共查询到20条相似文献,搜索用时 31 毫秒
1.
Gi Soo Kang Qin Li Haobin Chen Max Costa 《Mutation Research - Genetic Toxicology and Environmental Mutagenesis》2006,610(1-2):48
Several metals are carcinogenic but little is known about the mechanisms by which they cause cancer. A pathway that may contribute to metal ion induced carcinogenesis is by hypoxia signaling, which involves a disruption of cellular iron homeostasis by competition with iron transporters or iron-regulated enzymes. To examine the involvement of iron in the hypoxia signaling activity of these metal ions we investigated HIF-1α protein stabilization, IRP-1 activity, and ferritin protein levels in human lung carcinoma A459 cells exposed to various agents in serum- and iron-free salt–glucose medium (SGM) or in normal complete medium. We also studied the effects of excess exogenous iron on these responses induced by nickel ion exposure. Our results show the following: (1) SGM enhanced metals-induced HIF-1α stabilization and IRP-1 activation (e.g., nickel and cobalt ions). (2) If SGM was reconstituted with a slight excess level (25 μM of FeSO4) of iron, this enhancing ability was significantly decreased. (3) The effect of a high level of exogenous iron (500 μM of FeSO4) on metal-induced hypoxia and iron metabolism was highly dependent on the order of addition. If treatment with the Fe and metal ions was simultaneous (co-treatment), the effects of nickel ion exposure were overwhelmed, since the added Fe reversed HIF-1α stabilization, decreased IRP-1 activity, and increased ferritin level. Pre-treatment with iron was not able to reverse the responses caused by nickel ion exposure. These results imply that it is important to consider the available iron concentration and suitable exposure design when studying metal-induced hypoxia or metal-induced disruption of Fe homeostasis. 相似文献
2.
Nickel ions have been reported to exhibit differential effects on distinct subtypes of voltage-activated calcium channels.
To more precisely determine the effects of nickel, we have investigated the action of nickel on four classes of cloned neuronal
calcium channels (α1A, α1B, α1C, and α1E) transiently expressed in Xenopus oocytes. Nickel caused two major effects: (i) block detected as a reduction of the maximum slope conductance and (ii) a shift
in the current-voltage relation towards more depolarized potentials which was paralleled by a decrease in the slope of the
activation-curve. Block followed 1:1 kinetics and was most pronounced for α1C, followed by α1E > α1A > α1B channels. In contrast, the change in activation-gating was most dramatic with α1E, with the remaining channel subtypes significantly less affected. The current-voltage shift was well described by a simple
model in which nickel binding to a saturable site resulted in altered gating behavior. The affinity for both the blocking
site and the putative gating site were reduced with increasing concentration of external permeant ion. Replacement of barium
with calcium reduced both the degree of nickel block and the maximal effect on gating for α1A channels, but increased the nickel blocking affinity for α1E channels. The coexpression of Ca channel β subunits was found to differentially influence nickel effects on α1A, as coexpression with β2a or with β4 resulted in larger current-voltage shifts than those observed in the presence of β1b, while elimination of the β subunit almost completely abolished the gating shifts. In contrast, block was similar for the
three β subunits tested, while complete removal of the β subunit resulted in an increase in blocking affinity. Our data suggest
that the effect of nickel on calcium channels is complex, cannot be described by a single site of action, and differs qualitatively
and quantitatively among individual subtypes and subunit combinations.
Received: 12 October 1995/Revised: 17 January 1996 相似文献
3.
Nadia Ferlazzo Monica Curr Maria Laura Giunta Domenico Longo Valentina Rizzo Daniela Caccamo Riccardo Ientile 《Amino acids》2020,52(2):171-179
Agmatine, a metabolite generated by arginine decarboxylation, has been reported as neuromodulator and neuroactive substance. Several findings suggest that agmatine displays neuroprotective effects in several models of neurodegenerative disorders, such as Parkinson’s disease (PD). It has been hypothesized that biogenic amines may be involved in neuroprotection by scavenging oxygen radicals, thus preventing the generation of oxidative stress. Mitochondrial dysfunction, that leads to a reduction of oxygen consumption, followed by activation of prolyl hydroxylase and decrease of hypoxia-inducible factor 1 alpha (HIF-1α) levels, has been demonstrated to play a role in PD pathogenesis. Using rotenone-treated differentiated SH-SY5Y cells as the in vitro PD model, we here investigated the molecular mechanisms underlying agmatine neuroprotective effects. Our results showed that the preliminary addition of agmatine induces HIF-1α activation, and prevents the rotenone-induced production of free radical species, and the activation of apoptotic pathways by inhibiting mitochondrial membrane potential decrease and caspase 3 as well as cytochrome c increase. Notably, these effects are mediated by HIF-1α, as indicated by experiments using a HIF-1α inhibitor. The present findings suggest that the treatment with agmatine is able to counteract the neuronal cell injury evoked by mitochondrial toxins. 相似文献
4.
V. A. Kobliakov 《Biochemistry. Biokhimii?a》2010,75(6):675-685
This review analyzes the available information concerning mechanisms of non-genotoxic action of reactive oxygen species (ROS)
during tumor promotion and pathways of their generation under the influence of chemical compounds. Special attention is given
to the ability of ROS to induce pseudohypoxia through inhibition of prolyl oxidase, which is an oxygen sensor in the cell.
Functions of HIF-1α as a main contributor to the ROS-induced promotion are analyzed. Data suggest that an unregulated high
level of HIF-1α in the cell could induce the development of tumors. Hypothetical possibilities of ROS production under the
influence of different environmental pollutants, which are promoters of tumorigenesis, include functioning of cytochrome P450 during oxidation of substrates, functioning of the mitochondrial respiratory chain, and action of peroxisome proliferators. 相似文献
5.
Heat shock protein 90 is involved in regulation of hypoxia-driven proliferation of embryonic neural stem/progenitor cells 总被引:1,自引:0,他引:1
Xiong L Zhao T Huang X Liu ZH Zhao H Li MM Wu LY Shu HB Zhu LL Fan M 《Cell stress & chaperones》2009,14(2):183-192
Hypoxia may regulate the proliferation of diverse stem cells. Our previous study showed that hypoxia promoted the proliferation
of embryonic neural stem/progenitor cells (NPCs) and that hypoxia inducible factor-1(HIF-1) was critical in this process.
HIF-1 could be stabilized under hypoxic conditions, and heat shock protein 90 (HSP90) is an essential protein that controls
the activity and stabilization of HIF-1α. In the present work, we investigate whether HSP90 is involved in proliferation of
NPCs under hypoxia by regulating HIF-1α stabilization. Geldanamycin (GA), an HSP90 inhibitor, decreased the expression of
HIF-1α in NPCs during hypoxia-driven proliferation and reduced the expression level of HIF-1α protein under hypoxia in a time-dependent
manner. The proliferation of NPCs induced by hypoxia was inhibited after GA treatment for 24 h. Another HSP90 inhibitor, radicicol,
had the same effect on NPCs as GA. Furthermore, the expression of erythropoietin (EPO) and vascular endothelial growth factor
(VEGF) in NPCs under hypoxia was suppressed by GA. The above data indicated that HSP90 might be involved in regulation of
hypoxia-driven proliferation.
Both institutes have contributed equally to this work. 相似文献
6.
Recent studies suggest a novel role of HIF-1α under non-hypoxic conditions, including antibacterial and antiviral innate immune
responses. However, the identity of the pathogen-associated molecular pattern which triggers HIF-1α activation during the
antiviral response remains to be identified. Here, we demonstrate that cellular administration of double-stranded nucleic
acids, the molecular mimics of viral genomes, results in the induction of HIF-1α protein level as well as the increase in
HIF-1α target gene expression. Whole-genome DNA microarray analysis revealed that double-stranded nucleic acid treatment triggers
induction of a number of hypoxia-inducible genes, and induction of these genes are compromised upon siRNA-mediated HIF-1α
knock-down. Interestingly, HIF-1α knock-down also resulted in down-regulation of a number of genes involved in antiviral innate
immune responses. Our study demonstrates that HIF-1α activation upon nucleic acid-triggered antiviral innate immune responses
plays an important role in regulation of genes involved in not only hypoxic response, but also immune response.
These authors contributed equally to this work. 相似文献
7.
Evolution and Regulation of the Downstream Gene of Hypoxia-Inducible Factor-1α in Naked Carp (Gymnocypris przewalskii) from Lake Qinghai, China 总被引:1,自引:0,他引:1
The naked carp (Gymnocypris przewalskii) is a native teleost of Lake Qinghai (altitude, 3.2 km) on the Qinghai-Tibet Plateau in China. Hypoxia-inducible factor (HIF)-1α
of Gymnocypris przewalskii was cloned and a phylogenetic tree for vertebrate HIF-1α was constructed. By analysis of maximum likelihood models of codon
substitutions for HIF-1α, three positive sites in the branch lineages of crucian carp, eelpout, and flounder, and a higher
proportion of neutral sites in naked carp, antarctic eelpout, rainbow trout, and grayling, were detected among all teleosts.
It seems that low habitat temperatures relax the purifying selection of HIF-1α in these stenothermal coldwater fish, and both
cold and hypoxic lake water contributed to the evolution of the HIF-1α gene in the naked carp. Furthermore, Glut 1 mRNA, a
gene downstream from HIF-1α, has a time-course- and tissue-specific dependent response to hypoxic challenge. 相似文献
8.
Guo M Song LP Jiang Y Liu W Yu Y Chen GQ 《Apoptosis : an international journal on programmed cell death》2006,11(1):67-77
Hypoxia presents pro-apoptotic and anti-apoptotic biphasic effects that appear to be dependent upon cell types and conditions
around cells. The substantial reports demonstrated that commonly used hypoxia-mimetic agents cobalt chloride (CoCl2) and desferrioxamine (DFO) could also induce apoptosis in many different kinds of cells, but the mechanism was poorly understood.
In this work, we compare the apoptosis-inducing effects of these two hypoxia-mimetic agents with acute myeloid leukemic cell
lines NB4 and U937 as in vitro models. The results show that both of them induce these leukemic cells to undergo apoptosis with a loss of mitochondrial
transmembrane potentials (ΔΨ m), the activation of caspase-3/8 and the cleavage of anti-apoptotic protein Mcl-1, together
with the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein, a critical regulator for the cellular response
to hypoxia. Metavanadate and sodium nitroprusside significantly abrogate DFO rather than CoCl2-induced mitochondrial Δ Ψ m collapse, caspase-3/8 activation, Mcl-1 cleavage and apoptosis, but they fail to influence DFO
and CoCl2-induced HIF-1α protein accumulation. Moreover, inducible expression of HIF-1α gene dose not alter DFO and CoCl2-induced apoptosis in U937 cells. In conclusion, these results propose that although both DFO and CoCl2-induced leukemic cell apoptosis by mitochondrial pathway-dependent and HIF-1α-independent mechanisms, DFO and CoCl2-induced apoptosis involves different initiating signal pathways that remain to be investigated. 相似文献
9.
Several metals are carcinogenic but little is known about the mechanisms by which they cause cancer. A pathway that may contribute to metal ion induced carcinogenesis is by hypoxia signaling, which involves a disruption of cellular iron homeostasis by competition with iron transporters or iron-regulated enzymes. To examine the involvement of iron in the hypoxia signaling activity of these metal ions we investigated HIF-1alpha protein stabilization, IRP-1 activity, and ferritin protein levels in human lung carcinoma A459 cells exposed to various agents in serum- and iron-free salt-glucose medium (SGM) or in normal complete medium. We also studied the effects of excess exogenous iron on these responses induced by nickel ion exposure. Our results show the following: (1) SGM enhanced metals-induced HIF-1alpha stabilization and IRP-1 activation (e.g., nickel and cobalt ions). (2) If SGM was reconstituted with a slight excess level (25 microM of FeSO(4)) of iron, this enhancing ability was significantly decreased. (3) The effect of a high level of exogenous iron (500 microM of FeSO(4)) on metal-induced hypoxia and iron metabolism was highly dependent on the order of addition. If treatment with the Fe and metal ions was simultaneous (co-treatment), the effects of nickel ion exposure were overwhelmed, since the added Fe reversed HIF-1alpha stabilization, decreased IRP-1 activity, and increased ferritin level. Pre-treatment with iron was not able to reverse the responses caused by nickel ion exposure. These results imply that it is important to consider the available iron concentration and suitable exposure design when studying metal-induced hypoxia or metal-induced disruption of Fe homeostasis. 相似文献
10.
Multidrug resistance (MDR) is a significant problem underlying the poor prognosis associated with gliomas. Hypoxia-inducible
factor-1α (HIF-1α) is thought to induce the genes expression involved in MDR. To evaluate the effect of silencing HIF-1α in
human glioma T98G cells, cells were transfected with HIF-1α-small interference RNA (HIF-1α-siRNA) and cultured under hypoxic
conditions. The effect of HIF-1α-siRNA on HIF-1α and multidrug resistance-associated protein 1 gene (MRP1) and protein levels
was determined. Silencing rates of HIF-1α were 90%, 85%, and 88% at 24, 48, 72 h post-transfection, respectively. Corresponding
rates of HIF-1α protein were 74.5%, 61.1% and 59.1%. MRP1 protein levels decreased by 7.6%, 36.8% and 45.2%. HIF-1α-siRNA
transfected cells were significantly more sensitive to doxorubicin and etoposide compared to non-transfected cells. These
findings suggest that the HIF-1α plays a role in mediating chemotherapeutic drug resistance in glioma cells. HIF-1α silencing
may prove to be an effective therapeutic means of treating gliomas. 相似文献
11.
Choi IY Kim SJ Jeong HJ Park SH Song YS Lee JH Kang TH Park JH Hwang GS Lee EJ Hong SH Kim HM Um JY 《Molecular and cellular biochemistry》2007,305(1-2):153-161
The citrus unshiu peel has been used traditionally as a medicine to improve bronchial and asthmatic conditions or cardiac
and blood circulation in Korea, China, and Japan. Here, we report the effects of citrus unshiu peel water extract (CPWE) on
the phorbol myristate acetate (PMA) + calcium ionophore A23187-induced hypoxia-inducible factor-1α (HIF-1α) activation and
inflammatory cytokine production from the human mast cell line, HMC-1 cells. We compared CPWE with hesperidin, a common constituent
of citrus unshiu. CPWE and hesperidin inhibited the PMA + A23187-induced HIF-1α expression and the subsequent production of
vascular endothelial growth factor (VEGF). In addition, CPWE suppressed PMA + A23187-induced phosphorylation of the extracellular
signal-regulated kinase (ERK). We also show that the increased cytokines interleukin (IL)-1β, IL-8, and tumor necrosis factor
(TNF)-α level was significantly inhibited by treatment of CPWE or hesperidin. In the present study, we report that CPWE and
hesperidin are inhibitors of HIF-1α and cytokines on the mast cell-mediated inflammatory responses. 相似文献
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14.
Wu LY Wang Y Jin B Zhao T Wu HT Wu Y Fan M Wang XM Zhu LL 《Neurochemical research》2008,33(10):2118-2125
Nervous system development at early stage is in hypoxic environment. Very little is known about the role of hypoxia in neuronal
development. P19 embryonal carcinoma (EC) cells are a widely used model for studying early neuronal development. In this study
we investigated the roles of hypoxia in differentiation of dopaminergic neurons derived from P19 EC cells. Results demonstrate
that hypoxia increases the percentage of differentiated neurons, especially neurons of dopaminergic phenotype. To investigate
the potential mechanism involved in hypoxia promoted differentiation of dopaminergic neurons, we measured the expression of
hypoxia-inducible factor 1α (HIF-1α), based on its characteristic response to hypoxia. The result shows that HIF-1α mRNA level
in P19 EC cells increases after hypoxia treatment. It is known that HIF-1α regulates the expression of tyrosine hydroxylase
(TH) gene through binding to its promoter. Therefore, we propose that the underlying mechanism for hypoxia promoted differentiation
of dopaminergic neurons was mediated by HIF-1α up-regulation under hypoxia.
Yue Wang—Co-first author.
Special Issue in honor of Dr. Ji-Sheng Han. 相似文献
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18.
Zheng Y Shi X Wang M Jia Y Li B Zhang Y Liu Q Wang Y 《Molecular biology reports》2012,39(4):4229-4236
Overexpression of differentiated embryo chondrocyte 1 (DEC1) has been reported to contribute to the cellular differentiation,
proliferation, and apoptosis of various cancers. Our previous studies have shown that DEC1 was highly expressed in gastric
cancer (GCa) tissues. However, there is no report about the expression of DEC1 in GCa cell lines until now. In this study,
We evaluated the mRNA and protein expression of DEC1 and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions
in six GCa cell lines: BGC-823, MGC80-3, MKN1, AGS, FU97 and SGC-7901. An HIF-1α protein inhibitor was used to analyze the
association of DEC1 and HIF-1α expression. Under normoxia, the mRNA expression of both HIF-1α and DEC1 was moderate, whereas
the protein expression of DEC1 was higher than that of HIF-1α. Hypoxia induced the mRNA expression of DEC1 and the protein
expression of HIF-1α and DEC1 in a time-dependent manner but had no effect on the mRNA expression of HIF-1α. Furthermore,
inhibition of HIF-1α protein expression resulted in a significant decrease in both the mRNA and protein expression of DEC1.
Taken together, DEC1 expression is correlated with HIF-1α protein in GCa cell line, blockage of HIF-1α protein led to reduced
DEC1 expression. The efficacy of inhibiting HIF-1α and DEC1 expression should be tested in clinical trials as possible treatment
for GCa. 相似文献
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Hwang JM Weng YJ Lin JA Bau DT Ko FY Tsai FJ Tsai CH Wu CH Lin PC Huang CY Kuo WW 《Molecular and cellular biochemistry》2008,311(1-2):179-187
Chronic cardiac ischemia/hypoxia induces coronary collateral formation and cardiomyocyte proliferation. Hypoxia can induce
cellular adaptive responses, such as synthesis of VEGF for angiogenesis and IGF-2 for proliferation. Both reduce apoptotic
effects to minimize injury or damage. To investigate the mechanism of neoangiogenesis and proliferation of fetal heart under
umbilical cord compression situation, we used H9c2 cardiomyoblast cell culture, and in vivo embryonic hearts as our study
models. Results showed hypoxia induced not only the increase of IGF-2 and VEGF expression but also the activation of their
upstream regulatory genes, HIF-1α and Shh. The relationship between HIF-1α and Shh was further studied by using cyclopamine
and 2-ME2, inhibitor of Shh and HIF-1α signaling, respectively, in the cardiomyoblast cell culture under hypoxia. We found
that the two inhibitors not only blocked their own signal pathway, but also inhibited each other. The observations revealed
when fetal heart under hypoxia that HIF-1α and Shh pathways maybe involve in cell proliferation and neoangiogenesis to minimize
injury or damage, whereas the complex cross-talk between the two pathways remains unknown.
Pei-Cheng Lin, Chih-Yang Huang, and Wei-Wen Kuo contributed equally to this work. 相似文献