Family Studies of Type II CD36 Deficient Subjects: Linkage of a CD36 Allele to a Platelet-Specific mRNA Expression Defect(s) Causing Type II CD36 Deficiency

1995 ◽  
Vol 74 (02) ◽  
pp. 758-763 ◽  
Author(s):  
Hirokazu Kashiwagi ◽  
Yoshiaki Tomiyama ◽  
Satoru Kosugi ◽  
Masamichi Shiraga ◽  
Robert H Lipsky ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Family Studies ◽  
Positive Control ◽  
Type Ii ◽  
Cd36 Deficiency ◽  
Cd36 Expression ◽  
Silent Allele ◽  
Compound Heterozygotes ◽  
Cd36 Gene ◽  
Specific Mrna

SummaryWe performed family studies with type II CD36 deficiency. In the Mi.Y family, the proband (YII.1) and his brother (YII.2) displayed a type II deficient phenotype. In the mother(YI.2), binding of the anti CD36 monoclonal antibody, 0KM5, to both platelets and monocytes was reduced as compared to CD36 positive control cells. In the father (YI.1), while 0KM5 binding to his platelets was reduced, that of his monocytes was almost the same as normal control monocytes. Analysis of genomic DNA showed that YI.2, YII.1 and YII.2 were heterozygous for a proline90→serine mutation, and showed that both alleles of YI.1 did not have the mutation. Analysis of CD36 cDNA showed that the Pro90 form of CD36 cDNA could be detected in monocytes, but not in platelets from YII.1 and YII.2. These data indicated that YII.1 and YII.2 could be compound heterozygotes; an allele having a platelet-specific mRNA expression defect(s), which was responsible for the different CD36 expression between their platelets and monocytes, and the Ser90 allele. YI.1 was suggested to be a carrier of the platelet-specific silent allele. The platelet-specific silent allele was linked to a specific genotype of a polymorphic microsatellite sequence in the CD36 gene, supporting our hypothesis that mRNA expression defect(s) occurred at or near the CD36 gene. In a second type IICD36 deficient family, we also obtained results consistent with this hypothesis.

Phenotype-genotype Correlation in CD36 Deficiency Types I and II

2000 ◽  
Vol 84 (09) ◽  
pp. 436-441 ◽  
Author(s):  
Hidekatsu Yanai ◽  
Hironobu Fujiwara ◽  
Mie Morimoto ◽  
Keisuke Abe ◽  
Shigeru Yoshida ◽  
...  
Keyword(s):  
Minor Role ◽  
Type I ◽  
Cd36 Deficiency ◽  
Cd36 Expression ◽  
Previous Hypothesis ◽  
Flanking Region ◽  
Silent Allele ◽  
A Minor ◽  
Cd36 Gene ◽  
Genotype Correlation

SummaryCD36 deficiency was studied with attention to the phenotypegenotype relationship. The diagnosis of CD36 deficiency was made when CD36 was negative on platelets (type II) or on both platelets and monocytes (type I). Among 827 apparently healthy Japanese volunteers, the type I and II deficiencies were found in 8 (1.0%) and 48 (5.8%), respectively. The T for C substitution at nt478 for Pro90Ser and the insertion of A at nt1159 constituted the major causes of type I and II deficiencies. The dinucleotide deletion at nt539 had a minor role. In two family studies, we found a previously unreported polymorphic site in the 5’-proximal flanking region and the 3’-untranslated region. Including these new polymorphisms, DNA sequence other than the three known mutations affecting CD36 expression was not observed in the CD36 gene, calling into question the previous hypothesis that a platelet-specific silent allele exists near or at the CD36 gene.

scholarly journals Genomewide Analysis of Rat Barrel Cortex Reveals Time- and Layer-Specific mRNA Expression Changes Related to Experience-Dependent Plasticity

2011 ◽  
Vol 31 (16) ◽  
pp. 6140-6158 ◽  
Author(s):  
A. Valles ◽  
A. J. Boender ◽  
S. Gijsbers ◽  
R. A. M. Haast ◽  
G. J. M. Martens ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Barrel Cortex ◽  
Dependent Plasticity ◽  
Specific Mrna

scholarly journals Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1028
Author(s):  
Nikolaos Nikoleousakos ◽  
Panagiotis Dalezis ◽  
Aikaterini Polonifi ◽  
Elena G. Geromichalou ◽  
Sofia Sagredou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Positive Control ◽  
Ovarian Cancer Cells ◽  
Antitumor Effects

We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition activity and their DNA damaging effect against human ovarian carcinoma cells. These agents are conjugated with an alkylating component (POPA), which also served as a reference molecule (positive control), and were tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1, UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a standard third-generation PARP inhibitor, on a PARP assay investigating their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression analysis by qRT-PCR was produced in order to measure the absolute and the relative gene expression (in mRNA transcripts) between treated and untreated cells. All the investigated hybrid steroid alkylators and POPA decreased in vitro cell growth differentially, according to the sensitivity and different gene characteristics of each cell line, while ASA-A and ASA-B presented the most significant anticancer activity. Both these compounds induced PARP1/2 enzyme inhibition, DNA damage (alkylation) and upregulation of PARP mRNA expression, for all tested cell lines. However, ASA-C underperformed on average in the above tasks, while the compound ASA-B induced synthetic lethality effects on the ovarian cancer cells. Nevertheless, the overall outcome, leading to a drug-like potential, provides strong evidence toward further evaluation.

A putative growth-related renal Na(+)-Pi cotransporter

1997 ◽  
Vol 273 (3) ◽  
pp. R928-R933 ◽  
Author(s):  
D. M. Silverstein ◽  
M. Barac-Nieto ◽  
H. Murer ◽  
A. Spitzer
Keyword(s):  
Renal Cortex ◽  
Young Animal ◽  
Subtractive Hybridization ◽  
Type Ii ◽  
Chain Reaction ◽  
Adult Rats ◽  
Subtraction Hybridization ◽  
Adult Rat ◽  
Polymerase Chain ◽  
Specific Mrna

The mRNA that encodes for NaPi-2, the renal Na(+)-Pi cotransporter that is upregulated by Pi depletion in the adult rat, is low in the young animal. Yet, renal Na-Pi cotransport rates are higher in rapidly growing than in fully grown rats. The aim of this study was to unravel the molecular basis of this apparent discrepancy. Poly(A) RNA obtained from the renal cortex of young animals induced higher rates of Na(+)-Pi cotransport in oocytes than equal amounts of poly(A) mRNA obtained from the renal cortex of mature rats. Moreover, poly(A) RNA obtained from renal cortex of rapidly growing animals treated with antisense NaPi-2 oligomers or depleted of NaPi-2 transcripts by subtractive hybridization with cDNA generated from the renal cortex of adult rats retained its ability to induce Na(+)-Pi cotransport in oocytes. In addition, renal poly(A) RNA of the young subjected to subtraction hybridization generated a 379-base pair reverse transcriptase-polymerase chain reaction product common to all known type II Na(+)-Pi cotransporters. These observations permit us to surmise that the high rates of Na(+)-Pi cotransport prevailing during growth are due, at least in part, to the expression of a specific mRNA that is only partially homologous to that of NaPi-2.

LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits

2020 ◽  
Vol 12 (540) ◽  
pp. eaav0820 ◽  
Author(s):  
Marco A. S. Baptista ◽  
Kalpana Merchant ◽  
Ted Barrett ◽  
Sakshi Bhargava ◽  
Dianne K. Bryce ◽  
...  
Keyword(s):  
Lung Function ◽  
Nonhuman Primates ◽  
Drug Withdrawal ◽  
Positive Control ◽  
Repeat Dose ◽  
Type Ii ◽  
Histological Changes ◽  
Once Daily ◽  
Toxicology Study ◽  
Activating Mutation

The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson’s disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was ~50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.

Central stimulatory effect of leptin on T3production is mediated by brown adipose tissue type II deiodinase

2002 ◽  
Vol 283 (5) ◽  
pp. E980-E987 ◽  
Author(s):  
Philippe Cettour-Rose ◽  
Albert G. Burger ◽  
Christoph A. Meier ◽  
Theo J. Visser ◽  
Françoise Rohner-Jeanrenaud
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mrna Expression ◽  
Uncoupling Protein ◽  
Tissue Type ◽  
Type I ◽  
Type Ii ◽  
Brown Adipose ◽  
Small Doses ◽  
Food Consumed

To assess whether intracerebroventricular leptin administration affects monodeiodinase type II (D2) activity in the tissues where it is expressed [cerebral cortex, hypothalamus, pituitary, and brown adipose tissue (BAT)], hepatic monodeiodinase type I (D1) activity was inhibited with propylthiouracil (PTU), and small doses of thyroxine (T4; 0.6 nmol · 100 g body wt−1 · day−1) were supplemented to compensate for the PTU-induced hypothyroidism. Two groups of rats were infused with leptin for 6 days, one of them being additionally treated with reverse triiodothyronine (rT3), an inhibitor of D2. Control rats were infused with vehicle and pair-fed the amount of food consumed by leptin-infused animals. Central leptin administration produced marked increases in D2 mRNA expression and activity in BAT, changes that were likely responsible for increased plasma T3 and decreased plasma T4 levels. Indeed, plasma T3 and T4 concentrations were unaltered by central leptin administration in the presence of rT3. The additional observation of a leptin-induced increased mRNA expression of BAT uncoupling protein-1 suggested that the effect on BAT D2 may be mediated by the sympathetic nervous system.

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