The toxicological screening on a new anti-mycobacterial compound, derived of 5-aryl-2-thio-1,3,4-oxadiazole

UMF “Carol Davila” Bucureşti, Facultatea de Farmacie, Catedra Chimie farmaceutică și toxicologică, IP USMF “Nicolae Testemițanu”, Republica Moldova, Laboratorul de Sinteză organică, Institutul de Chimie a Academiei de Științe, Republica MoldovaObiectivul studiului: Tuberculoza reprezintă o problemă majoră de sănătate publică. Testarea unor substanţe active noi, cu potenţial antimicobacterian, constituie un obiectiv prioritar al cercetării ştiinţifice la nivel mondial. În acest studiu, ne-am propus ca obiectiv, investigarea profilului toxicologic al unui compus nou sintetizat: 2-(propiltio)-5H-[1,3,4]-tiadiazol[2,3-b] quinazolin- 5-ona, care a demonstrat o activitate antimicobacteriană remarcabilă in vitro. Material şi metode: Determinarea toxicităţii compusului de testat a fost realizată prin două metode: in vitro (inhibiţie pe celula vegetală) şi in vivo (şoareci albi, masculi, suşa NMRI). Testarea toxicităţii in vitro s-a realizat prin testul Triticum, care constă în determinarea diluţiei maxime active a substanţei studiate, care în funcţie de durata de acţiune influenţează alungirea radiculară şi filmul cariochinetic. S-au folosit cariopse de Triticum vulgare Mill, soiul Dropia, familia Poaceae. Pentru determinarea toxicităţii acute in vivo, s-au utilizat două metode care au vizat două aspecte: încadrarea substanţei de testat în clasele de toxicitate ale Sistemului Global Armonizat (GHS, Global Harmonized System – conform ghidului OECD 423) şi stabilirea DL50. La sfârşitul experimentului, animalele au fost sacrificate şi s-au recoltat probe de sânge pe care s-au efectuat examene hematologice şi biochimice. Pentru realizarea examenului histopatologic, au fost recoltate fragmente de organe fixate ulterior în soluţie 10% formaldehidă. Secţiunile histologice au fost colorate prin metoda hematoxilină- eozină. Rezultate: Rezultatele experimentale efectuate pe celula vegetală, au evidenţiat o relaţie liniară: concentraţie – efect inhibitor al alungirii radiculare. Determinarea toxicităţii in vivo, ne-a permis încadrarea substanţei de testat în clasele de toxicitate prevăzute de ghidul OECD 423, pentru determinarea toxicităţii acute. Concluzii: Cercetările privind toxicitatea compusului nou sintetizat: 2-(propiltio)-5H-[1,3,4]-tiadiazol[2,3-b] quinazolin- 5-ona, vor permite stabilirea dozelor eficace pentru investigarea profilului farmacologic la animale de laborator. Studiile au fost finanţate prin proiectul 14/ 23.12.2013 din competiţia „N. Testemiţanu”

Resveratrol Encapsulation and Release from Pristine and Functionalized Mesoporous Silica Carriers

Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase its dissolution rate. Pristine MCM-41, MCM-48, SBA-15, SBA-16, FDU-12 and MCF silica were obtained. The influence of SBA-15 functionalized with aminopropyl, isocyanate, phenyl, mercaptopropyl, and propionic acid moieties on resveratrol loading and release profiles was also assessed. The cytotoxic effects were evaluated for mesoporous carriers and resveratrol-loaded samples against human lung cancer (A549), breast cancer (MDA-MB-231) and human skin fibroblast (HSF) cell lines. The effect on apoptosis and cell cycle were assayed for selected resveratrol-loaded carriers. The polyphenol molecules are encapsulated only inside the mesopores, mostly in amorphous state. All materials containing either pristine or functionalized silica carriers increased polyphenol dissolution rate. The influence of the physico-chemical properties of the mesoporous carriers and resveratrol-loaded supports on the kinetic parameters was identified. Resv@SBA-15-SH and Resv@SBA-15-NCO samples exhibited the highest anticancer effect against A549 cells (IC50 values were 26.06 and 36.5 µg/mL, respectively) and against MDA-MB-231 (IC50 values were 35.56 and 19.30 µg/mL, respectively), which highlights their potential use against cancer

Versatile Biomaterial Platform Enriched with Graphene Oxide and Carbon Nanotubes for Multiple Tissue Engineering Applications

Carbon-based nanomaterials, such as graphene oxide (GO) or carbon nanotubes (CNTs) are currently used in various medical applications due to their positive influence on biocompatibility, adhesion, proliferation, and differentiation, as well as their contribution to modulating cell behavior in response to nanomaterial substrates. In this context, in this study, novel flexible membranes based on cellulose acetate (CA) enriched with CNT and GO in different percentages were tested for their versatility to be used as substrates for soft or hard tissue engineering (TE), namely, for their ability to support human adipose-derived stem cells (hASCs) adhesion during adipogenic or osteogenic differentiation. For this purpose, differentiation markers were assessed both at gene and protein levels, while histological staining was performed to show the evolution of the processes in response to CA-CNT-GO substrates. Micro-CT analysis indicated porous morphologies with open and interconnected voids. A slightly lower total porosity was obtained for the samples filled with the highest amount of GO and CNTs, but thicker walls, larger and more uniform pores were obtained, providing beneficial effects on cell behavior and increased mechanical stability. The addition of 1 wt% GO and CNT to the biocomposites enhanced hASCs adhesion and cytoskeleton formation. The evolution of both adipogenic and osteogenic differentiation processes was found to be augmented proportionally to the GO-CNT concentration. In conclusion, CA-CNT-GO biomaterials displayed good properties and versatility as platforms for cell differentiation with potential as future implantable materials in TE applications

Resveratrol Encapsulation and Release from Pristine and Functionalized Mesoporous Silica Carriers

Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase its dissolution rate. Pristine MCM-41, MCM-48, SBA-15, SBA-16, FDU-12 and MCF silica were obtained. The influence of SBA-15 functionalized with aminopropyl, isocyanate, phenyl, mercaptopropyl, and propionic acid moieties on resveratrol loading and release profiles was also assessed. The cytotoxic effects were evaluated for mesoporous carriers and resveratrol-loaded samples against human lung cancer (A549), breast cancer (MDA-MB-231) and human skin fibroblast (HSF) cell lines. The effect on apoptosis and cell cycle were assayed for selected resveratrol-loaded carriers. The polyphenol molecules are encapsulated only inside the mesopores, mostly in amorphous state. All materials containing either pristine or functionalized silica carriers increased polyphenol dissolution rate. The influence of the physico-chemical properties of the mesoporous carriers and resveratrol–loaded supports on the kinetic parameters was identified. Resv@SBA-15-SH and Resv@SBA-15-NCO samples exhibited the highest anticancer effect against A549 cells (IC50 values were 26.06 and 36.5 µg/mL, respectively) and against MDA-MB-231 (IC50 values were 35.56 and 19.30 µg/mL, respectively), which highlights their potential use against cancer

Mechanochemical Synthesis of Resveratrol–Piperazine Cocrystals

The 1:1 resveratrol–piperazine cocrystal was successfully synthesized and scaled-up to 300 g scale with the mechanochemical method, as a result of investigating key process parameters, namely the solvent and the grinding time. The use of water, ethanol or ethanol–water mixtures and reaction times up to 50 min were evaluated relative to the dry grinding process. Cocrystal formation and purity were monitored through X-ray diffraction and calorimetry measurements. The dry grinding resulted in an incomplete cocrystal formation, while the use of water or water–ethanol mixture yielded a monohydrate solid phase. Pure ethanol was found to be the optimal solvent for large-scale cocrystallization, as it delivered cocrystals with high crystallinity and purity after 10–30 min grinding time at the laboratory scale. Notably, a relatively fast reaction time (30–60 min) was sufficient for the completion of cocrystallization at larger scales, using a planetary ball mill and a plant reactor. Also, the obtained cocrystal increases the aqueous solubility of resveratrol by 6%–16% at pH = 6.8. Overall, this study highlights the potential of solvent-assisted mechanochemical synthesis as a promising new approach for the efficient production of pure resveratrol–piperazine cocrystals