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21.
22.
Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity 总被引:2,自引:0,他引:2
Wang Y White MG Akay C Chodroff RA Robinson J Lindl KA Dichter MA Qian Y Mao Z Kolson DL Jordan-Sciutto KL 《Journal of neurochemistry》2007,103(2):439-455
Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) -associated dementia is not known, a prominent role for NMDA receptor (NMDAR)-induced excitotoxicity has been demonstrated in neurons exposed to HIV-infected/activated macrophages. We hypothesized NMDAR-mediated activation of the calcium-dependent protease, calpain, would contribute to cell death by induction of cyclin-dependent kinase 5 (CDK5) activity. Using an in vitro model of HIV neurotoxicity, in which primary rat cortical cultures are exposed to supernatants from primary human HIV-infected macrophages, we have observed increased calpain-dependent cleavage of the CDK5 regulatory subunit, p35, to the constitutively active isoform, p25. Formation of p25 is dependent upon NMDAR activation and calpain activity and is coincident with increased CDK5 activity in this model. Further, inhibition of CDK5 by roscovitine provided neuroprotection in our in vitro model. Consistent with our observations in vitro, we have observed a significant increase in calpain activity and p25 levels in midfrontal cortex of patients infected with HIV, particularly those with HIV-associated cognitive impairment. Taken together, our data suggest calpain activation of CDK5, a pathway activated in HIV-infected individuals, can mediate neuronal damage and death in a model of HIV-induced neurotoxicity. 相似文献
23.
AIDS Dementia Complex (ADC) is a syndrome of cognitive, behavioral, and motor deficits resulting from HIV-1 infection within the brain. ADC is characterized by variable degrees of neuronal cell death and gliosis that likely result, at least, in part from release of metabolic products, cytokines, and viral proteins from infected macrophages, although a unifying explanation for the neurological dysfunction has yet to be established. Major unanswered questions include: (i) do neurologic symptoms result from neuronal cell death and/or dysfunction in surviving neurons?; (ii) are viral genomic sequences determinants of neurotoxicity?; (iii) is HIV infection of neurons and astrocytes relevant to pathogenesis?, and (iv) what circulating factors within the brain affect neuronal cell survival and function? This review addresses the association between HIV-1 replication within the brain, production of potential neurotoxins and possible mechanisms of induction of neurotoxicity and neuronal dysfunction contributing to the pathogenesis of ADC. 相似文献
24.
Cross SA Cook DR Chi AW Vance PJ Kolson LL Wong BJ Jordan-Sciutto KL Kolson DL 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(10):5015-5025
Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, inflammation and immune activation within both the CNS and periphery correlate with disease progression and morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes in the CNS and systemic compartments are needed for effective, adjunctive therapy. Using our in vitro model of HIV-mediated neurotoxicity, in which HIV-infected monocyte-derived macrophages release excitatory neurotoxins, we show that HIV infection dysregulates the macrophage antioxidant response and reduces levels of heme oxygenase-1 (HO-1). Furthermore, restoration of HO-1 expression in HIV-infected monocyte-derived macrophages reduces neurotoxin release without altering HIV replication. Given these novel observations, we have identified dimethyl fumarate (DMF), used to treat psoriasis and showing promising results in clinical trials for multiple sclerosis, as a potential neuroprotectant and HIV disease-modifying agent. DMF, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and neurotoxin release. Two distinct mechanisms are proposed: inhibition of NF-κB nuclear translocation and signaling, which could contribute to the suppression of HIV replication, and induction of HO-1, which is associated with decreased neurotoxin release. Finally, we found that DMF attenuates CCL2-induced monocyte chemotaxis, suggesting that DMF could decrease recruitment of activated monocytes to the CNS in response to inflammatory mediators. We propose that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and that DMF could serve as an adjunctive neuroprotectant and HIV disease modifier in ART-treated individuals. 相似文献
25.
26.
TT Chowdhury S Arghandawi J Brand OO Akanji DL Bader DM Salter DA Lee 《Arthritis research & therapy》2008,10(2):R35
Background
Nitric oxide and prostaglandin E2 (PGE2play pivotal roles in both the pathogenesis of osteoarthritis and catabolic processes in articular cartilage. These mediators are influenced by both IL-1β and mechanical loading, and involve alterations in the inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 enzymes. To identify the specific interactions that are activated by both types of stimuli, we examined the effects of dynamic compression on levels of expression of iNOS and COX-2 and involvement of the p38 mitogen-activated protein kinase (MAPK) pathway. 相似文献27.
Horizontal transmission, vertical inactivation, and stochastic loss of mariner-like transposable elements 总被引:8,自引:5,他引:8
Horizontal transmission has been well documented as a major mechanism for
the dissemination of mariner-like elements (MLEs) among species. Less well
understood are mechanisms that limit vertical transmission of MLEs
resulting in the "spotty" or discontinuous distribution observed in closely
related species. In this article we present evidence that the genome of the
common ancestor of the melanogaster species subgroup of Drosophila
contained an MLE related to the mellifera (honey bee) subfamily. Horizontal
transmission, approximately 3-10 MYA, is strongly suggested by the
observation that the sequence of the MLE in Drosophila erecta is 97%
identical in nucleotide sequence with that of an MLE in the cat flea,
Ctenocephalides felis. The D. erecta MLE has a spotty distribution among
species in the melanogaster subgroup. The element has a high copy number in
D. erecta and D. orena, a moderate copy number in D. teissieri and D.
yakuba, and was apparently lost ("stochastic loss") in the lineage leading
to D. melanogaster, D. simulans, D. mauritiana, and D. sechellia. In D.
erecta, most copies are concentrated in the heterochromatin. Two copies
from D. erecta, denoted De12 and De19, were cloned and sequenced, and they
appear to be nonfunctional ("vertical inactivation"). It therefore appears
that the predominant mode of MLE evolution is vertical inactivation and
stochastic loss balanced against occasional reinvasion of lineages by
horizontal transmission.
相似文献
28.
29.
Nonrandom location of IS1 elements in the genomes of natural isolates of Escherichia coli 总被引:2,自引:0,他引:2
We have studied the spatial distribution of IS1 elements in the genomes of
natural isolates comprising the ECOR reference collection of Escherichia
coli. We find evidence for nonrandomness at three levels. Many pairs of IS1
elements are in much closer proximity (< 10 kb) than can be accounted
for by chance. IS1 elements in close proximity were identified by
long-range PCR amplification of the genomic sequence between them. Each
amplified region was sequenced and its map location determined by database
screening of DNA hybridization. Among the ECOR strains with at least two
IS1 elements, 54% had one or more pairs of elements separated by < 10
kb. We propose that this type of clustering is a result of "local hopping,"
in which we assume that a significant proportion of tranposition events
leads to the insertion of a daughter IS element in the vicinity of the
parental element. A second level of nonrandomness is found in strains with
a modest number of IS1 elements that are mapped through the use of inverse
PCR to amplify flanking genomic sequences: in these strains, the insertion
sites tend to be clustered over a smaller region of chromosome than would
be expected by chance. A third level of nonrandomness is observed in the
composite distribution of IS elements across strains: among 20 mapped IS1
elements, none were found in the region of 48-77 minutes, a significant
gap. One region of the E. coli chromosome, at 98 min, had a cluster of IS1
elements in seven ECOR strains of diverse phylogenetic origin. We deduce
from sequence analysis that this pattern of distribution is a result of
initial insertion in the most recent common ancestor of these strains and
therefore not a hot spot of insertion. Analysis using long- range PCR with
primers for IS2 and IS3 also yielded pairs of elements in close proximity,
suggesting that these elements may also occasionally transpose by local
hopping.
相似文献
30.
Incorporation of axonally transported glycoproteins into axolemma during nerve regeneration 总被引:10,自引:4,他引:10 下载免费PDF全文
The insertion of axonally transported fucosyl glycoproteins into the axolemma of regenerating nerve sprouts was examined in rat sciatic motor axons at intervals after nerve crush. [(3)H]Fucose was injected into the lumbar ventral horns and the nerves were removed at intervals between 1 and 14 d after labeling. To follow the fate of the “pulse- labeled” glycoproteins, we examined the nerves by correlative radiometric and EM radioautographic approaches. The results showed, first, that rapidly transported [(3)H]fucosyl glycoproteins were inserted into the axolemma of regenerating sprouts as well as parent axons. At 1 d after delivery, in addition to the substantial mobile fraction of radioactivity still undergoing bidirectional transport within the axon, a fraction of label was already associated with the axolemma. Insertion of labeled glycoproteins into the sprout axolemma appeared to occur all along the length of the regenerating sprouts, not just in sprout terminals. Once inserted, labeled glycoproteins did not undergo extensive redistribution, nor did they appear in sprout regions that formed (as a result of continued outgrowth) after their insertion. The amount of radioactivity in the regenerating nerves decreased with time, in part as a result of removal of transported label by retrograde transport. By 7-14 d after labeling, radioautography showed that almost all the remaining radioactivity was associated with axolemma. The regenerating sprouts retained increased amounts of labeled glycoproteins; 7 or 14 d after labeling, the regenerating sprouts had over twice as much of radioactivity as comparable lengths of control nerves or parent axons. One role of fast axonal transport in nerve regeneration is the contribution to the regenerating sprout of glycoproteins inserted into the axolemma; these membrane elements are added both during longitudinal outgrowth and during lateral growth and maturation of the sprout. 相似文献