1.
Asymmetry Between Pre- and Postsynaptic Transient Nanodomains Shapes Neuronal Communication.
Heine, M, Holcman, D
Trends in neurosciences. 2020;(3):182-196
Abstract
Synaptic transmission and plasticity are shaped by the dynamic reorganization of signaling molecules within pre- and postsynaptic compartments. The nanoscale organization of key effector molecules has been revealed by single-particle trajectory (SPT) methods. Interestingly, this nanoscale organization is highly heterogeneous. For example, presynaptic voltage-gated calcium channels (VGCCs) and postsynaptic ligand-gated ion channels such as AMPA receptors (AMPARs) are organized into so-called nanodomains where individual molecules are only transiently trapped. These pre- and postsynaptic nanodomains are characterized by a high density of molecules but differ in their molecular organization and stability within the synaptic membrane. We review the main properties of these nanodomains, as well as the methods developed to extract parameters from SPT experiments. We discuss how such molecular dynamics influences synaptic transmission. The nanoscale organization of active synapses opens new insights into the dynamics and turnover of molecules as well as casting light on their contributions to signal transfer between individual neurons.
2.
Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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Plain language summary
Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.
Abstract
OBJECTIVE IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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The Brazilian Cardioprotective Nutritional Program to reduce events and risk factors in secondary prevention for cardiovascular disease: study protocol (The BALANCE Program Trial).
Weber, B, Bersch-Ferreira, ÂC, Torreglosa, CR, Ross-Fernandes, MB, da Silva, JT, Galante, AP, Lara, Ede S, Costa, RP, Soares, RM, Cavalcanti, AB, et al
American heart journal. 2016;(1):73-81.e1-2
Abstract
This article reports the rationale for the Brazilian Cardioprotective Nutritional Program (BALANCE Program) Trial. This pragmatic, multicenter, nationwide, randomized, concealed, controlled trial was designed to investigate the effects of the BALANCE Program in reducing cardiovascular events. The BALANCE Program consists of a prescribed diet guided by nutritional content recommendations from Brazilian national guidelines using a unique nutritional education strategy, which includes suggestions of affordable foods. In addition, the Program focuses on intensive follow-up through one-on-one visits, group sessions, and phone calls. In this trial, participants 45 years or older with any evidence of established cardiovascular disease will be randomized to the BALANCE or control groups. Those in the BALANCE group will receive the afore mentioned program interventions, while controls will be given generic advice on how to follow a low-fat, low-energy, low-sodium, and low-cholesterol diet, with a view to achieving Brazilian nutritional guideline recommendations. The primary outcome is a composite of death (any cause), cardiac arrest, acute myocardial infarction, stroke, myocardial revascularization, amputation for peripheral arterial disease, or hospitalization for unstable angina. A total of 2468 patients will be enrolled in 34 sites and followed up for up to 48 months. If the BALANCE Program is found to decrease cardiovascular events and reduce risk factors, this may represent an advance in the care of patients with cardiovascular disease.
4.
Neuronal differentiation by indomethacin and IBMX inhibits proliferation of small cell lung cancer cells in vitro.
Lange, A, Gustke, H, Glassmeier, G, Heine, M, Zangemeister-Wittke, U, Schwarz, JR, Schumacher, U, Lange, T
Lung cancer (Amsterdam, Netherlands). 2011;(2):178-87
Abstract
BACKGROUND Small cell lung cancer (SCLC) is one of the most aggressive malignancies implying a very poor prognosis for patients even under therapy. Since it is known that SCLC cells exhibit neurone-like characteristics, we investigated whether a neuronal induction medium (NID) consisting of indomethacin (200 μM), 3-isobutyl-1-methylxanthine (IBMX, 500 μM) and insulin (5 μg/ml) induces neuronal differentiation and by this reduces malignancy of SCLC in vitro. METHODS Anti-proliferative effects were tested by incubating five SCLC cell lines (OH1, OH3, SW2, H69 and H82) with NID for 72 h (XTT-assay). Afterwards, anti-proliferative as well as cytotoxic effects (lactate dehydrogenase [LDH] assay, electron microscopy) of a range of drug concentrations (indomethacin 6.25-800 μM, IBMX 15.625-2000 μM and combinations of both) regarding H82 and SW2 were analysed. We further investigated the presence of cyclooxygenase- (COX-) 1 and 2 (IHC, Western blot) as well as levels of COX-2 before and after treatment. Neuronal differentiation was evaluated by morphological analyses (electron microscopy), detection of CD 56 and CD 171 (FACS) and recording Na(+) and K(+) currents (patch clamp). RESULTS Proliferation of all cell lines was inhibited significantly in a dose dependent manner (linear regression), whereas SW2 and H82 were most sensitive. Treatment with insulin alone had no effect at all. Cytotoxic effects were only observed after incubation with high concentrations of indomethacin (H82) and combined treatment (SW2). COX-1 and 2 were detectable in H82 and SW2, whereas the level of COX-2 remained unaffected under treatment. By electron microscopy, we could not observe distinct neurone-like morphological changes after 72 h of treatment. However, the majority of H82 and SW2 cells expressed both CD 56 (NCAM) and CD 171 (L1), showing an increase of NCAM and L1 intensity at the cell surface after 7 and 14 days of treatment. We further demonstrated an up-regulation of neurone-specific Na(+) currents as well as a significant down-regulation of herg K(+) currents after NID treatment. CONCLUSION Our findings demonstrate significant anti-proliferative, non-toxic effects of indomethacin and IBMX on SCLC cells in vitro. Treated SCLC cells further possess increased neuronal characteristics in vitro, possibly leading to a reduced malignant potential.