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71.
Mariapia Vairetti Andrea Ferrigno Vittoria RizzoGiulia Ambrosi Alberto BianchiPlinio Richelmi Fabio BlandiniMarie-Therese Armentero 《生物化学与生物物理学报:疾病的分子基础》2012,1822(2):176-184
In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies. 相似文献
72.
A previous genome-wide association study (GWAS) failed to discover any nucleotide sequence variant associated with susceptibility to vascular dementia (VaD) and remained a problem of false negatives produced by a low statistical power. The current study was conducted to identify such potential false negatives and to provide comprehensive evidence for the most plausible predisposing genetic factor using large-scale Korean cohorts. We identified the gene encoding retinitis pigmentosa GTPase regulator-interacting protein 1-like (RPGRIP1L) with multiple nucleotide variants associated with susceptibility to VaD by a modest significant threshold (P<10(-4)). Genetic associations were intensively examined with its sequence variants using 207 VaD patients and 207 age- and gender-matched control subjects. Genetic association analysis with dense variants in the region associated with VaD revealed 3 variants (P<0.0017) in strong linkage. Further analysis with VaD-related phenotypes using Korean Association REsource (KARE) cohort data showed that the region of the gene was associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood pressure (BP) (P<7.6×10(-4)). The current study provided the first evidence of the association between RPGRIP1L gene and susceptibility of VaD. Functional studies are needed to understand underlying biological mechanism of the genetic association. 相似文献
73.
Adam M. Lopez Kenneth S. Posey Stephen D. Turley 《Biochemical and biophysical research communications》2014
Sterol O-acyltransferase 2 (SOAT2), also known as ACAT2, is the major cholesterol esterifying enzyme in the liver and small intestine (SI). Esterified cholesterol (EC) carried in certain classes of plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease (WD) or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to what effect the loss of SOAT2 function might have on tissue EC sequestration in LAL-deficient mice. When weaned at 21 days, Lal−/−:Soat2+/+ mice had a whole liver cholesterol content (mg/organ) of 24.7 mg vs 1.9 mg in Lal+/+:Soat2+/+ littermates, with almost all the excess sterol being esterified. Over the next 31 days, liver cholesterol content in the Lal−/−:Soat2+/+ mice increased to 145 ± 2 mg but to only 29 ± 2 mg in their Lal−/−:Soat2−/− littermates. The level of EC accumulation in the SI of the Lal−/−:Soat2−/− mice was also much less than in their Lal−/−:Soat2+/+ littermates. In addition, there was a >70% reduction in plasma transaminase activities in the Lal−/−:Soat2−/− mice. These studies illustrate how the severity of disease in a mouse model for CESD can be substantially ameliorated by elimination of SOAT2 function. 相似文献
74.
Elena Larrieta-Carrasco Paola León-Mimila Teresa Villarreal-Molina Hugo Villamil-Ramírez Sandra Romero-Hidalgo Leonor Jacobo-Albavera Roxana Gutiérrez-Vidal Blanca E. López-Contreras Luz E. Guillén-Pineda Fausto Sánchez-Muñoz Rafael Bojalil Ana M. Mejía-Domínguez Nahúm Méndez-Sánchez Aaron Domínguez-López Carlos A. Aguilar-Salinas Samuel Canizales-Quinteros 《Gene》2013
Background and aims
Non-alcoholic fatty liver disease (NAFLD) and elevated alanine transaminase (ALT) levels are common in obese Hispanic adults and children. Recently, a PNPLA3 gene variant (I148M) was strongly associated with NAFLD and higher ALT levels in obese adults, including Hispanics. The aims of this study were to estimate the frequency of elevated ALT levels, and to address the influence of obesity and PNPLA3/I148M on ALT levels in a general population sample of Mexican school-aged children.Methods
A total of 1037 non-related Mexican children aged 6 to 12 years were genotyped for the I148M variant. Anthropometric, clinical and metabolic parameters were collected from all participants.Results
Elevated ALT levels (> 35 U/L) were more frequent in obese (26.9%) and overweight (9.3%) than in normal weight children (2.2%). The M148M genotype was significantly associated with elevated ALT levels in this population (OR = 3.7, 95% CI 2.3–5.9; P = 3.7 × 10− 8), and children carrying the M148M genotype showed significantly lower HDL cholesterol levels and BMI z-core (P = 0.036 and 0.015, respectively). On stratifying by BMI percentile, this genotype conferred a much greater risk of elevated ALT levels in normal weight (OR = 19.9, 95% CI 2.5–157.7; P = 0.005) than overweight and obese children (OR = 3.4, 95% CI 1.3–8.9; P = 0.014 and OR = 3.1, 95% CI 1.7–5.5; P = 1.4 x10− 4, respectively).Conclusions
The I148M PNPLA3 variant is strongly associated with elevated ALT levels in normal weight and overweight/obese Mexican children. Thus, the M148M genotype may be considered as an important risk factor for liver damage in this population. 相似文献75.
Koichi Hirabayashi Masaaki Shiohara Kazuhiro Yamada Akane Sueki Yuichiro Ide Koichi Takeuchi Rokuro Hagimoto Tatsuya Kinoshita Akihiko Yabuhara S. Harvey Mudd Kenichi Koike 《Gene》2013
Background
There is not much information on established standard therapy for patients with severe methionine adenosyltransferase (MAT) I/III deficiency.Case presentation
We report a boy with MAT I/III deficiency, in whom plasma methionine and total homocysteine, and urinary homocystine were elevated. Molecular genetic studies showed him to have novel compound heterozygous mutations of the MAT1A gene: c.191T>A (p.M64K) and c.589delC (p.P197LfsX26). A low methionine milk diet was started at 31 days of age, and during continuing dietary methionine restriction plasma methionine levels have been maintained at less than 750 μmol/L. He is now 5 years old, and has had entirely normal physical growth and psychomotor development.Conclusions
Although some severely MAT I/III deficient patients have developed neurologic abnormalities, we report here the case of a boy who has remained neurologically and otherwise normal for 5 years during methionine restriction, suggesting that perhaps such management, started in early infancy, may help prevent neurological complications. 相似文献76.
P. PalsamyS. Subramanian 《生物化学与生物物理学报:疾病的分子基础》2011,1812(7):719-731
Hyperglycemia-mediated oxidative stress plays a crucial role in the progression of diabetic nephropathy. Hence, the present study was hypothesized to explore the renoprotective nature of resveratrol by assessing markers of oxidative stress, proinflammatory cytokines and antioxidant competence in streptozotocin-nicotinamide-induced diabetic rats. Oral administration of resveratrol to diabetic rats showed a significant normalization on the levels of creatinine clearance, plasma adiponectin, C-peptide and renal superoxide anion, hydroxyl radical, nitric oxide, TNF-α, IL-1β, IL-6 and NF-κB p65 subunit and activities of renal aspartate transaminase, alanine transaminase and alkaline phosphatase in comparison with diabetic rats. The altered activities of renal aldose reductase, sorbitol dehydrogenase and glyoxalase-I and elevated level of serum advanced glycation end products in diabetic rats were also reverted back to near normalcy. Further, resveratrol treatment revealed a significant improvement in superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase activities and vitamins C and E, and reduced glutathione levels, with a significant decline in lipid peroxides, hydroperoxides and protein carbonyls levels in diabetic kidneys. Similarly, mRNA and protein analyses substantiated that resveratrol treatment notably normalizes the renal expression of Nrf2/Keap1and its downstream regulatory proteins in the diabetic group of rats. Histological and ultrastructural observations also evidenced that resveratrol effectively protects the kidneys from hyperglycemia-mediated oxidative damage. These findings demonstrated the renoprotective nature of resveratrol by attenuating markers of oxidative stress in renal tissues of diabetic rats. 相似文献
77.
Pia Gruber Filipe Carvalho Marco P. C. Marques Brian O'Sullivan Fabiana Subrizi Dragana Dobrijevic John Ward Helen C. Hailes Pedro Fernandes Roland Wohlgemuth Frank Baganz Nicolas Szita 《Biotechnology and bioengineering》2018,115(3):586-596
78.
Dihydropyrimidinase-like protein 3 (DPYSL3), a member of TUC (TOAD-64/Ulip/CRMP), is believed to play a role in neuronal differentiation, axonal outgrowth and, possibly, neuronal regeneration. In primary cortical cultures, glutamate (NMDA) excitotoxicity and oxidative stress (H2O2) caused the cleavage of DPYSL3, resulting in the appearance of a doublet of 62 kDa and 60 kDa. Pre-treatment of cell cultures with calpain inhibitors, but not caspase 3 inhibitor, before exposure to NMDA or H2O2 completely blocked the appearance of the doublet, suggesting calpain-mediated truncation. Furthermore, in vitro digestion of DPYSL3 in cell lysate with purified calpain revealed a cleavage product identical to that observed in NMDA- and H2O2-treated cells, and its appearance was blocked by calpain inhibitors. Analysis of the DPYSL3 protein sequence revealed a possible cleavage site for calpain (Val-Arg-Ser) on the C-terminus of DPYSL3. Collectively, these studies demonstrate for the first time that DPYSL3 is a calpain substrate. The physiological relevance of the truncated DPYSL3 protein remains to be determined. 相似文献
79.
GABA shunt deficiencies and accumulation of reactive oxygen intermediates: insight from Arabidopsis mutants 总被引:1,自引:0,他引:1
In plants, succinic semialdehyde dehydrogenase (SSADH)-deficiency results in the accumulation of reactive oxygen intermediates (ROI), necrotic lesions, dwarfism, and hypersensitivity to environmental stresses. We report that Arabidopsis ssadh knockout mutants contain five times the normal level of gamma-hydroxybutyrate (GHB), which in SSADH-deficient mammals accounts for phenotypic abnormalities. Moreover, the level of GHB in Arabidopsis is light dependent. Treatment with gamma-vinyl-gamma-aminobutyrate, a specific gamma-aminobutyrate (GABA)-transaminase inhibitor, prevents the accumulation of ROI and GHB in ssadh mutants, inhibits cell death, and improves growth. These results provide novel evidence for the relationship between the GABA shunt and ROI, which may, in part, explain the phenotype of SSADH-deficient plants and animals. 相似文献
80.