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91.
Griffiths PC Paul A Khayat Z Wan KW King SM Grillo I Schweins R Ferruti P Franchini J Duncan R 《Biomacromolecules》2004,5(4):1422-1427
Bioresponsive poly(amidoamine)s (PAA)s are currently under development as endosomolytic polymers for intracellular delivery of proteins and genes. Here for the first time, small-angle neutron scattering (SANS) is used to systematically investigate the pH-dependent conformational change of an endosomolytic polymer, the PAA ISA 23. The radius of gyration of the ISA23 was determined as a function of pH and counterion, the aim being to correlate changes in polymer conformation with membrane activity assessed using a rat red blood cell haemolysis assay. With decreasing pH, the ISA23 radius of gyration increased to a maximum (R(g) approximately 80 A) around pH = 3, before subsequently decreasing once more. At high pH and therefore high ionic strengths, the polymer is negatively charged and adopts a rather compact structure (R(g) approximately 20 A), presumably with the dissociated carboxylic groups on the exterior of the polymer coil. At low pH, the coil again collapses (R(g) < 20 A), presumably due to the effects of the high ionic strength. It is concluded that the nature of the salt form has no direct bearing on the size of the polymer coil, but it does indirectly determine the prevailing pH and, hence, polymer conformation. Pulsed-gradient spin-echo NMR measurements were in good agreement with the SANS estimates of the radius of gyration, although ISA23 polydispersity does complicate the data interpretation/comparison. These results support the proposed mode of action of PAAs, namely a coil expansion on passing from a neutral pH (extracellular) to an acidic pH (endosomal and lysosomal) environments. The results do, however, suggest that the charge on the polymer shows a closer correlation with the haemolysis activity rather than the polymer conformation. 相似文献
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Pasquale Linciano Luca Pinzi Silvia Belluti Ugo Chianese Rosaria Benedetti Davide Moi Lucia Altucci Silvia Franchini Carol Imbriano Claudia Sorbi Giulio Rastelli 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):2080
Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG. A series of derivatives decorated with different aromatic or heteroaromatic linkers, and various cap groups were synthesised and biologically tested. In vitro tests demonstrated that some compounds are able to inhibit HDAC6 with good potency, the best candidate reaching an IC50 of 700 nM. Such good potency obtained with a completely new ZBG make these compounds particularly attractive. The effect of the most active inhibitors on the acetylation levels of histone H3 and α- tubulin and their anti-proliferative activity of DU145 cells were also investigated. Docking studies were performed to evaluate the binding mode of these new derivatives and discuss structure-activity relationships. 相似文献
96.
Kessiri Kongmanas Hongbin Xu Arman Yaghoubian Laura Franchini Luigi Panza Fiamma Ronchetti Kym Faull Nongnuj Tanphaichitr 《Journal of lipid research》2010,51(12):3548-3558
Seminolipid, also known as sulfogalactosylglycerolipid (SGG), plays important roles in male reproduction. Therefore, an accurate and sensitive method for SGG quantification in testes and sperm is needed. Here we compare SGG quantitation by the traditional colorimetric Azure A assay with LC-ESI-MS/MS using multiple reaction monitoring (MRM). Inclusion of deuterated SGG as the internal standard endowed accuracy to the MRM method. The results showed reasonable agreement between the two procedures for purified samples, but for crude lipid extracts, the colorimetric assay significantly overestimated the SGG content. Using ESI-MS/MS MRM, C16:0-alkyl/C16:0-acyl SGG of Cgt+/− mice was quantified to be 406.06 ± 23.63 μg/g testis and 0.13 ± 0.02 μg/million sperm, corresponding to 78% and 87% of the wild-type values, respectively. CGT (ceramide galactosyltransferase) is a critical enzyme in the SGG biosynthesis pathway. Cgt−/− males depleted of SGG are infertile due to spermatogenesis arrest. However, Cgt+/− males sire offspring. The higher than 50% expression level of SGG in Cgt+/− animals, compared with the wild-type expression, might be partly due to compensatory translation of the active CGT enzyme. The results also indicated that 78% of SGG levels in Cgt+/− mice were sufficient for normal spermatogenesis. 相似文献
97.
Xenopus froglets can perfectly heal skin wounds without scarring. To explore whether this capacity is maintained as development proceeds, we examined the cellular responses during the repair of skin injury in 8‐ and 15‐month‐old Xenopus laevis. The morphology and sequence of healing phases (i.e., inflammation, new tissue formation, and remodeling) were independent of age, while the timing was delayed in older frogs. At the beginning of postinjury, wound re‐epithelialization occurred in form of a thin epithelium followed by a multilayered epidermis containing cells with apoptotic patterns and keratinocytes stained by anti‐inducible nitric oxide synthase (iNOS) antibody. The inflammatory response, early activated by recruitment of blood cells immunoreactive to anti‐tumor necrosis factor (TNF)‐α, iNOS, transforming growth factor (TGF)‐β1, and matrix metalloproteinase (MMP)‐9, persisted over time. The dermis repaired by a granulation tissue with extensive angiogenesis, inflammatory cells, fibroblasts, and anti‐α‐SMA positive myofibroblasts. As the healing progressed, wounded areas displayed vascular regression, decrease in cellularity, and rearrangement of provisional matrix. The epidermis restored to a prewound morphology while granulation tissue was replaced by a fibrous tissue in a scar‐like pattern. The quantitative PCR analysis demonstrated an up‐regulated expression of Xenopus suppressor of cytokine signaling 3 (XSOCS-3) and Xenopus transforming growth factor-β2 (XTGF-β2) soon after wounding and peak levels were detected when granulation tissue was well developed with a large number of inflammatory cells. The findings indicate that X. laevis skin wound healing occurred by a combination of regeneration (in epidermis) and repair (in dermis) and, in contrast to froglet scarless wound healing, the growth to a more mature adult stage is associated with a decrease in regenerative capacity with scar‐like tissue formation. J. Morphol. 274:956–964, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
98.
Jo?o Paulo Lopes-Silva Jonatas Ferreira da Silva Santos Braulio Henrique Magnani Branco César Cavinato Cal Abad Luana Farias de Oliveira Irineu Loturco Emerson Franchini 《PloS one》2015,10(11)
ObjectivesThe aim of this study was to evaluate the effect of caffeine ingestion on performance and estimated energy system contribution during simulated taekwondo combat and on post-exercise parasympathetic reactivation.MethodsTen taekwondo athletes completed two experimental sessions separated by at least 48 hours. Athletes consumed a capsule containing either caffeine (5 mg∙kg-1) or placebo (cellulose) one hour before the combat simulation (3 rounds of 2 min separated by 1 min passive recovery), in a double-blind, randomized, repeated-measures crossover design. All simulated combat was filmed to quantify the time spent fighting in each round. Lactate concentration and rating of perceived exertion were measured before and after each round, while heart rate (HR) and the estimated contribution of the oxidative (WAER), ATP-PCr (WPCR), and glycolytic (W[La-]) systems were calculated during the combat simulation. Furthermore, parasympathetic reactivation after the combat simulation was evaluated through 1) taking absolute difference between the final HR observed at the end of third round and the HR recorded 60-s after (HRR60s), 2) taking the time constant of HR decay obtained by fitting the 6-min post-exercise HRR into a first-order exponential decay curve (HRRτ), or by 3) analyzing the first 30-s via logarithmic regression analysis (T30).ResultsCaffeine ingestion increased estimated glycolytic energy contribution in relation to placebo (12.5 ± 1.7 kJ and 8.9 ± 1.2 kJ, P = 0.04). However, caffeine did not improve performance as measured by attack number (CAF: 26. 7 ± 1.9; PLA: 27.3 ± 2.1, P = 0.48) or attack time (CAF: 33.8 ± 1.9 s; PLA: 36.6 ± 4.5 s, P = 0.58). Similarly, RPE (CAF: 11.7 ± 0.4 a.u.; PLA: 11.5 ± 0.3 a.u., P = 0.62), HR (CAF: 170 ± 3.5 bpm; PLA: 174.2 bpm, P = 0.12), oxidative (CAF: 109.3 ± 4.5 kJ; PLA: 107.9 kJ, P = 0.61) and ATP-PCr energy contributions (CAF: 45.3 ± 3.4 kJ; PLA: 46.8 ± 3.6 kJ, P = 0.72) during the combat simulation were unaffected. Furthermore, T30 (CAF: 869.1 ± 323.2 s; PLA: 735.5 ± 232.2 s, P = 0.58), HRR60s (CAF: 34 ± 8 bpm; PLA: 38 ± 9 bpm, P = 0.44), HRRτ (CAF: 182.9 ± 40.5 s, PLA: 160.3 ± 62.2 s, P = 0.23) and HRRamp (CAF: 70.2 ± 17.4 bpm; PLA: 79.2 ± 17.4 bpm, P = 0.16) were not affected by caffeine ingestion.ConclusionsCaffeine ingestion increased the estimated glycolytic contribution during taekwondo combat simulation, but this did not result in any changes in performance, perceived exertion or parasympathetic reactivation. 相似文献
99.
Gut bacterial communities are now known to influence a range of fitness related aspects of organisms. But how different the microbial community is in closely related species, and if these differences can be interpreted as adaptive is still unclear. In this study we compared microbial communities in two sets of closely related sympatric crater lake cichlid fish species pairs that show similar adaptations along the limnetic-benthic axis. The gut microbial community composition differs in the species pair inhabiting the older of two crater lakes. One major difference, relative to other fish, is that in these cichlids that live in hypersaline crater lakes, the microbial community is largely made up of Oceanospirillales (52.28%) which are halotolerant or halophilic bacteria. This analysis opens up further avenues to identify candidate symbiotic or co-evolved bacteria playing a role in adaptation to similar diets and life-styles or even have a role in speciation. Future functional and phylosymbiotic analyses might help to address these issues. 相似文献
100.
Santos VG Franchini E Lima-Silva AE 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(6):1743-1751
The purpose of this study was to determine the relationship between attack time (AT) and skipping time (ST) during the 2007 Taekwondo World Championship and 2008 Beijing Olympic Games. A total of 22 matches (65 rounds, 13 semifinals, and 8 finals) from the World Championship and 23 matches (63 rounds, 22 rounds with 16 athletes each and 1 quarterfinal round) from the Olympic Games, both in the male category, were assessed using time-motion analysis. The AT was considered as the total time during which the athlete attacked or tried to attack, whereas ST was the total time without attempting to attack. The ratio of AT to ST was ~ 1:7 based on the data pooled from the 2 competitions. The AT/ST ratio was significantly lower for the World Championship than for the Olympic Games (p ≤ 0.05). In the Olympic Games, no consistent differences across weight divisions were found. However, during the World Championship, the heavier weight divisions (>78 kg) exhibited a lower average AT, lower summed AT, lower attack numbers (ANs)and higher average ST than lighter weight divisions (<58 kg, p ≤ 0.05). For both competitions, the ST was lower, and the ANs and AT/ST ratio were higher in round 3 than in round 1 or 2. In conclusion, the results of this study suggest that matches in the Olympic Games were less cadenced than in the World Championship, but that in both competitions, the intensity of the match increased in round 3. Practically, these data suggest that coaches need to structure Taekwondo training sessions in a manner that allows the work/pause ratio to mirror the physical demand imposed during competitions. 相似文献