Mechanical reinforcement of granular hydrogels

Granular hydrogels are composed of hydrogel-based microparticles, so-called microgels, that are densely packed to form an ink that can be 3D printed, injected or cast into macroscopic structures. They are frequently used as tissue engineering scaffolds because microgels can be made biocompatible and the porosity of the granular hydrogels enables a fast exchange of reagents, waste products, and if properly designed even the infiltration of cells. Most of these granular hydrogels can be shaped into appropriate macroscopic structures, yet, these structures are mechanically rather weak. The poor mechanical properties prevent the use of these structures as load-bearing materials and hence, limit their field of applications. The mechanical properties of granular hydrogels depend on the composition of microgels and the interparticle interactions. In this review, we discuss different strategies to assemble microparticles into granular hydrogels and highlight the influence of inter-particle connections on the stiffness and toughness of the resulting materials. Mechanically strong and tough granular hydrogels have the potential to open up new fields of their use and thereby to contribute to fast advances in these fields. In particular, we envisage them to be well-suited as soft actuators and robots, tissue replacements, and adaptive sensors.

The mechanical properties of granular hydrogels are strongly influenced by interparticle interactions. In this review, we compare the storage, compressive and tensile moduli of granular hydrogels cured using various interparticle interactions.     

Modern Synthetic Strategies with Organoselenium Reagents: A Focus on Vinyl Selenones

In recent years, vinyl selenones were rediscovered as useful building blocks for new synthetic transformations. This review will highlight these advances in the field of multiple-bond-forming reactions, one-pot synthesis of carbo- and heterocycles, enantioselective construction of densely functionalized molecules, and total synthesis of natural products.     

ParaHydrogen Polarized Ethyl-[1-13C]pyruvate in Water,a Key Substrate for Fostering the PHIP-SAH Approach to Metabolic Imaging

An efficient synthesis of vinyl-[1-¹³C]pyruvate has been reported, from which ¹³C hyperpolarized (HP) ethyl-[1-¹³C]pyruvate has been obtained by means of ParaHydrogen Induced Polarization (PHIP). Due to the intrinsic lability of pyruvate, which leads quickly to degradation of the reaction mixture even under mild reaction conditions, the vinyl-ester has been synthesized through the intermediacy of a more stable ketal derivative. ¹³C and ¹H hyperpolarizations of ethyl-[1-¹³C]pyruvate, hydrogenated using ParaHydrogen, have been compared to those observed on the more widely used allyl-derivative. It has been demonstrated that the spin order transfer from ParaHydrogen protons to ¹³C, is more efficient on the ethyl than on the allyl-esterdue to the larger J-couplings involved. The main requirements needed for the biological application of this HP product have been met, i. e. an aqueous solution of the product at high concentration (40 mM) with a good ¹³C polarization level (4.8 %) has been obtained. The in vitro metabolic transformation of the HP ethyl-[1-¹³C]pyruvate, catalyzed by an esterase, has been observed. This substrate appears to be a good candidate for in vivo metabolic investigations using PHIP hyperpolarized probes.     

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [¹¹¹In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys.     

Synthesis and Evaluation of Thymol-Based Synthetic Derivatives as Dual-Action Inhibitors against Different Strains of H. pylori and AGS Cell Line

Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and ¹H/¹³C/¹⁹F NMR spectra. The analysis of structure–activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.     

Nutritional Value and Preventive Role of Nigella sativa L. and Its Main Component Thymoquinone in Cancer: An Evidenced-Based Review of Preclinical and Clinical Studies

In recent times, scientific attention has been paid to different foods and their bioactive components for the ability to inhibit the onset and progress of different types of cancer. Nigella sativa extract, powder and seed oil and its main components, thymoquinone and α-hederin, have showed potent anticancer and chemosensitizing effects against various types of cancer, such as liver, colon, breast, renal, cervical, lung, ovarian, pancreatic, prostate and skin tumors, through the modulation of various molecular signaling pathways. Herein, the purpose of this review was to highlight the anticancer activity of Nigella sativa and it constitutes, focusing on different in vitro, in vivo and clinical studies and projects, in order to underline their antiproliferative, proapoptotic, cytotoxic and antimetastatic effects. Particular attention has been also given to the synergistic effect of Nigella sativa and it constitutes with chemotherapeutic drugs, and to the synthesized analogs of thymoquinone that seem to enhance the chemo-sensitizing potential. This review could be a useful step towards new research on N. sativa and cancer, to include this plant in the dietary treatments in support to conventional therapies, for the best achievement of therapeutic goals.     

1H-NMR Profiling Shows as Specific Constituents Strongly Affect the International EVOO Blends Characteristics: The Case of the Italian Oil

Considering the growing number of extra virgin olive oil (EVOO) producers in the world, knowing the influence of olive oils with different geographical origins on the characteristics of the final blend becomes an interesting goal. The present work is focused on commercial organic EVOO blends obtained by mixing multiple oils from different geographical origins. These blends have been studied by ¹H-NMR spectroscopy supported by multivariate statistical analysis. Specific characteristics of commercial organic EVOO blends originated by mixing oils from Italy, Tunisia, Portugal, Spain, and Greece were found to be associated with the increasing content of the Italian component. A linear progression of the metabolic profile defined characteristics for the analysed samples—up to a plateau level—was found in relation to the content of the main constituent of the Italian oil, the monocultivar Coratina. The Italian constituent percentage appears to be correlated with the fatty acids (oleic) and the polyphenols (tyrosol, hydroxytyrosol, and derivatives) content as major and minor components respectively. These results, which highlight important economic aspects, also show the utility of ¹H-NMR associated with chemometric analysis as a powerful tool in this field. Mixing oils of different national origins, to obtain blends with specific characteristics, could be profitably controlled by this methodology.     

Design,Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates

Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin.     

Macrocyclization on the fullerene core: Direct regio- and diastereoselective multi-functionalization of [60]fullerene,and synthesis of fullerene-dendrimer derivatives

The macrocyclization between buckminsterfullerene, C₆₀, and bis-malonate derivatives in double Bingel reaction provides a versatile and simple method for the preparation of covalent bis-adducts of C₆₀ with high regio- and diastereoselectivity. A combination of spectral analysis, stereochemical considerations, and X-ray crystallography (Fig. 2) revealed that out of the possible in-in, in-out, and out-out stereoisomers, the reaction of bis-malonates linked by o-, m-, or p-xylylene tethers afforded only the out-out ones (Scheme 1). In contrast, the use of larger tethers derived from 1,10-phenanthroline also provided a first example, (±)- 19 (Scheme 2), of an in-out product. Starting from optically pure bis-malonate derivatives, the new bis-functionalization method permitted the diastereoselective preparation of optically active fullerene derivatives (Schemes 4 and 5) and, ultimately, the enantioselective preparation (enantiomeric excess ee > 97%) of optically active cis-3 bis-adducts whose chirality results exclusively from the addition pattern (Fig. 6). The macrocyclic fixation of a bis-malonate with an optically active, 9,9′-spirobi[9H-fluorene]-derived tether to C₆₀ under generation of 24 and ent- 24 with an achiral addition pattern (Scheme 4) was found to induce dramatic changes in the chiroptical properties of the tether chromophore such as strong enhancement and reversal of sign of the Cotton effects in the circular dichroism (CD) spectra (Figs. 4 and 5). By the same method, the functionafized bis-adducts 50 and 51 (Schemes 10 and 11) were prepared as initiator cores for the synthesis of the fullerene dendrimers 62 , 63 , and 66 (Schemes 12 and 13) by convergent growth. Finally, the new methodology was extended, to the regio- and diastereoselective construction of higher cyclopropanated adducts. Starting from mono-adduct 71 , a clipping reaction provided exclusively the all-cis-2 tris-adduct (±)- 72 (Scheme 14), whereas the similar reaction of bis-adduct 76 afforded the all-cis-2 tetrakis-adduct 77 (Scheme 15). Electrochemical investigations by steady-state voltammetry (Table 2) in CH₂Cl₂ (+0.1M Bu₄NPF₆) showed that all macroeyciic bis(methano)fullerenes underwent multiple reduction steps, and that regioisomerism was not much influencing the redox potentials, All cis-2 bis-adducts gave an instable dianion which decomposed during the electrochemical reduction. In CH₂Cl₂, the redox potential of the fullerene core in dendrimers 62, 63 , and 66 is not affected by differences in size and density of the surrounding poly(ether-amide) dendrons. The all-cis-2 tris- and tetrakis(meihano)fullercnes (±) -72 and 77 , respectively, are reduced at more negative potential than previously reported all-e tris- and tetrakis-adducts with methane bridges that are also located along an equatorial belt. This indicates a larger perturbation of the original fullerene π-chromophore and a larger raise in LUMO energy in the former derivatives.     

Synthesis and NMR characterization of 3,4′-dibutoxy-2,2′-bithiophene

3,4′-Dibromo-2,2′-bithiophene was converted, in high yield, into the corresponding dibutoxy derivative. The ¹H ¹³C and nmr data are discussed in comparison with those of 3,3′- and 4,4′-dibutoxy-2,2′-bithiophene in relation to regiochemistry.