共查询到20条相似文献,搜索用时 31 毫秒
1.
Pytlowany M Strosznajder JB Jeśko H Cakała M Strosznajder RP 《Acta biochimica Polonica》2008,55(2):339-347
Nitric oxide (NO) is a potent extracellular and intracellular physiological messenger. However, NO liberated in excessive amounts can be involved in macromolecular and mitochondrial damage in brain aging and in neurodegenerative disorders. The molecular mechanism of its neurotoxic action is not fully understood. Our previous data indicated involvement of NO in the release of arachidonic acid (AA), a substrate for cyclo- and lipoxygenases (COX and LOX, respectively). In this study we investigated biochemical processes leading to cell death evoked by an NO donor, sodium nitroprusside (SNP). We found that SNP decreased viability of pheochromocytoma (PC12) cells in a concentration- and time-dependent manner. SNP at 0.1 mM caused a significant increase of apoptosis-inducing factor (AIF) protein level in mitochondria. Under these conditions 80% of PC12 cells survived. The enhancement of mitochondrial AIF level might protect most of PC12 cells against death. However, NO released from 0.5 mM SNP induced massive cell death but had no effect on protein level and localization of AIF and cytochrome c. Caspase-3 activity and poly(ADP-ribose) polymerase-1 (PARP-1) protein levels were not changed. However, PARP activity significantly decreased in a time-dependent manner. Inhibition of both COX isoforms and of 12/15-LOX significantly lowered the SNP-evoked cell death. We conclude that AIF, cytochrome c and caspase-3 are not responsible for the NO-mediated cell death evoked by SNP. The data demonstrate that NO liberated in excess decreases PARP-1 activity. Our results indicate that COX(s) and LOX(s) are involved in PC12 cell death evoked by NO released from its donor, SNP. 相似文献
2.
3.
X Z Ding P Iversen M W Cluck J A Knezetic T E Adrian 《Biochemical and biophysical research communications》1999,261(1):218-223
Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from membrane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism, but their role in pancreatic cancer growth is unknown. The expression of 5-LOX and 12-LOX as well as their effects on cell proliferation was investigated in four human pancreatic cancer cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1). Expression of 5-LOX and 12-LOX mRNA was measured by nested RT-PCR. Effects of LOX inhibitors and specific LOX antisense oligonucleotides on pancreatic cancer cell proliferation were measured by (3)H-thymidine incorporation. Our results showed that (1) 5-LOX and 12-LOX were expressed in all pancreatic cancer cell lines tested, while they were not detectable in normal human pancreatic ductal cells; (2) both LOX inhibitors and LOX antisense markedly inhibited cell proliferation in a concentration-dependent and time-dependent manner; (3) the 5-LOX and 12-LOX metabolites 5-HETE and 12-HETE as well as arachidonic and linoleic acids directly stimulated pancreatic cancer cell proliferation; (4) LOX inhibitor-induced growth inhibition was reversed by 5-HETE and 12-HETE. The current studies indicate that both 5-LOX and 12-LOX expression is upregulated in human pancreatic cancer cells and LOX plays a critical role in pancreatic cancer cell proliferation. LOX inhibitors may be valuable for the treatment of pancreatic cancer. 相似文献
4.
Lipoxygenase inhibition induced apoptosis, morphological changes, and carbonic anhydrase expression in human pancreatic cancer cells 总被引:16,自引:0,他引:16
Ding XZ Kuszynski CA El-Metwally TH Adrian TE 《Biochemical and biophysical research communications》1999,266(2):392-399
Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from membrane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism. We previously reported that 5-LOX and 12-LOX are upregulated in human pancreatic cancer cells and that blockade of these enzymes abolishes pancreatic cancer cell growth. The present study was aimed at evaluating the effect of LOX inhibition on differentiation and apoptosis in pancreatic cancer cells in parallel with growth inhibition. Four human pancreatic cancer cell lines, PANC-1, MiaPaca2, Capan2, and HPAF, were used. Apoptosis was evaluated by three separate methods, including DNA propidium iodide staining, DNA fragmentation, and the TUNEL assay. Morphological changes and carbonic anhydrase activity were used to determine the effect of LOX inhibitors on differentiation. The general LOX inhibitor NDGA, the 5-LOX inhibitor Rev5901, and the 12-LOX inhibitor baicalein all induced apoptosis in all four pancreatic cancer cell lines, as confirmed by all three methods, suggesting that both the 5-LOX and 12-LOX pathways are important for survival of these cells. Furthermore, NDGA, Rev5901, or baicalein resulted in marked cellular morphological changes in parallel with increased intracellular carbonic anhydrase activity, indicating that LOX blockade induced a more differentiated phenotype in human pancreatic cancer cells. Together with our previous findings, this study suggests that perturbations of LOX activity affect pancreatic cancer cell proliferation and survival. Blockade of LOX enzymes may be valuable for the treatment of human pancreatic cancer. 相似文献
5.
Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma 总被引:4,自引:0,他引:4
Lovat PE Ranalli M Corazzari M Raffaghello L Pearson AD Ponzoni M Piacentini M Melino G Redfern CP 《Journal of cellular biochemistry》2003,89(4):698-708
The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity. 相似文献
6.
Adriana A Reyes Barcelo Francisco J Gonzalez-Velasquez Melissa A Moss 《Journal of biological engineering》2009,3(1):5-8
Background
Self-assembly of the amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). As a result, synthetic molecules capable of inhibiting Aβ self-assembly could serve as therapeutic agents and endogenous molecules that modulate Aβ self-assembly may influence disease progression. However, increasing evidence implicating a principal pathogenic role for small soluble Aβ aggregates warns that inhibition at intermediate stages of Aβ self-assembly may prove detrimental. Here, we explore the inhibition of Aβ1–40 self-assembly by serum albumin, the most abundant plasma protein, and the influence of this inhibition on Aβ1–40 activation of endothelial cells for monocyte adhesion. 相似文献7.
Insook Jang Sujin Park Jin Won Cho Kazim Yigitkanli Klaus van Leyen Jürgen Roth 《Experimental cell research》2014
12/15-lipoxygenase (12/15-LOX) is involved in organelle homeostasis by degrading mitochondria in maturing red blood cells and by eliminating excess peroxisomes in liver. Furthermore, 12/15-LOX contributes to diseases by exacerbating oxidative stress-related injury, notably in stroke. Nonetheless, it is unclear what the consequences are of abolishing 12/15-LOX activity. Mice in which the alox15 gene has been ablated do not show an obvious phenotype, and LOX enzyme inhibition is not overtly detrimental. We show here that liver histology is also unremarkable. However, electron microscopy demonstrated that 12/15-LOX knockout surprisingly leads to increased macroautophagy in the liver. Not only macroautophagy but also mitophagy and pexophagy were increased in hepatocytes, which otherwise showed unaltered fine structure and organelle morphology. These findings were substantiated by immunofluorescence showing significantly increased number of LC3 puncta and by Western blotting demonstrating a significant increase for LC3-II protein in both liver and brain homogenates of 12/15-LOX knockout mice. Inhibition of 12/15-LOX activity by treatment with four structurally different inhibitors had similar effects in cultured HepG2 hepatoma cells and SH-SY5Y neuroblastoma cells with significantly increased autophagy discernable already after 2 hours. Hence, our study reveals a link between ablation or inhibition of 12/15-LOX and stimulation of macroautophagy. The enhanced macroautophagy may be related to the known tissue-protective effects of LOX ablation or inhibition under various diseased conditions caused by oxidative stress and ischemia. This could provide an important cleaning mechanism of cells and tissues to prevent accumulation of damaged mitochondria and other cellular components. 相似文献
8.
Amyloid-beta peptide (Aβ) is known to induce the redox imbalance, mitochondrial dysfunction and caspase activation, resulting
in neuronal cell death. Treatment with antioxidants provided a new therapeutic strategy for Alzheimer’s disease (AD) patients.
Here we investigate the effects of purple sweet potato anthocyanins (PSPA), the known strong free radical scavengers, on Aβ
toxicity in PC12 cells. The results showed that pretreatment of PC12 cells with PSPA reduced Aβ-induced toxicity, intracellular
reactive oxygen species (ROS) generation and lipid peroxidation dose-dependently. In parallel, cell apoptosis triggered by
Aβ characterized with the DNA fragmentation and caspase-3 activity were also inhibited by PSPA. The concentration of intracellular
Ca2+ and membrane potential loss associated with cell apoptosis were attenuated by PSPA. These results suggested that PSPA could
protect the PC-12 cell from Aβ-induced injury through the inhibition of oxidative damage, intracellular calcium influx, mitochondria
dysfunction and ultimately inhibition of cell apoptosis. The present study indicates that PSPA may be a promising approach
for the treatment of AD and other oxidative-stress-related neurodegenerative diseases. 相似文献
9.
Bilobalide (BB), a sesquiterpenoid extract of Ginkgo biloba leaves, has been demonstrated to have neuroprotective effects. The neuroprotective mechanisms were suggested to be associated
with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Since some
members of intracellular signalling pathways such as PI3K have been demonstrated to be involved in amyloid precursor protein
(APP) processing, the present study investigated whether BB has an influence on the β-secretase-mediated APP cleavage via
PI3K-dependent pathway. Using HT22 cells and SAMP8 mice (a senescence-accelerated strain of mice), this study showed that
BB treatment reduced generation of two β-secretase cleavage products of APP, the amyloid β-peptide (Aβ) and soluble APPβ (sAPPβ),
via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3β (GSK3β) signaling might be involved in BB-induced Aβ
reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on β-site APP cleaving enzyme
1 (BACE-1) or γ-secretase but inhibited the β-secretase activity of another protease cathepsin B, suggesting that BB-induced
Aβ reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3β did
not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3β pathway was probably involved
in BB-induced Aβ reduction. Increasing evidence suggests that decreasing Aβ production in the brain via modulation of APP
metabolism should be beneficial for the prevention and treatment of Alzheimer’s disease (AD). BB may offer such an approach
to combat AD. 相似文献
10.
The effects of trans fatty acids, elaidic acid (trans-9, C18:1) and linoelaidic acid (trans-9, trans-12 C18:2), at 20 or 40 μM
in nerve growth factor differentiated PC12 cells with or without beta-amyloid peptide (Aβ) were examined. Elaidic acid treatment
alone did not affect cell viability and oxidative injury associated markers (P > 0.05). However, co-treatments of elaidic acid and Aβ led to more reduction in mitochondrial membrane potential (MMP) and
Na+-K+-ATPase activity, and more increase in DNA fragmentation and 8-hydroxydeoxyguanosine (8-OHdG) production than Aβ treatment
alone (P < 0.05). Linoelaidic acid alone exhibited apoptotic and oxidative effects in cells via decreasing MMP and Na+-K+-ATPase activity, increasing reactive oxygen species (ROS) level, lowering glutathione content and glutathione peroxidase
(GPX) activity (P < 0.05). The co-treatments of linoelaidic acid with Aβ further enhanced oxidative damage via enhancing the generation of
ROS, nitrite oxide and 8-OHdG, elevating caspase-3, caspase-8 and nitric oxide synthase activities, as well as declining GPX,
catalase and superoxide dismutase activities (P < 0.05). These results suggested that the interaction of linoelaidic acid and Aβ promoted oxidative stress and impaired mitochondrial
functions in neuronal cells. 相似文献
11.
Francis C. Dehle Heath Ecroyd Ian F. Musgrave John A. Carver 《Cell stress & chaperones》2010,15(6):1013-1026
Amyloid fibril formation is associated with diseases such as Alzheimer’s, Parkinson’s, and prion diseases. Inhibition of amyloid
fibril formation by molecular chaperone proteins, such as the small heat-shock protein αB-crystallin, may play a protective
role in preventing the toxicity associated with this form of protein misfolding. Reduced and carboxymethylated κ-casein (RCMκ-CN),
a protein derived from milk, readily and reproducibly forms fibrils at physiological temperature and pH. We investigated the
toxicity of fibril formation by RCMκ-CN using neuronal model PC12 cells and determined whether the inhibition of fibril formation
altered its cell toxicity. To resolve ambiguities in the literature, we also investigated whether fibril formation by amyloid-β1–40
(Aβ1–40), the peptide associated with Alzheimer’s disease, was inhibited by αB-crystallin and if this affected the toxicity of Aβ.
To this end, either RCMκ-CN or Aβ1–40 was incubated at neutral pH to induce fibril formation before treating PC12 cells and assessing cell viability. Incubated
(fibrillar) RCMκ-CN was more toxic to PC12 cells than native RCMκ-CN with the highest level of toxicity being associated with
mature fibrils and protofibrils. Furthermore, the toxicity of RCMκ-CN was attenuated when its fibril formation was inhibited,
either through the chaperone action of αB-crystallin or when it interacted with its natural binding partners in milk, αS- and β-casein. Likewise, incubating Aβ1–40 with αB-crystallin inhibited both Aβ1–40 fibril formation and the associated cell toxicity. Importantly, by inhibiting fibril formation, αB-crystallin prevents the
cell toxicity associated with protein misfolding. 相似文献
12.
Klampfl T Bogner E Bednar W Mager L Massudom D Kalny I Heinzle C Berger W Stättner S Karner J Klimpfinger M Fürstenberger G Krieg P Marian B 《Experimental cell research》2012,318(6):768-778
12(S)-Lipoxygenase (LOX) and its product 12(S)-hydroxyeicosatetraenic (HETE) acid have been implicated in angiogenesis and tumour invasion in several tumour types while their role in colorectal cancer progression has not yet been studied. We have analysed 12(S)-LOX expression in colorectal tumours and found gene expression up-regulated in colorectal cancer specimens for which the pathology report described involvement of inflammation. Using cell line models exposed to 12(S)-HETE or over-expressing 12(S)-LOX malignant cell growth as well as tumour cell migration was found to be stimulated. Specifically, Caco2 and SW480 cells over-expressing 12(S)-LOX formed fewer colonies from sparse cultures, but migrated better in filter-migration assays. SW480 LOX cells also had higher anchorage-independent growth capacity and a higher tendency to metastasise in vivo. Knock-down or inhibition of 12(S)-LOX inhibited cell migration and anchorage-independent growth in both 12(S)-LOX transfectants and SW620 cells that express high endogenous levels of 12(S)-LOX. On the cell surface E-cadherin and integrin-β1 expression were down-regulated in a 12(S)-LOX-dependent manner disturbing cell-cell interactions. The results demonstrate that 12(S)-LOX expression in inflammatory areas of colorectal tumours has the capacity to induce an invasive phenotype in colorectal cancer cells and could be targeted for therapy. 相似文献
13.
Juan Li Jinjia Hu Biyun Shao Wei Zhou Yongyao Cui Changzhi Dong Jean-Marc Miezan Ezoulin Xu Zhu Wenlong Ding Françoise Heymans Hongzhuan Chen 《Cellular and molecular neurobiology》2009,29(4):589-595
Amyloid-β (Aβ) plays a central role in the neuroinflammation and cholinergic neuronal apoptosis in Alzheimer’s disease, and
thus has been considered as a main determinant of this disease. In the previous study, we reported that PMS777, a novel bis-interacting
ligand for acetylcholinesterase (AChE) inhibition and platelet-activating factor (PAF) receptor antagonism, could significantly
attenuate PAF-induced neurotoxicity. Continuing our efforts, we further investigated the protective effect of PMS777 on Aβ-induced
neuronal apoptosis in vitro and neuroinflammation in vivo. PMS777 (1–100 μM) was found to inhibit Aβ-induced human neuroblastoma
SH-SY5Y cell apoptosis in a concentration-dependent manner. Concurrently, PMS777 increased ratio of bcl-2 to bax mRNA, and
inhibited both mRNA expression and activity of caspase-3 in SH-SY5Y cells after the exposure with Aβ. In vivo experimental
study demonstrated that PMS777 could attenuate Aβ-induced microglial and astrocytic activation in the rat hippocampus after
systemic administration. These results suggest that PMS777 potently protects against Aβ-induced neuronal apoptosis and neuroinflammation,
and warrants further investigations in connection with its potential value in the treatment of Alzheimer’s disease.
The authors Juan Li and Jinjia Hu contributed equally to this article. 相似文献
14.
(1) The present study was designed to investigate whether histamine is involved in the protective effect of carnosine on Aβ42-induced
impairment in differentiated PC12 cells. (2) PC12 cells were exposed to Aβ42 (5 μM) for 24 h after carnosine (5 mM) applied
for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase
inhibitor (α-fluoromethylhistidine) were added 15 min before carnosine. Cell viability, glutamate release or cell surface
expression of NMDA receptor was examined. (3) Aβ42 caused a concentration-dependent reduction of viability in PC12 cells and
pretreatment with carnosine ameliorated this impairment. This amelioration was reversed by the H3 receptor antagonists thioperamide and clobenpropit, but not by either the H1 receptor antagonist diphenhydramine or the H2 receptor antagonist zolantidine. Further, α-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase,
also had no effect. In the presence of Aβ42, carnosine significantly decreased glutamate release and carnosine increased the
surface expression of NMDA receptor. (4) These results indicate that the mechanism by which carnosine attenuates Aβ42-induced
neurotoxicity is independent of the carnosine–histidine–histamine pathway, but may act through regulation of glutamate release
and NMDA receptor trafficking. 相似文献
15.
Ethier C Labelle Y Poirier GG 《Apoptosis : an international journal on programmed cell death》2007,12(11):2037-2049
Poly(ADP-ribose) polymerase-1 (PARP-1) hyper-activation promotes cell death but the signaling events downstream of PARP-1
activation are not fully identified. To gain further information on the implication of PARP-1 activation and PAR synthesis
on signaling pathways influencing cell death, we exposed HeLa cells to the DNA alkylating agent N-methyl-N′-methyl-nitro-N-nitrosoguanidine (MNNG). We found that massive PAR synthesis leads to down-regulation of ERK1/2 phosphorylation, Bax translocation
to the mitochondria, release of cytochrome c and AIF and subsequently cell death. Inhibition of massive PAR synthesis following MNNG exposure with the PARP inhibitor
PJ34 prevented those events leading to cell survival, whereas inhibition of ERK1/2 phosphorylation by inhibiting MEK counteracted
the cytoprotective effect of PJ34. Together, our results provide evidence that PARP-1-induced cell death by MNNG exposure
in HeLa cells is mediated in part through inhibition of the MEK/ERK signaling pathway and that inhibition of massive PAR synthesis
by PJ34, which promotes sustained activation of ERK1/2, leads to cytoprotection. 相似文献
16.
Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels
is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death
and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone
(CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several
pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work
shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study,
we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron
microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells.
MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced
Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS
may be useful in the inhibition or prevention of AD development and progression. 相似文献
17.
Buntup D Skare O Solbu TT Chaudhry FA Storm-Mathisen J Thangnipon W 《Neurochemical research》2008,33(2):248-256
β-Amyloid (Aβ) peptides may cause malfunction and death of neurons in Alzheimer’s disease. We investigated the effect of Aβ
on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated
with Aβ(25-35) at 3 and 10 μM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed
neuronal–glial cell cultures (from P1 rats), Aβ reduced the concentration of system A glutamine transporter 1 (SAT1), by up
to 50% expressed relative to the neuronal marker microtubule-associated protein 2 (MAP2) in the same cell. No significant
effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter
1 (SN1). In neuronal cell cultures (from E18 rats), Aβ(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed
effect depends on the presence of astroglia. The results indicate that Aβ may impair neuronal function and transmitter synthesis,
and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake.
Special issue article in honor of Dr. Frode Fonnum. 相似文献
18.
Transglutaminase 2 silencing reduced the beta-amyloid-effects on the activation of human THP-1 cells
Monica Currò Nadia Ferlazzo Salvatore Condello Daniela Caccamo Riccardo Ientile 《Amino acids》2010,39(5):1427-1433
The aberrant expression and activation of transglutaminase 2 (TG2), the ubiquitous enzyme which catalyzes calcium-dependent
protein cross-linking reactions, has been reported in many inflammatory diseases. Chronic inflammation, mediated by prolonged
activation of brain-resident immunocompetent cells, appears to be involved in the pathogenesis of several age-related diseases,
such as Alzheimer’s disease. Given that increased TG2 expression has been observed in AD brains, this study was aimed to characterize
the role of TG2 in THP-1 monocytes stimulated with amyloid-beta (Aβ). Aβ1–42 treatment dose-dependently increased TG2 expression in THP-1 cells. In particular, a fivefold up-regulation of TG2, compared
with control cells, was observed in the presence of 0.5 μM Aβ1–42. At the same concentration, Aβ1–42 was able to promote monocyte maturation as suggested by increased expression of the cell surface antigen CD14 as well as
the adhesion-promoting factor fibronectin. The stimulation of THP-1 cells with Aβ1–42 also led to a significant up-regulation of tumor necrosis factor α (TNF-α) and matrix metalloproteinase 9 (MMP-9). Interestingly,
THP-1 cell transfection with small interfering RNA directed against TG2 was able to reduce Aβ1–42 increased levels of all the examined markers of monocyte maturation (CD14, fibronectin), and activation (TNF-α, MMP-9). These
results indicate that TG2 up-regulation is required for the functional THP-1 monocyte activation induced by Aβ1–42. This work suggests that TG2 inhibition may represent a therapeutic target to ameliorate the inflammation and progression
in Alzheimer’s disease. 相似文献
19.
Wang ZF Yan J Fu Y Tang XC Feng S He XC Bai DL 《Cellular and molecular neurobiology》2008,28(2):245-261
(1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311,
a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice
were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance.
PC12 cell injury was induced by β-amyloid 25–35 (Aβ25–35), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase
(AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability
and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine
or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against
Aβ25–35 peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect
an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising
candidate in neurodegenerative diseases, such as Alzheimer’s disease and Vascular dementia. 相似文献