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901.
Joo-Yong Lee Eunsil Cho Tae-Youn Kim Dong-Kyu Kim Richard D. Palmiter Irene Volitakis Jong S. Kim Ashley I. Bush Jae-Young Koh 《Biometals》2010,23(6):1085-1095
Both apolipoprotein E (apoE) and zinc are involved in amyloid β (Aβ) aggregation and deposition, in the hallmark neuropathology
of Alzheimer’s disease (AD). Recent studies have suggested that interaction of apoE with metal ions may accelerate amyloidogenesis
in the brain. Here we examined the impact of apoE deficiency on the histochemically reactive zinc pool in the brains of apoE
knockout mice. While there was no change in total contents of metals (zinc, copper, and iron), the level of histochemically
reactive zinc (principally synaptic zinc) was significantly reduced in the apoE-deficient brain compared to wild-type. This
reduction was accompanied by reduced expressions of the presynaptic zinc transporter, ZnT3, as well as of the δ-subunit of
the adaptor protein complex-3 (AP3δ), which is responsible for post-translational stability and activity of ZnT3. In addition,
the level of histochemically reactive zinc was also decreased in the cerebrovascular micro-vessels of apoE-deficient mice,
the site of cerebral amyloid angiopathy in AD. These results suggest that apoE may affect the cerebral free zinc pool that
contributes to AD pathology. 相似文献
902.
903.
Young Sik Cho Seung Yeon Park Hee Suk Shin Francis Ka-Ming Chan 《Molecules and cells》2010,29(4):327-332
Cell death occurs spontaneously or in response to external stimuli, and can be largely subdivided into apoptosis and necrosis
by the distinct morphological and biochemical features. Unlike apoptosis, necrosis was recognized as the passive and unwanted
cell demise committed in a non-regulated and disorganized manner. However, under specific conditions such as caspase intervention,
necrosis has been proposed to be regulated in a well-orchestrated way as a backup mechanism of apoptosis. The term programmed
necrosis has been coined to describe such an alternative cell death. Recently, at least some regulators governing programmed
necrosis have been identified and demonstrated to be interconnected via a wide network of signal pathways by further extensive
studies. There is growing evidence that programmed necrosis is not only associated with pathophysiological diseases, but also
provides innate immune response to viral infection. Here, we will introduce recent updates on the molecular mechanism and
physiological significance of programmed necrosis. 相似文献
904.
Eun-A Kim Hanwook Kim Jee-Yin Ahn Hoh-Gyu Hahn Key-Sun Kim Tae Ue Kim Sung-Woo Cho 《Molecules and cells》2010,30(1):51-57
We previously reported that KHG21834, a benzothiazole derivative, attenuates the beta-amyloid (Aβ)-induced degeneration of
both cortical and mesencephalic neurons in vitro. Central nervous system inflammation mediated by activated microglia is a key event in the development of neurodegenerative
disease. In this study, we show that KHG21834 suppresses inflammation-mediated cytokine upregulation. Specifically, KHG21834
induces significant reductions in the lipopolysaccharide-induced activation of microglia and production of proinflammatory
mediators such as tumor necrosis factor-α, interlukin-1β, nitric oxide, and inducible nitric oxide synthase. In addition,
KHG21834 blocks the expression of mitogen-activated protein kinases, including ERK, p38 MAPK, JNK, and Akt. In vivo intracerebroventricular infusion of KHG21834 also leads to decreases the level of interleukin-1β and tumor necrosis factor-α
in brain. These results, in combination with our previous findings on Aβ-induced degeneration, support the potential therapeutic
efficacy of KHG21834 for the treatment of neurodegenerative disorders via the targeting of key glial activation pathways. 相似文献
905.
Overexpression of the ethylene-responsive factor gene BrERF4 from Brassica rapa increases tolerance to salt and drought in Arabidopsis plants 总被引:1,自引:0,他引:1
906.
Microencapsulation of live probiotic bacteria 总被引:1,自引:0,他引:1
Scientific research regarding the use of live bacterial cells for therapeutic purposes has been rapidly growing over the years and has generated considerable interest to scientists and health professionals. Probiotics are defined as essential live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Due to considerable beneficial health effects, these microorganisms are increasingly incorporated into the dairy products; however, many reports demonstrated their poor survival and stability. Their survival in the gastrointestinal (GI) tract is also questionable. To overcome these problems, microencapsulation techniques are currently receiving considerable attention. This review describes the importance of live probiotic bacterial microencapsulation using an alginate microparticulate system and presents the potentiality of various coating polymers such as chitosan and polylysine for improving the stability of this microencapsulation. 相似文献
907.
Hyun-Hee Cho Catherine M. Cahill Charles R. Vanderburg Clemens R. Scherzer Bin Wang Xudong Huang Jack T. Rogers 《The Journal of biological chemistry》2010,285(41):31217-31232
Iron influx increases the translation of the Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE) RNA stem loop in its 5′-untranslated region. Equal modulated interaction of the iron regulatory proteins (IRP1 and IRP2) with canonical IREs controls iron-dependent translation of the ferritin subunits. However, our immunoprecipitation RT-PCR and RNA binding experiments demonstrated that IRP1, but not IRP2, selectively bound the APP IRE in human neural cells. This selective IRP1 interaction pattern was evident in human brain and blood tissue from normal and Alzheimer disease patients. We computer-predicted an optimal novel RNA stem loop structure for the human, rhesus monkey, and mouse APP IREs with reference to the canonical ferritin IREs but also the IREs encoded by erythroid heme biosynthetic aminolevulinate synthase and Hif-2α mRNAs, which preferentially bind IRP1. Selective 2′-hydroxyl acylation analyzed by primer extension analysis was consistent with a 13-base single-stranded terminal loop and a conserved GC-rich stem. Biotinylated RNA probes deleted of the conserved CAGA motif in the terminal loop did not bind to IRP1 relative to wild type probes and could no longer base pair to form a predicted AGA triloop. An AGU pseudo-triloop is key for IRP1 binding to the canonical ferritin IREs. RNA probes encoding the APP IRE stem loop exhibited the same high affinity binding to rhIRP1 as occurs for the H-ferritin IRE (35 pm). Intracellular iron chelation increased binding of IRP1 to the APP IRE, decreasing intracellular APP expression in SH-SY5Y cells. Functionally, shRNA knockdown of IRP1 caused increased expression of neural APP consistent with IRP1-APP IRE-driven translation. 相似文献
908.
Hajer Ouertatani-Sakouhi Farah El-Turk Bruno Fauvet Min-Kyu Cho Damla Pinar Karpinar Didier Le Roy Manfred Dewor Thierry Roger Jürgen Bernhagen Thierry Calandra Markus Zweckstetter Hilal A. Lashuel 《The Journal of biological chemistry》2010,285(34):26581-26598
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC50 values in the range of 0.2–15.5 μm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro1; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease. 相似文献
909.
William Ka Kei Wu Joseph Jao Yiu Sung Ka Fai To Le Yu Hai Tao Li Zhi Jie Li Kin Man Chu Jun Yu Chi Hin Cho 《Journal of cellular physiology》2010,223(1):178-186
The human cathelicidin LL‐37, a pleiotropic host defense peptide, is down‐regulated in gastric adenocarcinomas. We therefore investigated whether this peptide suppresses gastric cancer growth. LL‐37 lowered gastric cancer cell proliferation and delayed G1‐S transition in vitro and inhibits the growth of gastric cancer xenograft in vivo. In this connection, LL‐37 increased the tumor‐suppressing bone morphogenetic protein (BMP) signaling, manifested as an increase in BMP4 expression and the subsequent Smad1/5 phosphorylation and the induction of p21Waf1/Cip1. The anti‐mitogenic effect, Smad1/5 phosphorylation, and p21Waf1/Cip1 up‐regulation induced by LL‐37 were reversed by the knockdown of BMP receptor II. The activation of BMP signaling was paralleled by the inhibition of chymotrypsin‐like and caspase‐like activity of proteasome. In this regard, proteasome inhibitor MG‐132 mimicked the effect of LL‐37 by up‐regulating BMP4 expression and Smad1/5 phosphorylation. Further analysis of clinical samples revealed that LL‐37 and p21Waf1/Cip1 mRNA expressions were both down‐regulated in gastric cancer tissues and their expressions were positively correlated. Collectively, we describe for the first time that LL‐37 inhibits gastric cancer cell proliferation through activation of BMP signaling via a proteasome‐dependent mechanism. This unique biological activity may open up novel therapeutic avenue for the treatment of gastric cancer. J. Cell. Physiol. 223: 178–186, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
910.
Mast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcεRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B(4) receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA knockdown completely abolished the production of Th2 cytokines. Furthermore, BMMCs overexpressing BLT2 showed significantly enhanced production of Th2 cytokines compared with wild-type BMMCs. Additionally, we found that the generation of Nox1-derived reactive oxygen species occurs downstream of BLT2, thus mediating the synthesis of Th2 cytokines. Taken together, our results suggest that the BLT2-Nox1-reactive oxygen species cascade is a previously unsuspected mediatory signaling mechanism to Th2 cytokine production in Ag-stimulated BMMCs, thus contributing to allergic response. 相似文献