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1.
Chiara Pavanello Alice Ossoli Arianna Strazzella Patrizia Risè Fabrizio Veglia Marie Lhomme Paolo Parini Laura Calabresi 《Journal of lipid research》2022,63(7):100232
Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0–37.8] mg/dl) and slightly reduced in heterozygotes (218 [153–234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2. 相似文献
2.
Alessandro Stefani Antonio Pisani Nicola B. Mercuri Paolo Calabresi 《Molecular neurobiology》1996,13(1):81-95
Glutamatergic transmission in the central nervous system (CNS) is mediated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory proteins (G-proteins) and modulate different second messenger pathways. Multiple effects have been described following their activation; among others, regulation of fast synaptic transmission, changes in synaptic plasticity, and modification of the threshold for seizure generation. Some of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca2+) currents. Some HVA Ca2+ channels (N-, P-, and Q-type channels) are signaling components at most presynaptic active zones. Their mGluR-mediated inhibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal firing behavior and the integration of complex events at the somatic level. In addition, the mGluR-mediated effects on voltagegated Ca2+ signals have been suggested to strongly influence neurotoxicity. Rather different coupling mechanisms underlie the relation between mGluRs and Ca2+ currents: Together with a fast, membrane-delimited mechanism of action, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity of selective agonists and antagonists for the different subclasses of mGluRs had hampered the clear definition of the roles of mGluRs in brain function. However, the recent availability of new pharmacological tools is promising to provide a better understanding of the neuronal functions related to different mGluR subtypes. The analysis of the mGluR-mediated modulation of Ca2+ conductances will probably offer new insights into the characterization of synaptic transmission and the development of neuroprotective agents. 相似文献
3.
Jolanda?HM?van Bilsen Josée?PA?Wagenaar-Hilbers Maarten?JF?van der Cammen Mariska?EA?van Dijk Willem?van Eden Marca?HM?WaubenEmail author 《Arthritis research & therapy》2002,4(4):R2
We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental
arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the
course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration
of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the
MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP
peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development
of such therapies. 相似文献
4.
Quini CC Américo MF Corá LA Calabresi MF Alvarez M Oliveira RB Miranda JR 《Journal of biological engineering》2012,6(1):6-6
ABSTRACT: AC Biosusceptometry (ACB) was previously employed towards recording gastrointestinal motility. Our data show a reliable and successful evaluation of gastrointestinal transit of liquid and solid meals in rats, considering the methods scarcity and number of experiments needed to endorsement of drugs and medicinal plants. ACB permits real time and simultaneous experiments using the same animal, preserving the physiological conditions employing both meals with simplicity and accuracy. 相似文献
5.
Herman J. Kempen Monica Gomaraschi S. Eralp Bellibas Stephanie Plassmann Brad Zerler Heidi L. Collins Steven J. Adelman Laura Calabresi Peter L. J. Wijngaard 《Journal of lipid research》2013,54(9):2341-2353
MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation. 相似文献
6.
A study of bacterial surface oligosaccharides were investigated among
different strains of Neisseria gonorrhoeae to correlate structural features
essential for binding to the MAb 2C7. This epitope is widely expressed and
conserved in gonococcal isolates, characteristics essential to an effective
candidate vaccine antigen. Sample lipooligosaccharides (LOS), was prepared
by a modification of the hot phenol-water method from which de-O-acetylated
LOS and oligosaccharide (OS) components were analyzed by ES-MS-CID-MS and
ES-MSnin a triple quadrupole and an ion trap mass spectrometer,
respectively. Previously documented natural heterogeneity was apparent from
both LOS and OS preparations which was admixed with fragments induced by
hydrazine and mild acid treatment. Natural heterogeneity was limited to
phosphorylation and antenni extensions to the alpha-chain. Mild acid
hydrolysis to release OS also hydrolyzed the beta(1-->6) glycosidic
linkage of lipid A. OS structures were determined by collisional and
resonance excitation combined with MS and multistep MSn which provided
sequence information from both neutral loss, and nonreducing terminal
fragments. A comparison of OS structures, with earlier knowledge of MAb
binding, enzyme treatment, and partial acid hydrolysis indicates a generic
overlapping domain for 2C7 binding. Reoccurring structural features include
a Hepalpha(1-->3)Hepbeta(1-->5)KDO trisaccharide core branched on the
nonreducing terminus (Hep-2) with an alpha(1-->2) linked GlcNAc
(gamma-chain), and an alpha-linked lactose (beta-chain) residue. From the
central heptose (Hep-1), a beta(1-->4) linked lactose (alpha-chain),
moiety is required although extensions to this residue appear unnecessary.
相似文献
7.
Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1 总被引:1,自引:0,他引:1
Goldberg MS Pisani A Haburcak M Vortherms TA Kitada T Costa C Tong Y Martella G Tscherter A Martins A Bernardi G Roth BL Pothos EN Calabresi P Shen J 《Neuron》2005,45(4):489-496
The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1(-/-) mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1(-/-) mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1(-/-) mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions. 相似文献
8.
Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal 总被引:1,自引:0,他引:1
David M Kent Peter M Rothwell John PA Ioannidis Doug G Altman Rodney A Hayward 《Trials》2010,11(1):1-11
Background
This paper presents the study protocol for a pragmatic randomised controlled trial to evaluate the impact of a school based program developed to prevent teenage pregnancy. The program includes students taking care of an Infant Simulator; despite growing popularity and an increasing global presence of such programs, there is no published evidence of their long-term impact. The aim of this trial is to evaluate the Virtual Infant Parenting (VIP) program by investigating pre-conceptual health and risk behaviours, teen pregnancy and the resultant birth outcomes, early child health and maternal health.Methods and Design
Fifty-seven schools (86% of 66 eligible secondary schools) in Perth, Australia were recruited to the clustered (by school) randomised trial, with even randomisation to the intervention and control arms. Between 2003 and 2006, the VIP program was administered to 1,267 participants in the intervention schools, while 1,567 participants in the non-intervention schools received standard curriculum. Participants were all female and aged between 13-15 years upon recruitment. Pre and post-intervention questionnaires measured short-term impact and participants are now being followed through their teenage years via data linkage to hospital medical records, abortion clinics and education records. Participants who have a live birth are interviewed by face-to-face interview. Kaplan-Meier survival analysis and proportional hazards regression will test for differences in pregnancy, birth and abortion rates during the teenage years between the study arms.Discussion
This protocol paper provides a detailed overview of the trial design as well as initial results in the form of participant flow. The authors describe the intervention and its delivery within the natural school setting and discuss the practical issues in the conduct of the trial, including recruitment. The trial is pragmatic and will directly inform those who provide Infant Simulator based programs in school settings.Trial registration
ISRCTN24952438 相似文献9.
目的:探讨280例胃食管反流病(GERD)的分布特点及危险因素。方法:对临床诊断和胃镜确诊的280例GERD患者进行临床和风险因子相关性分析。结果:不论汉族还是维族,男性患者比例均明显高于女性;汉族患者高发年龄段早于维族患者(z=-2.939,P=0.003,);汉族和维族患者占反流性食管炎和Barrett食管比例分别为42.4%、81_3%及56.5%、18.8%,其中汉族患者Barrett食管比例较高(X2=14.358,P=0.000);肥胖、习惯性便秘、重体力活动者、饮食习惯不良在维族患者中的比例较高(P〈0.001)。结论:GERD与性别、年龄密切相关,男性多于女性,汉族患者发病年龄高峰旱于维族患者;汉族患者Barrett食管发生比例高于维族患者;肥胖、习惯性便秘、重体力活动、饮食习惯不良可能是GERD尤其是维族人群GERD的危险因素。 相似文献
10.
Caroline PA de Haan Rauni I Kivistö Marjaana Hakkinen Jukka Corander Marja-Liisa Hänninen 《BMC microbiology》2010,10(1):200