196,147 research outputs found
Liver regeneration in aged mice: new insights
No full textThe regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are involved in the impairment of liver mass recovery during aging. Among the intracellular factors, age-dependent decrease of BubR1 (budding uninhibited by benzimidazole-related 1), YAP (Yes-associated protein) and SIRT1 (Sirtuin-1) have been associated to dampening of tissue reconstitution and inhibition of cell cycle genes following partial hepatectomy. Extracellular factors, such as age-dependent changes in hepatic stellate cells affect liver regeneration through inhibition of progenitor cells and reduction of liver perfusion. Furthermore, chronic release of pro-inflammatory proteins by senescent cells (SASP) affects cell proliferation suggesting that senescent cell clearance might improve tissue regeneration. Accordingly, young plasma restores liver regeneration in aged animals through autophagy re-establishment. This review will discuss how intracellular and extracellular factors cooperate to guarantee a proper liver regeneration and the possible causes of its impairment during aging. The possibility that an improvement of the liver regenerative capacity in elderly might be achieved through elimination of senescent cells via autophagy or by administration of direct mitogenic agents devoid of cytotoxicity will also be entertained
Ionic Self Assembly in the Design of Fluorinated Ionic Liquid Crystals (ILCs)
No full textIonic liquid crystals are a class of compounds containing anions and cations, that combine the properties of liquid crystals and ionic liquids[1].
In the conventional design of ionic liquid crystalline compounds, an ionic core is connected with mesogenic groups via chemical covalent bonding . Alternatively, in ionic compounds, strong electrostatic interactions between cation and anion can be used to build up liquid crystalline order at supramolecular level. This general approach, called ionic self-assembly (ISA), allows one to create ionic phases and mesophases with highly organized supramolecular order [2].
In this context, a new series of fluorinated ionic liquids (ILs) and ionic liquid crystals (ILCs) was obtained starting from perfluoro-alkylated carboxylic acids and 1,2,4-oxadiazolyl-pyridine units (Figure 1). Their thermotropic properties were investigated by combined differential scanning calorimetry and polarized optical microscopy.
Figure 1.
[1] K.V. Axenov and S. Laschat, Materials, 4, 2011, 206; F. Lo Celso, I. Pibiri, A. Triolo, R. Triolo, A. Pace, S. Buscemi and N. Vivona, J. Mater. Chem., 17, 2007, 1201; V. Causin and G. Saielli, J. Mater. Chem., 19, 2009, 9153.
[2] C.F.J. Faul and M. Antonietti, Adv. Mater., 15, 2003, 673
Optimization of a new lead promoting the readthrough of the nonsense mutations for CFTR rescue in human CF cells
No full textOptimization of a new lead promoting the readthrough of the nonsense mutations for CFTR rescue in human CF cells
Laura Lentini, Raffaella Melfi, Sara Baldassano, Marco Tutone, Aldo Di Leonardo, Andrea Pace, Ivana Pibiri
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo
Background and rationale
Cystic Fibrosis patients with nonsense mutations in the CFTR gene have a more severe form of the disease. Nonsense mutations represent about 10% of the mutations that affect the CFTR gene and they are frequently associated to the classical F508 mutation (1). A potential treatment for this genetic alteration is to promote the translational readthrough of premature termination codons (PTCs) by Translational Read-Through-Inducing Drugs (TRIDs) (2-4).
Hypothesis and objectives
Our objective is to evaluate the functionality of the CFTR channel after treatment with a new molecule that we individuated in a precedent FFC project, and the activity of new lead molecules in cells stably expressing a nonsense-CFTR-mRNA (ns CFTR) in CF cellular model systems. We want also to study the supramolecular interactions among TRIDs, CFTR mRNA and the ribosomal A-site to identify the biological target and the mechanism of action.
Essential methods
QSAR, carried out on the basis of our preliminary results, will allow to achieve lead optimization and synthesize then a small library of analogs to be tested and compared to the Lead. We will mutagenize the CFTR cDNA by introducing the most diffuse nonsense mutations. Subsequently, FRT cells engineered with the vector expressing mutagenized nsCFTR, and nonsense-CF-human broncoepithelial cells will be grown in the air-liquid culture system to reproduce in vitro the epithelial organization. CFTR expression after treatments with our molecule will be evaluated by biomolecular techniques. CFTR activity will be revealed by specific CFTR-functionality assays. Finally, in vitro-in vivo (Zebrafish model) analyses of the safety profile for the set of synthesized molecules will complete the study.
Preliminary results
We screened the activity of several molecules synthetized by us in a precedent FFC project, identifying some molecules that showed high readthrough activity associated to the expression of the CFTR protein in ns CF immortalized cells.
Expected final results and their significance
We are confident that our findings will provide the validation of molecules with readthrough activity for the recovery of the CFTR function. Moreover, our pre-clinical study will assess the presence of toxic effects caused by the molecules in vivo.
References
1. Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis., Am J RespirCrit Care Med. 2010 Nov 15;182(10):1262-72.
2. Lentini L, Melfi R, Di Leonardo A, Spinello A, Barone G, Pace A, Palumbo Piccionello A, Pibiri I. Towards a rationale for the PTC124 (Ataluren) promoted read-through of premature stop codons: a computational approach and GFP-reporter cell-based assay. Mol. Pharm. 2014 11, 653-664.
3. Pibiri I, Lentini L, Melfi R, Gallucci G, Pace A, Spinello A, Barone G, Di Leonardo A. Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives European Journal of Medicinal Chemistry 06/2015; 101.
4. Nagel-Wolfrum K, Möller F, Penner I, Baasov T4, Wolfrum U. Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs), BioDrugs. 2016 Apr;30(2):49-74
Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats
No full textFASEB J. 2008 Aug;22(8):2981-9. Epub 2008 Apr 23.
Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats.
Perra A, Simbula G, Simbula M, Pibiri M, Kowalik MA, Sulas P, Cocco MT, Ledda-Columbano GM, Columbano A.
SourceDepartment of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari, Italy.
Abstract
Nonalcoholic fatty liver disease is the most common noninfectious liver disease in clinical practice, and there is an increasing need for new therapeutic approaches for the treatment of this liver disease. Here, we examined the effect of the thyroid hormone triiodothyronine (T3) and the agonist of the thyroid hormone receptor beta isoform (TRbeta), GC-1, on fatty liver and steatohepatitis induced in rodents by a choline-methionine deficient (CMD) diet. Male Fischer 344 rats fed a CMD diet for 1 wk developed a marked fatty liver and mild hepatitis. Concurrent administration of T3 resulted in a complete prevention of the fatty change associated with increased fatty acid mitochondrial and peroxisomal beta-oxidation. To investigate whether T3 could also reverse fully established fatty liver, rats were fed a CMD diet for 10 wk and then cofed T3 for 1 wk. Coadministration of T3 resulted in a complete regression of liver steatosis associated with a decrease of lipid peroxidation, cyclooxygenase-2 expression, and activation of phospho-STAT3 and phospho-SAPK/JNK. Finally, additional experiments showed that GC-1, which has no significant side effects on heart rate, prevented and reverted CMD-induced fat accumulation, and ameliorated steatohepatitis. These results indicate that TR agonists have the potential to inhibit or reverse hepatic steatosis induced by a nutritional model.
PMID:18434432[PubMed - indexed for MEDLINE
Gadd 45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia
No full textHepatology. 2005 Nov;42(5):1118-26.
Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia.
Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Menegazzi M, Moore DD, Huang W, Tian J, Locker J.
SourceDepartment of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy. [email protected]
Abstract
We previously observed that Gadd45/MyD118, a member of the Gadd45 family of inducible factors, showed the strongest immediate-early induction common to two distinctive proliferation responses of the liver: (1) regeneration induced by surgical partial hepatectomy and (2) hyperplasia induced by the primary mitogen TCPOBOP, a ligand of the constitutive androstane receptor (CAR). Gadd45 is known to be stimulated by nuclear factor (NF) B, which is activated by tumor necrosis factor alpha (TNF) in the early response to partial hepatectomy. We therefore investigated whether TNF and NFB also stimulated Gadd45 as part of the response to CAR ligands, or whether activation occurred by an alternative pathway. TCPOBOP effects were characterized in three mouse genotypes: wild-type, TNFR1-/-, and TNFR1-/-TNFR2-/-. The results showed that TCPOBOP did not activate NFB in any of the mice, but a strong induction of Gadd45 messenger RNA was observed in all three genotypes, where TCPOBOP also induced CyP2b10, a classical target gene of activated CAR, and cyclin D1, a proliferation linked gene. Thus, the absence of TNFR signaling and induction of NFB did not impair CAR-mediated gene induction. Moreover, hepatocyte proliferation was strongly induced, and at significantly higher levels than wild type, in both TNFR1-/- and TNFR1-/-TNFR2-/- mice. Further studies evaluated TCPOBOP-induced gene expression in CAR-/- mice, by microarray expression profiling and Northern blot. The induced changes in gene expression, including the stimulation of Gadd45, were almost completely abolished--hence all were mediated via CAR activation. In conclusion, in the liver, Gadd45 can be induced by a distinctive pathway that requires CAR and is independent of TNF-NFB. The greater induction of proliferation in TNFR-null mice suggests negative cross-talk between the CAR and TNF-NFB controls that regulate proliferation
Towards EEG-based Performance Assessment in Dataset Annotation Tasks
No full textArtificial intelligence is more and more adopted to complement human activity in solving complex tasks in several domains, including healthcare, security, finance, and automation. In order to be effective, several artificial intelligence tools rely on large training sets of carefully annotated data. Since labeling is mostly performed manually, it is a costly and error-prone process. Hence, there is increasing interest in devising innovative tools to support the annotation task. In this paper, we report an initial investigation on the application of EEG data mining for evaluating the performance of humans carrying out image annotation tasks. Our approach relies on a cheap portable EEG sensor and on supervised learning methods. We collected a dataset from five volunteers, and performed an initial evaluation of our technique. The achieved results are promising, and pave the way to several research directions. To the best of our knowledge, our work is the first one applying EEG data mining for assessing the performance of labelers
Molecular Targets of microRNAs during Liver Regeneration after Acute Injury: Recent Advances.
No full textExperimental models using 2/3 partial hepatectomy or chemical injury have helped identify the pathways associated with liver regeneration (LR). Several microRNAs (miRNAs) have been identified as modulators of LR, but the molecular mechanisms underlying their activity are still unclear. Given the development of new therapies targeting miRNAs, this is an important question to address. This review discusses recent studies exploring the molecular mechanisms of miRNA-dependent regulation of LR. In particular, the finding that circ-RBM23 promotes LR by sequestering cytoplasmic miRNA139-5p has furthered the understanding of the molecular mechanisms underlying circRNA activity. Interestingly, although miRNAs are generally considered negative regulators of their target mRNAs, miRNAs182-5p promotes LR by upregulating Cyp7a. Furthermore, mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) were shown to enhance LR after 2/3 partial hepatectomy by releasing miRNAs that inhibit gene expression to promote an anti-inflammatory response or miRNA-regulatory factors. Since the administration of MSCs-EVs has no hepatotoxic side effects, this may represent a therapeutic strategy to promote LR. miRNAs also mediate LR after chemical injury. This is the case for miR194 and miR21, whose downregulation activates pro-regeneration pathways to ameliorate acetaminophen-induced liver injury. In addition, the downregulation of miR21 has been shown to improve autophagy and haemostasis after acetaminophen overdose. Although further studies are needed to improve their efficacy as therapeutics, the evidence gathered in this review has led to a better understanding of the molecular mechanisms associated with the control of LR by miRNAs
Fast dictionary-based compression for inverted indexes
No full textDictionary-based compression schemes provide fast decoding operation, typically at the expense of reduced compression effectiveness compared to statistical or probability-based approaches. In this work, we apply dictionary-based techniques to the compression of inverted lists, showing that the high degree of regularity that these integer sequences exhibit is a good match for certain types of dictionary methods, and that an important new trade-off balance between compression effectiveness and compression efficiency can be achieved. Our observations are supported by experiments using the document-level inverted index data for two large text collections, and a wide range of other index compression implementations as reference points. Those experiments demonstrate that the gap between efficiency and effectiveness can be substantially narrowed
Theoretical study of photoinduced ring-isomerization in the 1,2,4-oxadiazole series
No full textA theoretical study of photoinduced ring-isomerization of 3-amino-5-methyl- and 3-amino-5-phenyl-1,2,4-oxadiazoles is reported. The results well agree with the reported experimental data: in particular, they explain the ring-photoisomerization into the corresponding 2-amino-1,3,4-oxadiazoles through a ring contraction-ring expansion route; moreover, the occurrence of competing pathways involving both the ring contraction and the internal cyclization–isomerization mechanism during irradiation of the 5-alkyl substituted substrates in the presence of a base has been also substantiated
Aqueous selective photocatalytic oxidation of salicyl alcohol by TiO2 catalysts: Influence of some physico-chemical features
No full textPartial photocatalytic oxidation of salicyl alcohol (2-hydroxybenzyl alcohol) to salicylaldehyde in water was investigated under environmental friendly conditions in the presence of home-prepared and commercial TiO2 (Merck and Aeroxide P25) samples under UVA irradiation. The photocatalysts were characterized by using BET, XRD, SEM and/or TEM techniques. The effects of crystallinity degree, pH (3–11) and presence of a hole trap (ethanol) on the photocatalytic activity and product selectivity were investigated. 4-Hydroxybenzyl alcohol was also used to study the influence of the position of the substituent group in the aromatic ring. High alcohols conversion and product selectivity values were obtained at pH = 11 by using well crystallized TiO2 samples. The conversion values significantly decreased by increasing the hole trap concentration, whereas the selectivity values increased slightly. The selectivity towards the corresponding aldehyde after 30% of alcohol conversion was significantly higher for 4-HBA (48%) than for 2-HBA (32%), due to the role of the para position of the substituent group. In order to clarify the different selectivity of the products, various experiments have been also performed starting from the products; these results indicate that the selectivity is also strongly dependent on the stability of the formed products under the experimental conditions used. By concluding, this article reports that the conversion and selectivity values for the studied reaction depend both on the TiO2 type and on the substrate
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