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1.
Chuncheng Lu Miaofei Xu Ying Wang Yufeng Qin Guizhen Du Wei Wu Xiumei Han Chao Ji Yanli Yang Aihua Gu Yankai Xia Ling Song Shoulin Wang Xinru Wang 《PloS one》2013,8(1)
Background
The meiotic program initiation pathway genes (CYP26B1, NANOS1 and STRA8) have been proposed to play key roles in spermatogenesis.Objective
To elucidate the exact role of the genetic variants of the meiosis initiation genes in spermatogenesis, we genotyped the potential functional genetic variants of CYP26B1, NANOS1 and STRA8 genes, and evaluated their effects on spermatogenesis in our study population.Design, Setting, and Participants
In this study, all subjects were volunteers from the affiliated hospitals of Nanjing Medical University between March 2004 and July 2009 (NJMU Infertile Study). Total 719 idiopathic infertile cases were recruited and divided into three groups according to WHO semen parameters: 201 azoospermia patients (no sperm in the ejaculate even after centrifugation), 155 oligozoospermia patients (sperm counts <20×106/ml) and 363 infertility/normozoospermia subjects (sperm counts >20×106/ml). The control group consisted of 383 subjects with normal semen parameters, all of which had fathered at least one child without assisted reproductive technologies.Measurements
Eight single nucleotide polymorphisms (SNPs) in CYP26B1, NANOS1 and STRA8 genes were determined by TaqMan allelic discrimination assay in 719 idiopathic infertile men and 383 healthy controls.Results and Limitations
The genetic variant rs10269148 of STRA8 gene showed higher risk of spermatogenic impairment in the groups of abnormospermia (including azoospermia subgroup and oligozoospermia subgroup) and azoospermia than the controls with odds ratios and 95% confidence intervals of 2.52 (1.29–4.94) and 2.92 (1.41–6.06), respectively (P = 0.006, 0.002 respective). Notably, larger sample size studies and in vivo or in vitro functional studies are needed to substantiate the biological roles of these variants.Conclusions
Our results provided epidemiological evidence supporting the involvement of genetic polymorphisms of the meiotic program initiation genes in modifying the risk of azoospermia and oligozoospermia in a Han-Chinese population. 相似文献2.
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Background
Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis.Methodology/Principal Finding
We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm.Conclusions
This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line. 相似文献5.
Background
In Malaysia, researchers and medical practitioners are unfamiliar with Naegleria infections. Thus little is known about the existence of pathogenic Naegleria fowleri, and the resultant primary amoebic meningoencephalitis (PAM) is seldom included in the differential diagnosis of central nervous system infections. This study was conducted to detect the presence of Naegleria species in various environmental samples.Methods/Findings
A total of 41 Naegleria-like isolates were isolated from water and dust samples. All these isolates were subjected to PCR using two primer sets designed from the ITS1-ITS2 regions. The N. fowleri species-specific primer set failed to produce the expected amplicon. The Naegleria genus-specific primers produced amplicons of 408 bp (35), 450 bp (2), 457 bp (2) or 381 bp (2) from all 41 isolates isolated from aquatic (33) and dust (8) samples. Analysis of the sequences from 10 representative isolates revealed that amplicons with fragments 408, 450 and 457 bp showed homology with non-pathogenic Naegleria species, and 381 bp showed homology with Vahlkampfia species. These results concurred with the morphological observation that all 39 isolates which exhibited flagella were Naegleria, while 2 isolates (AC7, JN034055 and AC8, JN034056) that did not exhibit flagella were Vahlkampfia species.Conclusion
To date, pathogenic species of N. fowleri have not been isolated from Malaysia. All 39 isolates that produced amplicons (408, 450 and 457 bp) from the genus-specific primers were identified as being similar to nonpathogenic Naegleria. Amplicon 408 bp from 5 representative isolates showed 100% and 99.7% identity to Naegleria philippinensis isolate RJTM (AM167890) and is thus believed to be the most common species in our environment. Amplicons 450 bp and 457 bp were respectively believed to be from 2 new species of Naegleria, since representative isolates showed lower homology and had a longer base pair length when compared to the reference species in the Genbank, Naegleria schusteri (AJ566626) and Naegleria laresi (AJ566630), respectively. 相似文献6.
Abjal Pasha Shaik Abbas H Alsaeed S Kiranmayee VK Bammidi Asma Sultana 《Bioinformation》2013,9(1):29-36
Cubilin, (CUBN; also known as intrinsic factor-cobalamin receptor [Homo sapiens Entrez Pubmed ref NM_001081.3; NG_008967.1;
GI: 119606627]), located in the epithelium of intestine and kidney acts as a receptor for intrinsic factor – vitamin B12 complexes.
Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. The current study investigated the possible role
of CUBN in evolution using phylogenetic testing. A total of 588 BLAST hits were found for the cubilin query sequence and these
hits showed putative conserved domain, CUB superfamily (as on 27th Nov 2012). A first-pass phylogenetic tree was constructed to
identify the taxa which most often contained the CUBN sequences. Following this, we narrowed down the search by manually
deleting sequences which were not CUBN. A repeat phylogenetic analysis of 25 taxa was performed using PhyML, RAxML and
TreeDyn softwares to confirm that CUBN is a conserved protein emphasizing its importance as an extracellular domain and being
present in proteins mostly known to be involved in development in many chordate taxa but not found in prokaryotes, plants and
yeast.. No horizontal gene transfers have been found between different taxa. 相似文献
7.
Zito CR Jilaveanu LB Anagnostou V Rimm D Bepler G Maira SM Hackl W Camp R Kluger HM Chao HH 《PloS one》2012,7(2):e31331
Introduction
We assessed expression of p85 and p110α PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines.Methods
Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor, NVP-BEZ235 alone and with an EGFR inhibitor.Results
p85 and p110α tend to be co-expressed (p<0.001); p85 expression was higher in adenocarcinomas than squamous cell carcinomas. High p85 expression was associated with advanced stage and poor survival. p110α expression correlated with mTOR (ρ = 0.276). In six NSCLC cell lines, addition of rapamycin to LY294002 or NVP-BKM120 was synergistic. Even very low rapamycin concentrations (1 nM) resulted in sensitization to PI3K inhibitors. NVP-BEZ235 was highly active in NSCLC cell lines with IC50s in the nanomolar range and resultant down-regulation of pAKT and pP70S6K. Adding Erlotinib to NVP-BEZ235 resulted in synergistic growth inhibition.Conclusions
The association between PI3K expression, advanced stage and survival in NSCLC suggests that it might be a valuable drug target. Concurrent inhibition of PI3K and mTOR is synergistic in vitro, and a dual PI3K/mTOR inhibitor was highly active. Adding EGFR inhibition resulted in further growth inhibition. Targeting the PI3K/AKT/mTOR pathway at multiple levels should be tested in clinical trials for NSCLC. 相似文献8.
Bianca Bianco Milton Ghirelli-Filho Camila M. Cavalheiro Viviane Cavalcanti Carla Peluso Marcello M. Gava Sidney Glina Denise M. Christofolini Caio P. Barbosa 《Gene》2013
Purpose
In recent years, considerable concern has been expressed about the deleterious effects of reactive oxygen species (ROS) on sperm function, because ROS at high levels is potentially detrimental to sperm function and quality. Nitric oxide (NO) is a powerful anti-oxidant present in seminal plasma. The aim of the study was to analyze the distribution of the of endothelial nitric oxide synthase (eNOS) gene (T-786C, G894T, e 4a/b) polymorphisms in idiopathic infertile Brazilian men and evaluate the possible role of these polymorphisms in sperm count.Methods
A case–control study was performed comprising 208 infertile men [n = 74 with non-obstructive azoospermia and n = 134 with severe oligozoospermia] and 201 fertile men as controls. Genotyping of eNOS polymorphisms was performed by real time (T-786C and G894T) and conventional PCR (4a/b). The results were analyzed statistically and a p-value < 0.05 was considered significant.Results
According to the sperm count, relatively similar eNOS polymorphism genotypes and allele frequencies were found among the groups. Combined genotypes of the eNOS polymorphisms did not identify a haplotype associated with idiopathic infertility, even when the patients were separated in non-obstructive azoospermia or severe oligozoospermia.Conclusion
In conclusion, the findings demonstrate that, in Brazilian population studied, genetic variations, T-786C, G894T, and e 4a/b, of the eNOS gene are not associated with male infertility. 相似文献9.
Background
Resistance to trastuzumab is a clinical problem, partly due to overriding activation of MAPK/PI3K signalling. Sprouty-family proteins are negative regulators of MAPK/PI3K signalling, but their role in HER2-therapy resistance is unknown.Patients and Methods
Associations between Sprouty gene expression and clinicopathological features were investigated in a breast cancer microarray meta-analysis. Changes in expression of Spry2 and feedback inhibition on trastuzumab resistance were studied in SKBr3 and BT474 breast carcinoma cell lines using cell viability assays. Spry2 protein expression was measured by quantitative immunofluorescence in a cohort of 122 patients treated with trastuzumab.Results
Low gene expression of Spry2 was associated with increased pathological grade, high HER2 expression, and was a significant independent prognostic factor. Overexpression of Spry2 in SKBr3s resulted in enhanced inhibition of cell viability after trastuzumab treatment, and the PI3K-inhibitor LY294002 had a similar effect. Low Spry2 expression was associated with increased risk of death (HR = 2.28, 95% CI 1.22–4.26; p = 0.008) in trastuzumab-treated patients, including in multivariate analysis. Stratification of trastuzumab-treated patients using PTEN and Spry2 was superior to either marker in isolation.Conclusion
In breast cancers with deficient feedback inhibition, combinatorial therapy with negative regulators of growth factor signalling may be an effective therapeutic strategy. 相似文献10.
Caglayan E Romeo GR Kappert K Odenthal M Südkamp M Body SC Shernan SK Hackbusch D Vantler M Kazlauskas A Rosenkranz S 《PloS one》2010,5(10):e13608
Background
Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo.Methodology
Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans.Principal Findings
In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10−6 M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70S6 kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group).Conclusions
Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target. 相似文献11.
VE Martins CH Alencar MT Kamimura FM de Carvalho Araújo SG De Simone RF Dutra MI Guedes 《PloS one》2012,7(7):e41386
Background
Aedes aegypti and Aedes albopictus perform an important role in the transmission of the dengue virus to human populations, particularly in the tropical and subtropical regions of the world. Despite a lack of understanding in relation to the maintenance of the dengue virus in nature during interepidemic periods, the vertical transmission of the dengue virus in populations of A. aegypti and A. albopictus appears to be of significance in relation to the urban scenario of Fortaleza.Methods
From March 2007 to July 2009 collections of larvae and pupae of Aedes spp were carried out in 40 neighborhoods of Fortaleza. The collections yielded 3,417 (91%) A. aegypti mosquitoes and 336 (9%) A. albopictus mosquitoes. Only pools containing females, randomly chosen, were submitted to the following tests indirect immunofluorescence (virus isolation), RT-PCR/nested-PCR and nucleotide sequencing at the C-prM junction of the dengue virus genome.Results
The tests on pool 34 (35 A. albopictus mosquitoes) revealed with presence of DENV-3, pool 35 (50 A. aegypti mosquitoes) was found to be infected with DENV-2, while pool 49 (41 A. albopictus mosquitoes) revealed the simultaneous presence of DENV-2 and DENV-3. Based on the results obtained, there was a minimum infection rate of 0.5 for A. aegypti and 9.4 for A. albopictus. The fragments of 192 bp and 152 bp related to DENV-3, obtained from pools 34 and 49, was registered in GenBank with the access codes HM130699 and JF261696, respectively.Conclusions
This study recorded the first natural evidence of the vertical transmission of the dengue virus in populations of A. aegypti and A. albopictus collected in Fortaleza, Ceará State, Brazil, opening a discuss on the epidemiological significance of this mechanism of viral transmission in the local scenario, particularly with respect to the maintenance of these viruses in nature during interepidemic periods. 相似文献12.
13.
The keratinase degrade highly rigid, cross linked structural polypeptides with different efficiency depending on the type of source. Two newly isolated strains of Bacillus subtilis (RSE163 and RSE165; NCBI Accession no JQ887983 and JQ887982) were found to be efficient keratinase producers with unusual catalytic activity result in different morphological changes in degradation pattern of feather, confirmed by their scanned electron micrographs. Maximum keratinolytic activity of both the strains B. subtilis RSE163 and RSE165 were found to be 366 ± 15.79 and 194 ± 7.26 U after 72 h of incubation. While the disulphide reductase activity of RSE163 and RSE165 estimated 0.24 ± 0.05 and 0.15 ± 0.03 U/ml of enzyme after 24 h of incubation. A total of 16 free amino acids of variable concentration were also analyzed in the cell free supernatant of hydrolyzed feather from two strains. Present study demonstrates the action of two different keratinases in feather degradation.
Electronic supplementary material
The online version of this article (doi:10.1007/s12088-014-0477-5) contains supplementary material, which is available to authorized users. 相似文献14.
Baumeister S Wiesner J Reichenberg A Hintz M Bietz S Harb OS Roos DS Kordes M Friesen J Matuschewski K Lingelbach K Jomaa H Seeber F 《PloS one》2011,6(5):e19334
Background
Highly charged compounds typically suffer from low membrane permeability and thus are generally regarded as sub-optimal drug candidates. Nonetheless, the highly charged drug fosmidomycin and its more active methyl-derivative FR900098 have proven parasiticidal activity against erythrocytic stages of the malaria parasite Plasmodium falciparum. Both compounds target the isoprenoid biosynthesis pathway present in bacteria and plastid-bearing organisms, like apicomplexan parasites. Surprisingly, the compounds are inactive against a range of apicomplexans replicating in nucleated cells, including Toxoplasma gondii.Methodology/Principal Findings
Since non-infected erythrocytes are impermeable for FR90098, we hypothesized that these drugs are taken up only by erythrocytes infected with Plasmodium. We provide evidence that radiolabeled FR900098 accumulates in theses cells as a consequence of parasite-induced new properties of the host cell, which coincide with an increased permeability of the erythrocyte membrane. Babesia divergens, a related parasite that also infects human erythrocytes and is also known to induce an increase in membrane permeability, displays a similar susceptibility and uptake behavior with regard to the drug. In contrast, Toxoplasma gondii-infected cells do apparently not take up the compounds, and the drugs are inactive against the liver stages of Plasmodium berghei, a mouse malaria parasite.Conclusions/Significance
Our findings provide an explanation for the observed differences in activity of fosmidomycin and FR900098 against different Apicomplexa. These results have important implications for future screens aimed at finding new and safe molecular entities active against P. falciparum and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery. 相似文献15.
Background
Pten functionally acts as a tumor suppressor gene. Lately, tissue-specific ablation of Pten gene in mice has elucidated the role of Pten in different tumor progression models. However, a temporally controlled Pten loss in all adult tissues to examine susceptibility of various tissues to Pten-deficient tumorigenesis has not been addressed yet. Our goal was to explore the genesis of Pten-deficient malignancies in multiple tissue lineages of the adult mouse.Methods and Findings
We utilized an inducible Cre/loxP system to delete Pten exon 5 in the systemic organs of ROSA26 (R26)-CreERT;Ptenfx/fx mice. On reaching 45 weeks 4OHT-induced Pten loss, we found that the R26-CreERT;Ptenfx/fx mice developed a variety of malignancies. Overall tumor mean latency was 17 weeks in the Pten-deficient mice. Interestingly, mutant females developed malignancies more quickly at 10∼11 weeks compared with a tumor latency of 21 weeks for mutant males. Lymphoma incidence (76.9% in females; 40.0% in males) was higher than the other malignancies found in the mutant mice. Mutant males developed prostate (20.0%), intestinal cancer (35.0%) and squamous cell carcinoma (10.0%), whereas the mutant females developed squamous cell carcinoma (15.4%) and endometrial cancer (46.1%) in addition to lymphomas. Furthermore, we tested the pharmacological inhibition of the PTEN downstream effectors using LY294002 on Pten-deficient prostate hyperplasia. Our data revealed that, indeed, the prostate hyperplasia resulting from the induced Pten loss was significantly suppressed by LY294002 (p = 0.007).Conclusions
Through monitoring a variety of Pten-deficient tumor formation, our results revealed that the lymphoid lineages and the epithelium of the prostate, endometrium, intestine and epidermis are highly susceptible to tumorigenesis after the Pten gene is excised. Therefore, this R26-CreERT; Ptenfx/fx mouse model may provide an entry point for understanding the role of Pten in the tumorigenesis of different organs and extend the search for potential therapeutic approaches to prevent Pten-deficient malignancies. 相似文献16.
Yu Qi Qiao Mei Lan Huang An Tao Xu Di Zhao Zhi Hua Ran Jun Shen 《Journal of biomedical science》2013,20(1):87
Background
Long non-coding RNAs (lncRNAs) have different functions in cells. They work as signals, decoys, guides, and scaffolds. Altered lncRNA levels can affect the expression of gene products. There are seldom studies on the role of lncRNAs in inflammatory bowel disease (IBD).Results
Quantitative RT-PCR showed that DQ786243 was significantly overexpressed in clinical active CD patients compared with clinical inactive CD patients (P = 0.0118) or healthy controls (P = 0.002). CREB was also more highly expressed in active CD than in inactive CD (P = 0.0034) or controls (P = 0.0241). Foxp3 was interestingly lower in inactive CD than in active CD (P = 0.0317) or controls (P = 0.0103), but there were no apparent differences between active CD and controls. CRP was well correlated with DQ786243 (r = 0.489, P = 0.034), CREB (r = 0.500, P = 0.029) and Foxp3 (r = 0.546, P = 0.016). At 48 hours after DQ786243 transfection, qRT-PCR showed both CREB (P = 0.017) and Foxp3 (P = 0.046) had an increased mRNA expression in Jurkat cells. Western blot showed the same pattern. After DQ786243 transfection, CREB phosphorylation ratio (p-CREB/t-CREB) was increased (P = 0.0043).Conclusion
DQ786243 can be related with severity of CD. It can affect the expression of CREB and Foxp3 through which regulates the function of Treg. CREB itself seems not the mediator of DQ786243 to up-regulate Foxp3. The phosphorylation of CREB might play a more important role in the process. 相似文献17.
Background
There is large variability among lung squamous cell carcinoma patients in response to treatment with cisplatin based chemotherapy. LncRNA is potentially a new type of predictive marker that can identify subgroups of patients who benefit from chemotherapy and it will have great value for treatment guidance.Methods
Differentially expressed lncRNAs and mRNA were identified using microarray profiling of tumors with partial response (PR) vs. with progressive disease (PD) from advanced lung squamous cell carcinoma patients treated with cisplatin based chemotherapy and validated by quantitative real-time PCR (qPCR). Furthermore, the expression of AC006050.3-003 was assessed in another 60 tumor samples.Results
Compared with the PD samples, 953 lncRNAs were consistently upregulated and 749 lncRNAs were downregulated consistently among the differentially expressed lncRNAs in PR samples (Fold Change≥2.0-fold, p <0.05). Pathway analyses showed that some classical pathways, including “Nucleotide excision repair,” that participated in cisplatin chemo response were differentially expressed between PR and PD samples. Coding-non-coding gene co-expression network identified many lncRNAs, such as lncRNA AC006050.3-003, that potentially played a key role in chemo response. The expression of lncRNA AC006050.3-003 was significantly lower in PR samples compared to the PD samples in another 60 lung squamous cell carcinoma patients. Receiver operating characteristic curve analysis revealed that lncRNA AC006050.3-003 was a valuable biomarker for differentiating PR patients from PD patients with an area under the curve of 0.887 (95% confidence interval 0.779, 0.954).Conclusions
LncRNAs seem to be involved in cisplatin-based chemo response and may serve as biomarkers for treatment response and candidates for therapy targets in lung squamous cell carcinoma. 相似文献18.
Background
Legionella pneumophila, is an intracellular pathogen that causes Legionnaires'' disease in humans, a potentially lethal pneumonia. L. pneumophila has the ability to enter and replicate in the host and is essential for pathogenesis.Methodology/Principal Findings
Phagocytosis was measured by cell invasion assays. Construction of PI3K mutant by PCR cloning and expression of dominant negative mutant was detected by Western blot. PI3K activity was measured by 32P labeling and detection of phospholipids products by thin layer chromatography. Infection of macrophages with virulent L. pneumophila stimulated the formation of phosphatidylinositol 3-phosphate (PIP3), a phosphorylated lipid product of PI3K whereas two structurally distinct phosphatidylinositol 3 kinase (PI3K) inhibitors, wortmannin and LY294002, reduced L. pneumophila entry into macrophages in a dose-dependent fashion. Furthermore, PI3K activation led to Akt stimulation, a serine/threonine kinase, which was also inhibited by wortmannin and LY294002. In contrast, PI3K and protein kinase B (PKB/Akt) activities were lower in macrophages infected with an avirulent bacterial strain. Only virulent L. pneumophila increased lipid kinase activity present in immunoprecipitates of the p85α subunit of class I PI3K and tyrosine phosphorylated proteins. In addition, macrophages expressing a specific dominant negative mutant of PI3K reduced L. pneumophila entry into these cells.Conclusion/Significance
Entry of L. pneumophila is mediated by PI3K/Akt signaling pathway. These results suggest an important role for PI3K and Akt in the L. pneumophila infection process. They point to possible novel strategies for undermining L. pneumophila host uptake and reducing pathogenesis of Legionnaires'' disease. 相似文献19.
Beate Fuchs Markus Rupp Hossein A Ghofrani Ralph T Schermuly Werner Seeger Friedrich Grimminger Thomas Gudermann Alexander Dietrich Norbert Weissmann 《Respiratory research》2011,12(1):20
Background
Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.Methods
We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.Results
OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.Conclusion
These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG. 相似文献20.
G Yu W Yao J Wang X Ma W Xiao H Li D Xia Y Yang K Deng H Xiao B Wang X Guo W Guan Z Hu Y Bai H Xu J Liu X Zhang Z Ye 《PloS one》2012,7(8):e42377