the 12-amino acid consensus motif within the CCD of Angptl4, especially
the three polar residues within this motif, is responsible for its interaction
with and inhibition of LPL by blocking the enzyme dimerization.Lipoprotein lipase
(LPL)3 is an
endothelium-bound enzyme that catalyzes the hydrolysis of plasma triglyceride
(TG) associated with chylomicrons and very low density lipoproteins
(1,
2). This enzyme plays a major
role in maintaining lipid homeostasis by promoting the clearance of TG-rich
lipoproteins from the bloodstream. Abnormality in LPL functions has been
associated with a number of pathological conditions, including
atherosclerosis, dyslipidemia associated with diabetes, and Alzheimer disease
(1).LPL is expressed in a wide variety of cell types, particularly in
adipocytes and myocytes (2). As
a rate-limiting enzyme for clearance of TG-rich lipoproteins, the activity of
LPL is tightly modulated by multiple mechanisms in a tissue-specific manner in
response to nutritional changes
(3,
4). The enzymatic activity of
LPL in adipose tissue is enhanced after feeding to facilitate the storage of
TG, whereas it is down-regulated during fasting to increase the utilization of
TG by other tissues (5). The
active form of LPL is a noncovalent homodimer with the subunits associated in
a head-to-tail manner, and the dissociation of its dimeric form leads to the
formation of a stable inactive monomeric conformation and irreversible enzyme
inactivation (6). At the
post-translational level, the LPL activity is regulated by numerous
apolipoprotein co-factors. For instance, apoCII, a small apolipoprotein
consisting of 79 amino acid residues in human, activates LPL by directly
binding to the enzyme (7,
8). By contrast, several other
apolipoproteins such as apoCI, apo-CIII, and apoE have been shown to inhibit
the LPL activity in vitro
(3).Angiopoietin-like proteins (Angptl) are a family of secreted proteins
consisting of seven members, Angptl1 to Angptl7
(9,
10). All the members of the
Angptl family share a similar domain organization to those of angiopoietins,
with an NH2-terminal coiled-coil domain (CCD) and a COOH-terminal
fibrinogen-like domain. Among the seven family members, only Angptl3 and
Angptl4 have been shown to be involved in regulating triglyceride metabolism
(10,
11). The biological functions
of Angptl3 in lipid metabolism were first discovered by Koishi et al.
(12) in their positional
cloning of the recessive mutation gene responsible for the hypolipidemia
phenotype in a strain of obese mouse KK/snk. Subsequent studies have
demonstrated that Angptl3 increases plasma TG levels by inhibiting the LPL
enzymatic activity
(13–15).
Angptl4, also known as fasting-induced adipocyte factor, hepatic
fibrinogen/angiopoietin-related protein, or peroxisome proliferator-activated
receptor-γ angiopoietin-related, is a secreted glycoprotein abundantly
expressed in adipocyte, liver, and placenta
(16–18).
In addition to its role in regulating angiogenesis, a growing body of evidence
demonstrated that Angptl4 is an important player of lipid metabolism
(10,
11). Elevation of circulating
Angptl4 by transgenic or adenoviral overexpression, or by direct
supplementation of recombinant protein, leads to a marked elevation in the
levels of plasma TG and low density lipoprotein cholesterol in mice
(19–22).
By contrast, Angptl4 knock-out mice exhibit much lower plasma TG and
cholesterol levels compared with the wild type littermates
(19,
20). Notably, treatment of
several mouse models (such as C57BL/6J, ApoE–/–,
LDLR–/–, and db/db obese/diabetic mice) with a
neutralizing antibody against Angptl4 recapitulate the lipid phenotype found
in Angptl4 knock-out mice
(19). The role of Angptl4 as a
physiological inhibitor of LPL is also supported by the finding that its
expression levels in adipose tissue change rapidly during the fed-to-fasting
transitions and correlate inversely with LPL activity
(23). In humans, a genetic
variant of the ANGPTL4 gene (E40K) has been found to be associated
with significantly lower plasma TG levels and higher high density lipoprotein
cholesterol concentrations in several ethnic groups
(24–26).Angptl3 and Angptl4 share many common biochemical and functional properties
(10). In both humans and
rodents, Angptl3 and Angptl4 are proteolytically cleaved at the linker region
and circulate in plasma as two truncated fragments, including
NH2-terminal CCD and COOH-terminal fibrinogen-like domain
(14,
27–29).
The effects of both Angptl3 and Angptl4 on elevating plasma TG levels are
mediated exclusively by their NH2-terminal CCDs
(15,
22,
23,
27,
30). The CCDs of Angptl3 and
Angptl4 have been shown to inhibit the LPL activity in vitro as well
as in mice
(23,30,31).
Angptl4 inhibits LPL by promoting the conversion of the catalytically active
LPL dimers into catalytically inactive LPL monomers, thereby leading to the
inactivation of LPL (23,
31). However, the detailed
structural and molecular basis underlying the LPL inhibition by Angptl3 and
Angptl4 remain poorly characterized at this stage.In this study, we analyzed all known amino acid sequences of Angptl3 and
Angptl4 from various species and found a short motif,
LAXGLLXLGXGL (where X represents polar
amino acid residues), which corresponds to amino acid residues 46–57 and
44–55 of human Angptl3 and Angptl4, respectively, is highly conserved
despite the low degree of their overall homology (∼30%). Using both in
vitro and in vivo approaches, we demonstrated that this 12-amino
acid sequence motif, in particular the three polar amino acid residue within
this motif, is essential for mediating the interactions between LPL and
Angpt4, which in turn disrupts the dimerization of the enzyme. 相似文献
968.
Xiaoyan Hui Weidong Zhu Yu Wang Karen S. L. Lam Jialiang Zhang Donghai Wu Edward W. Kraegen Yixue Li Aimin Xu 《The Journal of biological chemistry》2009,284(21):14050-14057
Major urinary protein-1 (MUP-1) is a low molecular weight secreted protein
produced predominantly from the liver. Structurally it belongs to the
lipocalin family, which carries small hydrophobic ligands such as pheromones.
However, the physiological functions of MUP-1 remain poorly understood. Here
we provide evidence demonstrating that MUP-1 is an important player in
regulating energy expenditure and metabolism in mice. Both microarray and
real-time PCR analysis demonstrated that the MUP-1 mRNA abundance in the liver
of db/db obese mice was reduced by ∼30-fold compared
with their lean littermates, whereas this change was partially reversed by
treatment with the insulin-sensitizing drug rosiglitazone. In both dietary and
genetic obese mice, the circulating concentrations of MUP-1 were markedly
decreased compared with the lean controls. Chronic elevation of circulating
MUP-1 in db/db mice, using an osmotic pump-based protein
delivery system, increased energy expenditure and locomotor activity, raised
core body temperature, and decreased glucose intolerance as well as insulin
resistance. At the molecular level, MUP-1-mediated improvement in metabolic
profiles was accompanied by increased expression of genes involved in
mitochondrial biogenesis, elevated mitochondrial oxidative capacity, decreased
triglyceride accumulation, and enhanced insulin-evoked Akt signaling in
skeletal muscle but not in liver. Altogether, these findings raise the
possibility that MUP-1 deficiency might contribute to the metabolic
dysregulation in obese/diabetic mice, and suggest that the beneficial
metabolic effects of MUP-1 are attributed in part to its ability in increasing
mitochondrial function in skeletal muscle.The liver is the primary organ for carbohydrate and lipid metabolism,
including gluconeogenesis, glycogenesis, cholesterol biosynthesis, and
lipogenesis (1,
2). These metabolic events in
the liver are tightly controlled by several pancreatic hormones including
insulin and glucagon. In addition, the liver itself is one of the largest
endocrine organs in the body, secreting numerous humoral factors involved in
the regulation of systemic glucose and lipid homeostasis. The importance of
the liver-derived humoral factors in maintaining glucose metabolism is
highlighted by the observation that glucose uptake by skeletal muscle is
severely impaired by surgical or pharmacological blockade of hepatic
parasympathetic nerves (3). In
the past several years, a number of liver-derived humoral metabolic factors,
including bone morphogenetic protein-9 (BMP-9)
(4), fibroblast growth factor
21 (FGF21)
(5–7),
retinol-binding protein 4 (RBP4)
(8,
9), adropin
(10), and angiopoietin-like
proteins (Angptl) 3, 4, and 6
(11–13),
have been identified, and their roles in glucose and lipid metabolism have
been characterized in great detail. Noticeably, BMP-9, FGF21, and Angptl6
exhibit potent insulin-sensitizing and glucose-lowering effects in animal
models, and they have been proposed as potential candidates for the treatment
of insulin resistance and type II diabetes
(4,
6,
7,
13).To search for novel liver-derived secretory factors involved in the
regulation of glucose homeostasis, we used microarray analysis as a global
screening for systematic identification of genes differentially expressed in
the liver of C57BLKS db/db mice (a genetically inherited
diabetic mouse model that is characterized by severe insulin resistance and
hyperglycemia) and their lean littermates. We found that the mRNA level of
mouse major urinary protein-1
(MUP-1)2 was markedly
down-regulated in db/db mice, and the change was largely
normalized upon treatment with the PPARγ agonist rosiglitazone. MUP-1 is
a small molecular weight secreted protein abundantly expressed in the liver
(14). Its expression in the
liver is enhanced by administration of the hepatotoxic agent
dimethylnitrosamine (15) but
is reduced by interleukin 6-induced acute phase response in mice
(16). Like other members of
the MUP family, MUP-1 has been proposed to act as a pheromone-binding protein
in urine (17), thereby
accelerating puberty and promoting aggressive behavior in male mice. However,
the precise functions of MUPs have yet to be determined.MUP-1 belongs to the lipocalin superfamily, the members of which share a
common tertiary structure with a cup-shaped hydrophobic ligand binding pocket
surrounded by an eight-stranded β-barrel
(18,
19). This structure confers
upon lipocalins the ability to bind and transport a wide variety of small
lipophilic substances, including fatty acids, cholesterols, prostaglandins,
and pheromones. Noticeably, several members of the lipocalin family, including
RBP4, lipocalin-2, and adipocyte fatty acid-binding protein (A-FABP), have
recently been shown to be important mediators of obesity-related insulin
resistance and glucose intolerance
(8,
20–22).
Unlike MUP-1, the expression of RBP4, lipocalin-2, and A-FABP are elevated in
obesity and diabetes (9,
20,
23).In this study, we investigated the metabolic role of MUP-1 in mice. Our
results demonstrated that MUP-1 was abundantly present in the circulation. In
genetic and dietary obese mouse models, the serum and urine concentrations of
MUP-1 were remarkably decreased. Replenishment of recombinant MUP-1 led to
improved glucose tolerance and insulin sensitivity, as well as increased
energy expenditure and locomotor activity in db/db diabetic
mice. Our data suggest that MUP-1 not only serves as a circulating biomarker,
negatively correlated with obesity-related metabolic disorders, but also plays
an active role in regulating energy homeostasis and insulin sensitivity in
mice. 相似文献
969.