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61.
Diet‐induced Renal Changes in Zucker Rats Are Ameliorated by the Superoxide Dismutase Mimetic TEMPOL
Philip J. Ebenezer Nithya Mariappan Carrie M. Elks Masudul Haque Joseph Francis 《Obesity (Silver Spring, Md.)》2009,17(11):1994-2002
Diabetic nephropathy is the leading cause of renal failure in the United States. The obese Zucker rat (OZR; fa/fa) is a commonly used model of type 2 diabetes and metabolic syndrome (MetS), and of the nephropathy and renal oxidative stress commonly seen in these disorders. Heterozygous lean Zucker rats (LZRs; fa/+) are susceptible to high‐fat diet (HFD)‐induced obesity and MetS. The present study was designed to investigate whether 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐N‐oxyl (TEMPOL), a membrane‐permeable radical scavenger, could alleviate the renal effects of MetS in OZR and LZR fed a HFD, which resembles the typical “Western” diet. OZR and LZR were fed a HFD (OZR‐HFD and LZR‐HFD) or regular diet (OZR‐RD and LZR‐RD) and allowed free access to drinking water or water containing 1 mmol/l TEMPOL for 10 weeks. When compared to OZR‐RD animals, OZR‐HFD animals exhibited significantly higher levels of total renal cortical reactive oxygen species (ROS) production, plasma lipids, insulin, C‐reactive protein, blood urea nitrogen (BUN), creatinine (Cr), and urinary albumin excretion (P < 0.05); these changes were accompanied by a significant decrease in plasma high‐density lipoprotein levels (P < 0.05). The mRNA expression levels of desmin, tumor necrosis factor‐α (TNF‐α), nuclear factor κB (NFκB), and NAD(P)H oxidase‐1 (NOX‐1) were significantly higher in the renal cortical tissues of OZR‐HFD animals; NFκB p65 DNA binding activity as determined by electrophoretic mobility shift assay was also significantly higher in these animals. The same trends were noted in LZR‐HFD animals. Our data demonstrate that TEMPOL may prove beneficial in treating the early stages of the nephropathy often associated with MetS. 相似文献
62.
Wenying Wang Maria Cristina Perez Flores Choong-Ryoul Sihn Hyo Jeong Kim Yinuo Zhang Karen J. Doyle Nipavan Chiamvimonvat Xiao-Dong Zhang Ebenezer N. Yamoah 《The Journal of general physiology》2015,145(3):201-212
Kv7.1 voltage-gated K+ (Kv) channels are present in the apical membranes of marginal cells of the stria vascularis of the inner ear, where they mediate K+ efflux into the scala media (cochlear duct) of the cochlea. As such, they are exposed to the K+-rich (∼150 mM of external K+ (K+e)) environment of the endolymph. Previous studies have shown that Kv7.1 currents are substantially suppressed by high K+e (independent of the effects of altering the electrochemical gradient). However, the molecular basis for this inhibition, which is believed to involve stabilization of an inactivated state, remains unclear. Using sequence alignment of S5-pore linkers of several Kv channels, we identified a key residue, E290, found in only a few Kv channels including Kv7.1. We used substituted cysteine accessibility methods and patch-clamp analysis to provide evidence that the ability of Kv7.1 to sense K+e depends on E290, and that the charge at this position is essential for Kv7.1’s K+e sensitivity. We propose that Kv7.1 may use this feedback mechanism to maintain the magnitude of the endocochlear potential, which boosts the driving force to generate the receptor potential of hair cells. The implications of our findings transcend the auditory system; mutations at this position also result in long QT syndrome in the heart. 相似文献
63.
64.
Xiaojing Wang Snezana Levic Michael Anne Gratton Karen Jo Doyle Ebenezer N. Yamoah Anthony E. Pegg 《The Journal of biological chemistry》2009,284(2):930-937
Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the
SpmS and Phex genes, were found to be profoundly hearing
impaired. This defect was due to alteration in polyamine content due to the
absence of spermine synthase, the product of the SpmS gene. It was
reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that
ubiquitously expresses spermine synthase under the control of a composite
cytomegalovirus-IE enhancer/chicken β-actin promoter. There was an almost
complete loss of the endocochlear potential in the Gy mice, which parallels
the hearing deficiency, and this was also reversed by the production of
spermine from the spermine synthase transgene. Gy mice showed a striking toxic
response to treatment with the ornithine decarboxylase inhibitor
α-difluoromethylornithine (DFMO). Within 2–3 days of exposure to
DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor
function resulting in death within 5 days. This effect was due to an inability
to maintain normal balance and was also prevented by the transgenic expression
of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no
effect on balance. The loss of balance in Gy mice treated with DFMO was due to
inhibition of polyamine synthesis because it was prevented by administration
of putrescine. Our results are consistent with a critical role for polyamines
in regulation of Kir channels that maintain the endocochlear potential and
emphasize the importance of normal spermidine:spermine ratio in the hearing
and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes
for ornithine decarboxylase and S-adenosylmethionine decarboxylase,
which are enzymes needed for the synthesis of putrescine, spermidine, and
spermine, are lethal at early stages of embryonic development
(1,
2). There is convincing
evidence that the formation of hypusine in eIF5A, which requires spermidine as
a precursor, is essential for eukaryotes
(3). However, the function(s)
of spermine is not so well established. Yeast mutants with inactivated
spermine synthase grow at a normal rate
(4). Mammalian cells in culture
also grow normally in the presence of inhibitors of spermine synthase
(5) or after inactivation of
the spermine synthase gene (SpmS)
(6–8).
Inactivation of both of the genes that were originally described as encoding
spermine synthases in plants leads to profound developmental defects
(9–11),
but recently it was discovered that one of these genes actually encodes a
thermospermine synthase, and it appears that the lack of thermospermine may be
responsible for these defects
(12).In contrast, spermine is clearly required for normal development in
mammals. The rare human Snyder-Robinson syndrome is caused by mutations in
SpmS located in the X chromosome that drastically reduces the amount
of spermine synthase (13,
14). This leads to mental
retardation, hypotonia, cerebellar circuitry dysfunction, facial asymmetry,
thin habitus, osteoporosis, and kyphoscoliosis. Male mice, which have an X
chromosomal deletion that includes SpmS and have no detectable
spermine synthase activity, do survive but are only viable on the B6C3H
background
(15–17).
This mouse strain having an X-linked dominant mutation was isolated from a
female offspring of an irradiated mouse and was termed gyro
(Gy)2 based on a
circling behavior pattern in affected males
(18). Subsequent studies have
shown that the Gy mice have a deletion of part of the X chromosome that
inactivates both Phex, a gene that regulates phosphate metabolism,
and SpmS (16,
19). The lack of SpmS
causes a total absence of spermine
(6,
7,
15,
16). Such Gy mice suffer from
hypophosphatemia, have a greatly reduced size, sterility, and neurological
abnormalities, and have a short life span
(6,
16,
18). All of these changes
except the hypophosphatemia are reversed when spermine synthase activity is
restored (20).The original characterization of Gy mice also reported preliminary
indications that these mice had hearing defects lacking the Preyer reflex
(21,
22). This is of particular
interest in the context of polyamine metabolism because a drug,
α-difluoromethylornithine (DFMO, Eflornithine), that targets ornithine
decarboxylase has been shown to cause occasional hearing loss in some patients
(23–26).
Although DFMO was ineffective for cancer treatment, it is an extremely
promising agent for cancer chemoprevention
(27,
28). When combined with
sulindac, DFMO treatment produced a substantial reduction in the recurrence of
colorectal adenomas in a large clinical trial
(27). DFMO is a major drug for
the treatment of African sleeping sickness caused by Trypanosoma
brucei (29,
30). It is also used as a
topically applied cream for treatment of unwanted facial hair in women
(31,
32). DFMO is generally well
tolerated even at high doses, but reversible hearing loss has been reported in
multiple clinical trials (25,
33), and a rarer irreversible
defect has also been reported
(34). These side effects are
not observed at lower doses of DFMO
(26,
27).Ototoxicity has been demonstrated to occur in experimental animals treated
with DFMO including rats (35),
guinea pigs (36), gerbils
(37), and mice
(38). Using
immunohistochemistry, a high level of ornithine decarboxylase was observed in
the inner ear of the rat, with the highest in the organ of Corti and lateral
wall followed by the cochlear nerve
(39). Measurements of
polyamines in the relevant structures are very difficult due to the small
amount of tissue available, but as expected, DFMO treatment reduced polyamine
levels and ornithine decarboxylase activity in the inner ear of the guinea pig
(36). A plausible explanation
for the importance of polyamines in auditory physiology is based on their well
documented role as regulators of potassium channels
(38). The inward rectification
of Kir channels is caused by blockage of the outward current by polyamines
(40–42).
Studies of the cloned mouse cochlear lateral wall-specific Kir4.1 channel
showed that inward rectification was reduced and that there was a marked
reduction in endocochlear potential (EP). It was proposed that DFMO treatment
increases the outward Kir4.1 current, resulting in a drop in EP
(38).In the experiments reported here, we have studied in more detail the role
of polyamines in auditory physiology using Gy mice and crosses of these mice
with transgenic CAG/SpmS mice
(43). These mice express
spermine synthase under the control of a composite cytomegalovirus-IE
enhancer/chicken β-actin promoter, which was designed to provide
ubiquitous expression
(44–46).
Assays of the spermine synthase activity in CAG/SpmS line 8 confirmed that
there was a high level of expression of the transgene in many different organs
and that this level was maintained for at least 1 year
(43). Our studies confirm that
Gy mice are totally deaf and that this condition is reversed by the expression
of the SpmS gene. These changes are due to a virtually complete loss
of the EP in the Gy mice. We have also examined the effect of DFMO on the Gy
mice. Unexpectedly, it was found that these mice show a rapid and profound
toxicity to this drug, leading to death within a few days. Within 5 days of
exposure to DFMO in the drinking water, the DFMO-treated mice suffered a
catastrophic loss of balance due to inner ear effects. This toxicity was also
prevented by the transgenic expression of spermine synthase in the Gy
background. 相似文献
65.
Wenying Wang Hyo Jeong Kim Jeong-Han Lee Victor Wong Choong-Ryoul Sihn Ping Lv Maria Cristina Perez Flores Atefeh Mousavi-Nik Karen Jo Doyle Yanfang Xu Ebenezer N. Yamoah 《The Journal of biological chemistry》2014,289(24):16802-16813
The KCNE3 β-subunit interacts with and regulates the voltage-dependent gating, kinetics, and pharmacology of a variety of Kv channels in neurons. Because a single neuron may express multiple KCNE3 partners, it is impossible to predict the overall functional relevance of the single transmembrane domain peptide on the pore-forming K+ channel subunits with which it associates. In the inner ear, the role of KCNE3 is undefined, despite its association with Meniere disease and tinnitus. To gain insights on the functional significance of KCNE3 in auditory neurons, we examined the properties of spiral ganglion neurons (SGNs) in Kcne3 null mutant neurons relative to their age-matched controls. We demonstrate that null deletion of Kcne3 abolishes characteristic wide variations in the resting membrane potentials of SGNs and yields age-dependent alterations in action potential and firing properties of neurons along the contour of the cochlear axis, in comparison with age-matched wild-type neurons. The properties of basal SGNs were markedly altered in Kcne3−/− mice compared with the wild-type controls; these include reduced action potential latency, amplitude, and increased firing frequency. Analyses of the underlying conductance demonstrate that null mutation of Kcne3 results in enhanced outward K+ currents, which is sufficient to explain the ensuing membrane potential changes. Additionally, we have demonstrated that KCNE3 may regulate the activity of Kv4.2 channels in SGNs. Finally, there were developmentally mediated compensatory changes that occurred such that, by 8 weeks after birth, the electrical properties of the null mutant neurons were virtually indistinguishable from the wild-type neurons, suggesting that ion channel remodeling in auditory neurons progresses beyond hearing onset. 相似文献
66.
Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts 总被引:5,自引:0,他引:5
Xu Y Tuteja D Zhang Z Xu D Zhang Y Rodriguez J Nie L Tuxson HR Young JN Glatter KA Vázquez AE Yamoah EN Chiamvimonvat N 《The Journal of biological chemistry》2003,278(49):49085-49094
67.
High-throughput genomic technologies enable researchers to identify genes that are co-regulated with respect to specific experimental conditions. Numerous statistical approaches have been developed to identify differentially expressed genes. Because each approach can produce distinct gene sets, it is difficult for biologists to determine which statistical approach yields biologically relevant gene sets and is appropriate for their study. To address this issue, we implemented Latent Semantic Indexing (LSI) to determine the functional coherence of gene sets. An LSI model was built using over 1 million Medline abstracts for over 20,000 mouse and human genes annotated in Entrez Gene. The gene-to-gene LSI-derived similarities were used to calculate a literature cohesion p-value (LPv) for a given gene set using a Fisher's exact test. We tested this method against genes in more than 6,000 functional pathways annotated in Gene Ontology (GO) and found that approximately 75% of gene sets in GO biological process category and 90% of the gene sets in GO molecular function and cellular component categories were functionally cohesive (LPv<0.05). These results indicate that the LPv methodology is both robust and accurate. Application of this method to previously published microarray datasets demonstrated that LPv can be helpful in selecting the appropriate feature extraction methods. To enable real-time calculation of LPv for mouse or human gene sets, we developed a web tool called Gene-set Cohesion Analysis Tool (GCAT). GCAT can complement other gene set enrichment approaches by determining the overall functional cohesion of data sets, taking into account both explicit and implicit gene interactions reported in the biomedical literature. Availability: GCAT is freely available at http://binf1.memphis.edu/gcat. 相似文献
68.
Lin YW Lin HY Tsou YL Chitra E Hsiao KN Shao HY Liu CC Sia C Chong P Chow YH 《PloS one》2012,7(1):e30507
Enterovirus (EV) 71 infection is known to cause hand-foot-and-mouth disease (HFMD) and in severe cases, induces neurological disorders culminating in fatality. An outbreak of EV71 in South East Asia in 1997 affected over 120,000 people and caused neurological disorders in a few individuals. The control of EV71 infection through public health interventions remains minimal and treatments are only symptomatic. Recently, human scavenger receptor class B, member 2 (SCARB2) has been reported to be a cellular receptor of EV71. We expressed human SCARB2 gene in NIH3T3 cells (3T3-SCARB2) to study the mechanisms of EV71 entry and infection. We demonstrated that human SCARB2 serves as a cellular receptor for EV71 entry. Disruption of expression of SCARB2 using siRNAs can interfere EV71 infection and subsequent inhibit the expression of viral capsid proteins in RD and 3T3-SCARB2 but not Vero cells. SiRNAs specific to clathrin or dynamin or chemical inhibitor of clathrin-mediated endocytosis were all capable of interfering with the entry of EV71 into 3T3-SCARB2 cells. On the other hand, caveolin specific siRNA or inhibitors of caveolae-mediated endocytosis had no effect, confirming that only clathrin-mediated pathway was involved in EV71 infection. Endocytosis of EV71 was also found to be pH-dependent requiring endosomal acidification and also required intact membrane cholesterol. In summary, the mechanism of EV71 entry through SCARB2 as the receptor for attachment, and its cellular entry is through a clathrin-mediated and pH-dependent endocytic pathway. This study on the receptor and endocytic mechanisms of EV71 infection is useful for the development of effective medications and prophylactic treatment against the enterovirus. 相似文献
69.
C. Brad Wilson Leslie D. McLaughlin Anand Nair Philip J. Ebenezer Rahul Dange Joseph Francis 《PloS one》2013,8(10)
This study sought to analyze specific pathophysiological mechanisms involved in the progression of post-traumatic stress disorder (PTSD) by utilizing an animal model. To examine PTSD pathophysiology, we measured damaging reactive oxygen species and inflammatory cytokines to determine if oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation were upregulated in response to constant stress. Pre-clinical PTSD was induced in naïve, male Sprague-Dawley rats via a predator exposure/psychosocial stress regimen. PTSD group rats were secured in Plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen. In addition, PTSD group rats were subjected to psychosocial stress whereby their cage cohort was changed daily. This model has been shown to cause heightened anxiety, exaggerated startle response, impaired cognition, and increased cardiovascular reactivity, all of which are common symptoms seen in humans with PTSD. At the conclusion of the predator exposure/psychosocial stress regimen, the rats were euthanized and their brains were dissected to remove the hippocampus, amygdala, and pre-frontal cortex (PFC), the three areas commonly associated with PTSD development. The adrenal glands and whole blood were also collected to assess systemic oxidative stress. Analysis of the whole blood, adrenal glands, and brain regions revealed oxidative stress increased during PTSD progression. In addition, examination of pro-inflammatory cytokine (PIC) mRNA and protein demonstrated neurological inflammatory molecules were significantly upregulated in the PTSD group vs. controls. These results indicate oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation may play a critical role in the development and further exacerbation of PTSD. Thus, PTSD may not be solely a neurological pathology but may progress as a systemic condition involving multiple organ systems. 相似文献
70.
E N Vithana L Abu-Safieh M J Allen A Carey M Papaioannou C Chakarova M Al-Maghtheh N D Ebenezer C Willis A T Moore A C Bird D M Hunt S S Bhattacharya 《Molecular cell》2001,8(2):375-381
We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138). A positional cloning approach supported by bioinformatics identified PRPF31 comprising 14 exons and encoding a protein of 499 amino acids. The level of sequence identity to the yeast PRP31 gene indicates that PRPF31 is also likely to be involved in pre-mRNA splicing. Mutations that include missense substitutions, deletions, and insertions have been identified in four RP11-linked families and three sporadic RP cases. The identification of mutations in a pre-mRNA splicing gene implicates defects in the splicing process as a novel mechanism of photoreceptor degeneration. 相似文献