35 research outputs found
Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia
: Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL
Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia
Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL
Polar Head Modified Phospholipids by Phospholipase D-Catalyzed Transformations of Natural Phosphatidylcholine for Targeted Applications: An Overview
This review describes the use of phospholipaseD(PLD) to performthe transphosphatidylation
of themost common natural phospholipid (PL), phosphatidylcholine (PC) to obtain polar headmodified
phospholipids with real targeted applications. The introduction of different polar heads with distinctive
physical and chemical properties such as charge, polarity and dimensions allows the obtainment of very
different PLs, which can be exploited in very diverse fields of application. Moreover, the inclusions of a
bioactivemoiety in the PL polar head constitutes a powerful tool for the stabilization and administration
of active ingredients. The use of this biocatalytic approach allows the preparation of compounds
which cannot be easily obtained by classical chemical methods, by using mild and green reaction
conditions. PLD is a very versatile enzyme, able to catalyze both the hydrolysis of PC to choline and
phosphatidic acid (PA), and the transphosphatidylation reaction in the presence of an appropriate
alcohol. The yield of production of the desired product and the ratio with the collateral PA formation is
highly dependent on parameters such as the nature and concentration of the alcohol and the enzymatic
source. The application of PLD catalyzed transformations for the production of a great number of PLs
with important uses in medical, nutraceutical and cosmetic sectors will be discussed in this work
Atti degli incontri sulle opere di Dante: Commedia: Inferno
Il volume raccoglie gli atti dei seminari organizzati dalla Società Dantesca Italiana nell'ambito della serie Lopereseguite, relativi al testo critico della Commedia e allo studio della prima cantica
Reactive Deep Eutectic Solvents (RDESs): A New Tool for Phospholipase D-Catalyzed Preparation of Phospholipids
The use of Reactive Deep Eutectic Solvents (RDESs) in the preparation of polar head modified phospholipids (PLs) with phospholipase D (PLD)-catalyzed biotransformations has been investigated. Natural phosphatidylcholine (PC) has been submitted to PLD-catalyzed transphosphatidylations using a new reaction medium composed by a mixture of RDES/buffer. Instead of exploiting deep eutectic solvents conventionally, just as the reaction media, these solvents have been designed here in order to contribute actively to the synthetic processes by participating as reagents. RDESs were prepared using choline chloride or trimethyl glycine as hydrogen-bond acceptors and glycerol or ethylene glycol, as hydrogen-bond donors as well as nucleophiles for choline substitution. Specifically designed RDES/buffer reaction media allowed the obtainment of PLs with optimized yields in the perspective of a sustainable process implementation
Dependence of 1H-NMR T1 relaxation time of trimethylglycine betaine deep eutectic solvents on the molar composition and on the presence of water
1
H-NMR spin lattice relaxation times (T1), measured by inversion recovery technique, allowed to establish
the stoichiometric coefficient (ratio between the H-bond acceptor and H-bond donor) of a series of
trimethylglycine betaine/diol based deep eutectic solvents (DESs); ethylene glycol, triethylene glycol and
1,3-propandiol were selected as H-bond donors. The maximum amount of water tolerated by the DES,
before its complete hydration, was determined as well. Finally, the method was validated comparing the
eutectic composition of the betaine/glycol system with that determined by means of differential
scanning calorimetry analysis; the stoichiometric coefficients were identica
PRELIMINARY STUDIES ON THE EFFECTS OF COMBINED STEAMING AND VACUUMTHERMAL TREATMENTS ON TURKEY OAK (QUERCUS CERRIS L.)
Turkey oak is a wood species widely distributed in south-eastern Europe and in Italy, where it is mainly present in the Apenni -
ne Mountains. Compared to other oaks, Turkey oak is less valued because of its easy tendency to crack, its lower technological
quality, and its lower durability. The aim of the present work was to improve wood quality by treating Turkey oak through
combined steaming and thermal treatment in vacuum conditions. Wood was steamed at a temperature between 100 to 110 °C
and thermally treated in vacuum conditions at 160 °C using two different technologies, i.e., the press vacuum plant and the Termovuoto
® plant. The treated material was characterized in terms of mass loss, color change, hygroscopicity and compression
strength for both heartwood and sapwood. Results slightly differed according to the treatment or combination of treatments
adopted. In general, a significant increase in dimensional stability and an improved color homogenization were obtained together
with the maintenance of a good wood quality. Concerning mechanical properties, thermo-vacuum treatment increased the
compression strength, while steaming had the opposite effect