共查询到20条相似文献,搜索用时 15 毫秒
1.
Marjanne D. van der Hoek Ole Madsen Jaap Keijer Feike R. van der Leij 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(8):909-918
Carnitine/choline acyltransferases play diverse roles in energy metabolism and neuronal signalling. Our knowledge of their evolutionary relationships, important for functional understanding, is incomplete. Therefore, we aimed to determine the evolutionary relationships of these eukaryotic transferases. We performed extensive phylogenetic and intron position analyses. We found that mammalian intramitochondrial CPT2 is most closely related to cytosolic yeast carnitine transferases (Sc-YAT1 and 2), whereas the other members of the family are related to intraorganellar yeast Sc-CAT2. Therefore, the cytosolically active CPT1 more closely resembles intramitochondrial ancestors than CPT2. The choline acetyltransferase is closely related to carnitine acetyltransferase and shows lower evolutionary rates than long chain acyltransferases. In the CPT1 family several duplications occurred during animal radiation, leading to the isoforms CPT1A, CPT1B and CPT1C. In addition, we found five CPT1-like genes in Caenorhabditis elegans that strongly group to the CPT1 family. The long branch leading to mammalian brain isoform CPT1C suggests that either strong positive or relaxed evolution has taken place on this node. The presented evolutionary delineation of carnitine/choline acyltransferases adds to current knowledge on their functions and provides tangible leads for further experimental research. 相似文献
2.
Dai Y Wolfgang MJ Cha SH Lane MD 《Biochemical and biophysical research communications》2007,359(3):469-474
Hypothalamic neurons monitor peripheral energy status and produce signals to adjust food intake and energy expenditure to maintain homeostasis. However, the molecular mechanisms by which these signals are generated remain unclear. Fluctuations in the level of hypothalamic malonyl-CoA are known to serve as an intermediary in regulating energy homeostasis and it has been proposed that the brain-specific carnitine palmitoyltransferase-1c (CPT1c) serves as a target of malonyl-CoA in the central nervous system (CNS). Here, we report that CPT1c is widely expressed in neurons throughout the CNS including the hypothalamus, hippocampus, cortex, and amygdala. CPT1c is enriched in neural feeding centers of the hypothalamus with mitochondrial localization as an outer integral membrane protein. Ectopic over-expression of CPT1c by stereotactic hypothalamic injection of a CPT1c adenoviral vector is sufficient to protect mice from body weight gain when fed a high-fat diet. These findings show that CPT1c is appropriately localized in regions and cell types to regulate energy homeostasis and that its over-expression in the hypothalamus is sufficient to protect mice from adverse weight gain caused by high-fat intake. 相似文献
3.
One particularly interesting single nucleotide polymorphism (SNP), rs6235 (encoding an S690T substitution), in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene has been widely associated with obesity in several European cohorts. The present study was intended to investigate the association between the PCSK1 rs6235 SNP and the prevalence of overweight or obesity, or obesity-related metabolic traits in a Taiwanese population. A total of 964 Taiwanese subjects with general health examinations were analyzed. Our data revealed no association of PCSK1 rs6235 with the risk of obesity or overweight in the complete subjects. However, the PCSK1 rs6235 SNP exhibited a significant association with overweight among the male subjects (P = 0.03), but not among the female subjects. Furthermore, the carriers of GG variant had a significantly higher waist circumference than those with the CC variant (82.5 ± 11.5 vs. 81.2 ± 10.2 cm; P = 0.01) and those with the CG variant (82.5 ± 11.5 vs. 81.4 ± 10.4 cm; P = 0.021). In addition, the carriers of GG variant had a higher diastolic blood pressure than those with the CC variant (81.9 ± 14.2 vs. 80.3 ± 12.9 mm Hg; P = 0.023). Our study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects. 相似文献
4.
Sara Violante Lodewijk IJlst Heleen te Brinke Janet Koster Isabel Tavares de Almeida Ronald J.A. Wanders Fátima V. Ventura Sander M. Houten 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(9):1467-1474
Fatty acid β-oxidation may occur in both mitochondria and peroxisomes. While peroxisomes oxidize specific carboxylic acids such as very long-chain fatty acids, branched-chain fatty acids, bile acids, and fatty dicarboxylic acids, mitochondria oxidize long-, medium-, and short-chain fatty acids. Oxidation of long-chain substrates requires the carnitine shuttle for mitochondrial access but medium-chain fatty acid oxidation is generally considered carnitine-independent. Using control and carnitine palmitoyltransferase 2 (CPT2)- and carnitine/acylcarnitine translocase (CACT)-deficient human fibroblasts, we investigated the oxidation of lauric acid (C12:0). Measurement of the acylcarnitine profile in the extracellular medium revealed significantly elevated levels of extracellular C10- and C12-carnitine in CPT2- and CACT-deficient fibroblasts. The accumulation of C12-carnitine indicates that lauric acid also uses the carnitine shuttle to access mitochondria. Moreover, the accumulation of extracellular C10-carnitine in CPT2- and CACT-deficient cells suggests an extramitochondrial pathway for the oxidation of lauric acid. Indeed, in the absence of peroxisomes C10-carnitine is not produced, proving that this intermediate is a product of peroxisomal β-oxidation. In conclusion, when the carnitine shuttle is impaired lauric acid is partly oxidized in peroxisomes. This peroxisomal oxidation could be a compensatory mechanism to metabolize straight medium- and long-chain fatty acids, especially in cases of mitochondrial fatty acid β-oxidation deficiency or overload. 相似文献
5.
Lihuan Guan Yixin Chen Yongtao Wang Huizhen Zhang Shicheng Fan Yue Gao Tingying Jiao Kaili Fu Jiahong Sun Aiming Yu Min Huang Huichang Bi 《Journal of cellular physiology》2019,234(2):1707-1719
The carnitine palmitoyltransferase (CPT) family is essential for fatty acid oxidation. Recently, we found that CPT1C, one of the CPT1 isoforms, plays a vital role in cancer cellular senescence. However, it is unclear whether other isoforms (CPT1A, CPT1B, and CPT2) have the same effect on cellular senescence. This study illustrates the different effects of CPT knockdown on PANC-1 cell proliferation and senescence and MDA-MB-231 cell proliferation and senescence, as demonstrated by cell cycle kinetics, Bromodeoxyuridine incorporation, senescence-associated β-galactosidase activity, colony formation, and messenger RNA (mRNA) expression of key senescence-associated secretory phenotype factors. CPT1C exhibits the most substantial effect on cell senescence. Lipidomics analysis was performed to further reveal that the knockdown of CPTs changed the contents of lipids involved in mitochondrial function, and lipid accumulation was induced. Moreover, the different effects of the isoform deficiencies on mitochondrial function were measured and compared by the level of radical oxygen species, mitochondrial transmembrane potential, and the respiratory capacity, and the expression of the genes involved in mitochondrial function were determined at the mRNA level. In summary, CPT1C exerts the most significant effect on mitochondrial dysfunction-associated tumor cellular senescence among the members of the CPT family, which further supports the crucial role of CPT1C in cellular senescence and suggests that inhibition of CPT1C may represent as a new strategy for cancer treatment through the induction of tumor senescence. 相似文献
6.
Context
Myostatin (MSTN) is a member of the TGF-β superfamily of signal transduction proteins, which plays an important role in muscular growth and lipid metabolism.Objective
To study the association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects.Design
297 healthy and 606 over-weight/obesity Chinese north Han subjects were selected as healthy control group and overweight/obesity group, respectively. The methods of DNA Sequencing, Restriction Fragment Length Polymorphism (RFLP) and TaqMan® probe were used to screen myostatin gene SNPs and clarify genotype in every individual.Results
Total 11 SNPs in MSTN gene were identified by DNA sequencing and three SNPs including rs35781413 (G/A), rs3791783 (A/G) and rs3791782 (A/G) were selected for further study in total 903 samples. The results showed that the frequency of AA genotype of rs3791783 A/G SNP was significantly higher (56.4% vs. 50.8%) and the frequency GG genotype was significantly lower (3.2% vs. 6.7%) in overweight/obese patients than in normal weight subjects. A logistic regression analysis under a recessive inheritance model (AA + AG vs.GG) demonstrated that the Odd ratio for AA + AG vs.GG were 1.985 (95% CI 1.078-3.643; P = 0.029). Among three genotypes of rs3791783, the subjects with AA genotype have much more higher body weight, BMI, waist circumference, TC, TG and LDL-C than those with GG genotype.Conclusions
Our data firstly suggest that genetic variant rs3791783 A/G in myostatin gene are associated with obesity. The A allele carriers in rs3791783 SNP have an increased susceptibility to obesity compared with the G allele carriers. Participants with AA genotype in rs3791783 SNP site will have higher risk suffered from overweight or obesity than those with GG genotype. 相似文献7.
Jiwen Wang Jia Gao Yingjie Li Xiaoxia Zhao Wei Gao Li Peng Dangui Yan Lisheng Liu Dongmei Li Lili Wei Jun Qi Changchun Zhou 《Gene》2013
Accumulating evidences indicate that the functional FAS− 1377G > A, − 670A > G and FASL− 844T > C polymorphisms affect the risk of several kinds of cancers. However, their roles in the development of larynx and hypopharynx squamous cell carcinoma (SCC) were still unknown in the Chinese. In the current study, we examined whether these functional genetic variants were associated with the risk of larynx and hypopharynx squamous SCC in a Han Chinese population. The FAS and FASL polymorphisms were genotyped in 300 patients with laryngeal and hypopharyngeal SCC and 300 control subjects by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that subjects carrying the FASL–844CT or TT genotype had a significantly decreased risk of developing laryngeal and hypopharyngeal SCC [odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.51–0.93; P = 0.016; or, OR = 0.41; 95% CI = 0.20–0.86; P = 0.009] compared with those carrying the CC genotype. Joint gene-smoking and gene-drinking effects were also observed, with the OR of CC genotype for smokers or drinkers were 5.15 (95%CI = 3.24–8.97) or 12.52 (95%CI = 7.31–22.47), respectively. Therefore, the FASL− 844T > C polymorphism is associated with genetic susceptibility of developing laryngeal and hypopharyngeal SCC in a Han Chinese population. 相似文献
8.
Sol EM Sargsyan E Akusjärvi G Bergsten P 《Biochemical and biophysical research communications》2008,375(4):517-521
Effects of non-esterified fatty acids (FAs) are accentuated when applied together with elevated glucose through preferential use of glucose as fuel, which leads to decreased oxidation of FAs. We examined how over-expression of the mitochondrial FA transporter carnitine palmitoyltransferase 1 (CPT1) affects glucose-stimulated insulin secretion (GSIS), apoptosis and ER stress in INS-1E cells cultured in the presence of elevated levels of glucose and palmitate. INS-1E cells were infected with Tet-ON regulated adenovirus containing CPT1 and cultured for 48 h in the presence of 0.5 mM palmitate and 20 mM glucose. Over-expressing CPT1 lowered basal insulin secretion in a dose-dependent manner thereby improving GSIS from INS-1E cells. Also, apoptosis was alleviated and ER-stress markers p-eIF2α and CHOP were decreased in cells over-expressing CPT1. We conclude that regulated over-expression of CPT1 is beneficial for glucolipotoxic beta-cells. 相似文献
9.
The polymorphisms in trefoil factor (TFF) gene family that protect gastrointestinal epithelium might influence individual vulnerability to gastric cancer (GC) and atrophic gastritis. We used the Sequenom MassARRAY platform to identify the genotypes of TFF2 rs3814896 and TFF3 rs9981660 polymorphisms in 478 GC patients, 652 atrophic gastritis patients, and 724 controls. For the TFF2 rs3814896 polymorphism, in the subgroup aged ≤ 50 years, we found that AG + GG genotypes were associated with a 0.746-fold decreased risk of atrophic gastritis [p = 0.023, 95% confidence interval (CI) = 0.580–0.960], a 0.626-fold decreased risk of GC (p = 0.005, 95% CI = 0.451–0.868), and a 0.663-fold decreased risk of diffuse-type GC (p = 0.034, 95% CI = 0.452–0.970) compared with the common AA genotype. For the TFF3 rs9981660 polymorphism, in the male subgroup, individuals with variant AG + AA genotype were associated with a 0.761-fold decreased risk of diffuse-type GC compared with the common GG genotype (p = 0.043, 95% CI = 0.584–0.992). Additionally, we found that in subjects aged ≤ 50 years compared with common AA genotype, TFF2 rs3814896 AG + GG genotypes were associated with increased TFF2 mRNA levels in the total gastric cancer specimens and in the diffuse-type gastric cancer specimens; and in males aged ≤ 50 years compared with common GG genotype, TFF3 rs9981660 AA + AG genotypes were associated with TFF3 mRNA levels in diffuse-type gastric cancer tissues and their corresponding non-cancerous tissues. To our knowledge, this is the first report of an association between the TFF2 rs3814896 AG + GG genotypes and decreased risks of GC, diffuse-type GC, and atrophic gastritis in younger people aged ≤ 50 years, and an association between TFF3 rs9981660 AG + AA genotype and decreased risk of diffuse-type GC in men. Moreover, we found that TFF2 rs3814896 AG + GG genotypes in people aged ≤ 50 years and TFF3 rs9981660 AG + AA genotypes in younger males with diffuse-type GC were associated with higher levels of TFF2 and TFF3 mRNA respectively. 相似文献
10.
Sophie Brunner-Ziegler Georgiana-Aura Giurgea Raute Sunder-Plassmann Alexandra Hammer Christian Margeta Martin Brunner Renate Koppensteiner Christine Mannhalter 《Gene》2013
Background
In recent years reduced bone mineral density (BMD) and osteoporosis have become major public health problems. Single nucleotide polymorphisms (SNPs) in the cytochrome P450 2C9 (CYP2C9) gene influence the response to oral anticoagulant drugs, which are positively associated with the risk to develop osteoporosis. The aim of the present investigation was to clarify a potential role of CYP2C9 sequence variations and susceptibility to develop osteoporosis.Subjects and methods
Ninety two consecutive angiologic outpatients, mean age: 60.3 ± 14.4, without secondary causes of bone loss were genotyped and classified as patients with normal BMD, osteopenia and osteoporosis according to WHO criteria by dual-energy X-ray absorptiometry at the lumbar spine and/or the femoral neck. Potential association between the CYP2C9 genotype and BMD was tested.Results
59% of the patients (n = 54) presented with reduced BMD and were compared to 38 age-matched persons with normal BMD. The genotype distribution showed 15% heterozygous for CYP2C9*2 p.Arg144Cys, 14% for CYP2C9*3 p.IIe359Leu, 2% for both polymorphisms, and 69% had wildtype genotypes. Patients with CYP2C9 mutations had significantly lower BMD values at the femoral neck and displayed a four-fold higher adjusted risk to suffer from reduced BMD than individuals with wildtype genotypes (p = 0.02).Discussion
Oral anticoagulant treatment is common in angiologic outpatients. The gene variants CYP2C9*2 and CYP2C9*3 have been shown to require lower maintenance doses of oral anticoagulant drugs. An association between oral anticoagulant drugs and the susceptibility to develop osteoporosis in relation to sequence variations in the CYP2C9 gene is suggested to be mediated via the glucocorticoid synthesis pathway.Conclusion
The CYP2C9*2/CYP2C9*3 variants were significantly associated with femoral BMD in a selected elderly Austrian population. These variants could contribute to the complex risk to develop osteoporosis. 相似文献11.
Linlin Li Kaiping Gao Jingzhi Zhao Tianping Feng Lei Yin Jinjin Wang Chongjian Wang Chunyang Li Yan Wang Qian Wang Yujia Zhai Haifei You Yongcheng Ren Bingyuan Wang Dongsheng Hu 《Gene》2014
Few genome-wide association studies have considered interactions between multiple genetic variants and environmental factors associated with disease. The interaction was examined between a glucagon gene (GCG) polymorphism and smoking, alcohol consumption and physical activity and the association with risk of type 2 diabetes mellitus (T2DM) in a case–control study of Chinese Han subjects. The rs12104705 polymorphism of GCG and interactions with environmental variables were analyzed for 9619 participants by binary multiple logistic regression. Smoking with the C-C haplotype of rs12104705 was associated with increased risk of T2DM (OR = 1.174, 95% CI = 1.013–1.361). Moderate and high physical activity with the C-C genotype was associated with decreased risk of T2DM as compared with low physical activity with the genotype (OR = 0.251, 95% CI = 0.206–0.306 and OR = 0.190, 95% CI = 0.164–0.220). However, the interaction of drinking and genotype was not associated with risk of T2DM. Genetic polymorphism in rs12104705 of GCG may interact with smoking and physical activity to modify the risk of T2DM. 相似文献
12.
Tapas K. Makar Dr. Arthur J. L. Cooper Beth Tofel-Grehl Howard T. Thaler John P. Blass 《Neurochemical research》1995,20(6):705-711
Glutathione and total carnitine (i.e., free carnitine plus acid-soluble carnitine esters) were measured in an affected (superior frontal gyrus; SFG) and unaffected (cerebellum: CBL) region of Alzheimer disease (AD) and control brains. Average glutathione content in AD SFG (n=13) and AD CBL (n=7) (7.9±2.1 and 11.9±4.0 nmol/mg protein, respectively (mean ±S.D.)) was similar to that in control SFG (n=13) and CBL (n=6) (7.7±2.0 and 11.6±2.6 nmol/mg protein, respectively). However, glutathione increased significantly with age in AD brain (p=0.003) but not in control brain. Average total carnitine in AD SFG (84±47 pmol/mg protein; n=10) and AD CBL (108±86 pmol/mg protein; n=7) was not significantly different from that in the corresponding regions of control brain (148±97 (n=10) and 144±107 (n=6) pmol/mg protein, respectively). However, a significant decline of total carnitine with age in both regions was noted for AD brain, but not for control brain. Carnitine acetyltransferase activity in the AD SFG (n=13) was not significantly different from that of control SFG (n=13) (1.83±1.05 and 2.04±0.82 nmol/min/mg protein, respectively). However, carnitine acetyltransferase activity of AD CBL (n=7) was significantly lower than that of control CBL (n=6) (1.33±0.88 versus 2.26±0.66 nmol/min/mg protein; p=0.05). 相似文献
13.
El-Aroussy W Rizk A Mayhoub G Aleem SA El-Tobgy S Mokhtar MS 《Molecular and cellular biochemistry》2000,213(1-2):37-41
L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure.To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions.Plasma carnitine was significantly higher in patients with DCM (37.05 ± 7.62, p < 0.0001) and with RHD (47.2 ± 8.04, p < 0.0001) vs. the control subjects (14.4 ± 5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13 ± 14.11, p < 0.0001) and in RHD 43.53 ± 15.5, p < 0.0001), than the control (25.1 ± 5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: %FS < 25% (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m2 (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions. 相似文献
14.
Chen Y Mizuguchi H Yao D Ide M Kuroda Y Shigematsu Y Yamaguchi S Yamaguchi M Kinoshita M Kido H 《FEBS letters》2005,579(10):2040-2044
To assess the etiology of influenza-associated encephalopathy (IAE), a surveillance effort was conducted during 2000-2003 in South-West Japan. All fatal and handicapped patients except one (4/34 patients) exhibited a disorder of mitochondrial beta-oxidation evoked by the inactivated carnitine palmitoyltransferase II (CPT II) with transiently elevated serum acylcarnitine ratios (C(16:0) + C(18:1))/C(2) > 0.09 during high-grade fever. Analyses of genotypes and allele compositions of CPT II revealed a thermolabile phenotype of compound heterozygotes for [1055T > G/F352C] and [1102G > A/V368I], which shows a higher frequency in IAE patients than healthy volunteers (P < 0.025). The thermolabile phenotype of CPT II variations may be a principal genetic background of IAE in Japanese. 相似文献
15.
Adiponectin, a protein exclusively secreted by adipose tissue and present at low levels in obese individuals, is now widely recognized as a key determinant of insulin sensitivity and protection against obesity-associated metabolic syndrome. In Jordan, prevalence of diabetes (17.1%) is twice that of the United States (7.8%). In this study, we examined the contribution of the promoter variant rs266729 (− 11377C>G) of the ADIPOQ gene as a risk factor for diabetic patients in Jordan. DNA was extracted from blood samples for patients and controls .Polymerase chain reaction and restriction fragment length polymorphism were used to genotype this variant. A total of 420 type 2 diabetic patients and 230 controls were successfully genotyped. The results showed a significant genotypic (p = 0.00001) and allelic (p = 0.01) association with variant in the diabetic patients as compared to controls. This suggests that the ADIPOQ gene plays a major role in increasing the risk of diabetes, at least in the Jordanian Arab population. 相似文献
16.
Reimi Iida Naoshi Takeyama Naohiro Iida Takaya Tanaka 《Molecular and cellular biochemistry》1991,103(1):23-30
Summary Saponin-permeabilization (30 µg/ml) of the platelet plasma membrane, which enables access of added compounds to mitochondrial overt carnitine palmitoyltransferase (CPT I), was applied to allow the rapid determination of CPT I activity in situ. The effects of diabetes and short-term incubation with insulin in vitro on the kinetic parameters and malonyl-CoA sensitivity of CPT I were also studied in rat platelets. CPT I exhibited ordinary Michaelis-Menten kinetics when platelets were incubated with palmitoyl-CoA. Malonyl-CoA showed an I50 (concentration giving 50% inhibition of CPT activity) of 0.92 ± 0.11 µM in permeabilized platelets. Platelets obtained from diabetic rats (induced by streptozotocin injection) exhibited an increased Vmax. and I50 for malonyl-CoA, and an unaltered Km for palmitoyl-CoA. In contrast, preincubation of platelets prepared from both fed control rats and diabetic rats with insulin (100 and 150 µ-cU/ml) led to a decrease in enzyme activity when assayed with 75 µM palmitoyl-CoA and 0.5 mM L-carnitine as substrates. These in vivo and in vitro results suggested that insulin directly modulated rat platelet CPT I activity, as it does in the liver. 相似文献
17.
Altaf-M. Khan Min Li Solange Abdulnour-Nakhoul Jerome L. Maderdrut Eric E. Simon Vecihi Batuman 《Peptides》2012
We investigated whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) ameliorates kidney injury after ischemia/reperfusion (IR) by modulating Toll-like receptor (TLR)-associated signaling pathways. Male C57BL/6 mice were subjected to bilateral renal ischemia for 45 min. PACAP38, 20 μg in 100 μl of saline, was administered i.p. at 24 and 48 h after IR, and mice were euthanized at 72 h. In IR mice, PACAP38 maintained serum creatinine near control levels (0.81 ± 0.08 vs. 0.69 ± 0.17 mg/dl in controls, p = NS, vs. 1.8 ± 0.03 in saline-treated IR mice, p < 0.01) and significantly reduced the expression of kidney injury biomarkers. PACAP38 significantly reduced the levels of apoptosis and neutrophil infiltration, and protected against tubular damage. With PCR arrays, 59 of 83 TLR-related genes significantly changed their expression after IR. TLR2 increased 162 fold, followed by Fas-associated death domain (37 fold) and TLR6 (24 fold), while ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) decreased 55 fold. PACAP38 given 24 and 48 h after IR injury significantly reversed these changes in 56 genes, including TLR2, TLR3, TLR4, TLR6, and genes in the NF-κB pathways. The alterations in TLR2, TLR3, TLR6, and UBE2V1 were confirmed by RT-PCR. After IR, PACAP38 also suppressed protein levels of TLR-associated cytokines. PACAP38 reversed the changes in IR-activated TLR-associated NF-κB signaling pathways even when treatment was delayed 24 h. Therefore, PACAP38 could be an effective therapeutic for unexpected IR-mediated renal injury. The prominently IR-induced TLR-related genes identified in this study could be novel drug targets. 相似文献
18.
Apostolis Papapostolou Kostas Spengos Irene Fylaktou Myrto Poulou Ilias Gountas Sophia Kitsiou-Tzeli Emmanuel Kanavakis Maria Tzetis 《Gene》2014
ALOX5AP (5-lipoxygenase) has been recognized as a susceptibility gene for stroke. Using a case–control design, the whole coding and adjoining intronic regions of ALOX5AP were sequenced to study the role of SNPs and their interplay with other risk factors in Greek patients with stroke. Patients (n = 213) were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Their mean age of was 58.9 ± 14.64, comprising 145 males. The control group consisted of 210 subjects, ethnicity, sex and age matched, with no stroke history. Risk factors (hyperlipidemia, hypertension, atrial fibrillation, migraine, CAD, diabetes, smoking and alcohol consumption) were assessed as confounding factors and comparisons were done using logistic regression analysis. SNPs rs4769055, rs202068154 and rs3803277 located in intronic regions of the gene and according to in silico programs EX_SKIP and HSF possibly affecting splicing of exons 1 and 2 of ALOX5AP, showed significantly different frequencies between patients and controls. The genotype frequencies of rs4769055: AA, of rs202068154: AC and of rs3803277: CA were significantly higher (p < 0.001, 0.058) in controls than in patients. The results were indicative of a protective role of the three SNPs either in homozygosity or heterozygosity for MAF and more specifically rs3803277: CA/AA genotypes were protective against SVO stroke subtype. 相似文献
19.
20.
Min Yao Min Cai Dengfu Yao Xi Xu Rongrong Yang Yuting Li Yuanyuan Zhang Hiroshi Kido Dengbing Yao 《PloS one》2015,10(3)
Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated CPT II variants in patient fibroblasts, [c.1102 G>A (p.V368I)] (heterozygous), [c.1102 G>A (p.V368I)] (homozygous), and [c.1055 T>G (p.F352C)] (heterozygous) + [c.1102 G>A (p.V368I)] (homozygous) compared with fibroblasts from healthy controls. CPT II variants exerted an effect of dominant negative on the homotetrameric proteins that showed thermal instability, reduced residual enzyme activities and a short half-life. Moreover, CPT II variant fibroblasts showed a significant decrease in fatty acid β-oxidation and adenosine triphosphate generation, combined with a reduced mitochondrial membrane potential, resulting in cellular apoptosis. Collectively, our data indicate that the CPT II deficiency induces an energy crisis of the fatty acid metabolic pathway. These findings may contribute to the elucidation of the genetic factors involved in metabolic disorder encephalopathy caused by the CPT II deficiency. 相似文献