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251.
Incorporation and metabolism of c9,t11 and t10,c12 conjugated linoleic acid (CLA) isomers in rat brain 总被引:1,自引:0,他引:1
Fa M Diana A Carta G Cordeddu L Melis MP Murru E Sogos V Banni S 《Biochimica et biophysica acta》2005,1736(1):61-66
Conjugated linoleic acid (CLA) has been shown to exert several biological activities in different organs, in particular organs such as adipose and mammary tissue where CLA accumulates preferentially because of its high incorporation into neutral lipids. However, despite numerous studies carried out in different experimental models, both in vivo and in vitro, very little is known about the accumulation and metabolism of CLA in the brain. In this communication we present data showing that the two CLA isomers c9,t11 and t10,c12 are actively incorporated and metabolised in rat brain, and in cultures of astrocytes in vitro with patterns remarkably similar to those previously reported to occur in other tissues and cells. However, beta oxidation of CLA was found to be more efficient in brain than in other tissues, with t10,c12 a better substrate than the c9,t11 isomer. CLA incorporation and metabolism have been linked to antiinflammatory and antiproliferative activities in experimental models. Therefore, CLA activity in brain could have a positive impact on neurological disorders, such as Alzheimer's disease, Parkinson's disease and adrenoleukodystrophy, where an observed increase in inflammatory responses seems to contribute heavily to the pathogenesis. 相似文献
252.
Banni S Petroni A Blasevich M Carta G Angioni E Murru E Day BW Melis MP Spada S Ip C 《Biochimica et biophysica acta》2004,1682(1-3):120-127
In a previous paper, we showed that naturally occurring conjugated linoleic acid (CLA) from butter fat is metabolized in vivo to higher metabolites such as conjugated diene (CD) 18:3, CD 20:3 and CD 20:4, all the while retaining the conjugated diene structure. In this paper, we describe the detection of two more metabolites with characteristic conjugated diene UV spectra. HPLC retention times, UV and MS spectra identified the CLA metabolites as CD 16:2 and CD 16:3. The accumulation of CD 16:2 was significantly higher than that of CD 16:3 in all tissues examined. Tissue distributions of CD 16:2 and CD 16:3 were similar, with plasma and adipose tissue showing the highest levels, while kidney had the lowest and the liver an intermediate level. CD 16 fatty acids accounted for about 20% of the total CLA metabolites. The kidney, however, was an exception where CD 16 fatty acids accounted for only 11% of total metabolites. Analyses of liver lipid classes showed that CD 16:2 and CD 16:3 were preferentially incorporated into neutral lipids. This preferential incorporation was very similar to CLA as shown previously. We hypothesize that CD 16:2 and CD 16:3 may be derived from partial beta-oxidation of CLA and CD 20:4, respectively, even though we cannot rule out that CD 16:3 may also be derived from CD 18:3 and CD 20:3. Incubation of skin human fibroblasts from X-linked adrenoleukodystrophy (ALD) patients with c9,t11 CLA showed that CD 16:2 formation in ALD cells was about 50% lower than control cells. This result may tempt to hypothesize that, at least in part, CD 16:2 is beta-oxidized in peroxisomes. 相似文献
253.
Romani A Coinu R Carta S Pinelli P Galardi C Vincieri FF Franconi F 《Free radical research》2004,38(1):97-103
Oxidative stress is involved in the pathogenesis of numerous diseases. Nevertheless, no optimal natural antioxidant has been found for therapeutics, therefore polyphenol antioxidants have been looked for in myrtle leaves, a plant that in folk medicine has been used as anti-inflammatory drug. Antioxidant-rich fractions were prepared from myrtle (Myrtus communis L.) leaves liquid-liquid extraction (LLE) with different solvents. All myrtle extracts were very rich in polyphenols. In particular, hydroalcoholic extracts contain galloyl-glucosides, ellagitannins, galloyl-quinic acids and flavonol glycosides; ethylacetate extract and aqueous residues after LLE are enriched in flavonol glycosides and hydrolysable tannins (galloyl-glucosides, ellagitannins, galloyl-quinic acids), respectively. Qualitative and quantitative analysis for the single unidentified compound was also performed. Human LDL exposed to copper ions was used to evaluate the antioxidant activity of the myrtle extracts. Addition of these extracts did not affect the basal oxidation of LDL but dose-dependently decreased the oxidation induced by copper ions. Moreover, the myrtle extracts reduce the formation of conjugated dienes. The antioxidant effect of three myrtle extracts decreased in the following order: hydroalcoholic extracts, ethylacetate and aqueous residues after LLE. The extracts had the following IC50: 0.36, 2.27 and 2.88 μM, when the sum of total phenolic compounds was considered after the correction of molecular weight based on pure compounds. Statistical analysis showed a significant difference among hydroalcoholic extracts vs. the ethylacetate and aqueous residues after LLE. These results suggest that the myrtle extracts have a potent antioxidant activity mainly due to the presence of galloyl derivatives. 相似文献
254.
255.
Caputo V Cianetti L Niceta M Carta C Ciolfi A Bocchinfuso G Carrani E Dentici ML Biamino E Belligni E Garavelli L Boccone L Melis D Andria G Gelb BD Stella L Silengo M Dallapiccola B Tartaglia M 《American journal of human genetics》2012,90(1):161-169
Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth. 相似文献
256.
257.
Winum JY Carta F Ward C Mullen P Harrison D Langdon SP Cecchi A Scozzafava A Kunkler I Supuran CT 《Bioorganic & medicinal chemistry letters》2012,22(14):4681-4685
A series of 50 sulfamates were obtained by reacting 4-aminophenol with isocyanates followed by sulfamoylation. Most of the new compounds were nanomolar inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII, whereas they inhibited less cytosolic offtarget isoforms CA I and II. Some of these sulfamates showed significant antiproliferative activity in several breast cancer cell lines, such as SKBR3, MCF10A, ZR75/1, MDA-MB-361 and MCF7, constituting interesting anticancer leads. 相似文献
258.
Carta F Maresca A Scozzafava A Supuran CT 《Bioorganic & medicinal chemistry letters》2012,22(1):267-270
The inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) with (thio)coumarins has been recently reported (Maresca et al., J. Am. Chem. Soc. 2009, 131, 3057). Here we demonstrate that a series of γ- and δ-(thio)lactones also act as mechanism based, prodrug type CA inhibitors, similar to the (thio)coumarins. Through the esterase activity of CA, these compounds are hydrolyzed in situ to the corresponding hydroxy/keto/mercapto acids which thereafter act as inhibitors. CA isoforms I and IX were efficiently inhibited by simple such compounds, with K(I)s in the range of 0.92-19.1μM, whereas CA II was not inhibited at all. Isoform-selective CA inhibitors which spare the ubiquitous off-target CA II may have interesting applications for example for selectively inhibiting the tumor-associated CA IX, a validated anticancer target. 相似文献
259.
Elena Andreucci Jessica Ruzzolini Silvia Peppicelli Francesca Bianchini Anna Laurenzana Fabrizio Carta 《Journal of enzyme inhibition and medicinal chemistry》2019,34(1):117-123
Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells. Here, we demonstrate that the SLC-0111 CAIX inhibitor potentiates cytotoxicity of Dacarbazine and Temozolomide currently used for advanced melanoma treatment. SLC-0111 also increases breast cancer cell response to Doxorubicin and enhances 5-Fluorouracil cytostatic activity on colon cancer cells. These findings disclose the possibility to extend the use of CAIX inhibitors in the combination therapy of various cancer histotypes. 相似文献
260.
Malik Khelfaoui Frédéric Gambino Xander Houbaert Bruno Ragazzon Christian Müller Mario Carta Frédéric Lanore Bettadapura N. Srikumar Philippe Gastrein Marilyn Lepleux Chun-Lei Zhang Marie Kneib Bernard Poulain Sophie Reibel-Foisset Nicolas Vitale Jamel Chelly Pierre Billuart Andreas Lüthi Yann Humeau 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1633)
Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs. 相似文献