Nanoparticles in Cancer Diagnosis and Treatment.

The use of tailored medication delivery in cancer treatment has the potential to increase efficacy while decreasing unfavourable side effects. For researchers looking to improve clinical outcomes, chemotherapy for cancer continues to be the most challenging topic. Cancer is one of the worst illnesses despite the limits of current cancer therapies. New anticancer medications are therefore required to treat cancer. Nanotechnology has revolutionized medical research with new and improved materials for biomedical applications, with a particular focus on therapy and diagnostics. In cancer research, the application of metal nanoparticles as substitute chemotherapy drugs is growing. Metals exhibit inherent or surface-induced anticancer properties, making metallic nanoparticles extremely useful. The development of metal nanoparticles is proceeding rapidly and in many directions, offering alternative therapeutic strategies and improving outcomes for many cancer treatments. This review aimed to present the most commonly used nanoparticles for cancer applications.

Hydroxy-3-Phenylcoumarins as Multitarget Compounds for Skin Aging Diseases: Synthesis, Molecular Docking and Tyrosinase, Elastase, Collagenase and Hyaluronidase Inhibition, and Sun Protection Factor.

Skin aging is a progressive biological process of the human body, and it is not only time-dependent. Differently substituted 3-phenylcoumarins proved to efficiently inhibit tyrosinase. In the current work, new substitution patterns have been explored, and the biological studies were extended to other important enzymes involved in the processes of skin aging, as elastase, collagenase and hyaluronidase. From the studied series, five compounds presented inhibitory activity against tyrosinase, one compound against elastase, eight compounds against collagenase and two compounds against hyaluronidase, being five compounds dual inhibitors. The 3-(4'-Bromophenyl)-5,7-dihydroxycoumarin (1) and 3-(3'-bromophenyl)-5,7-dihydroxycoumarin (2) presented the best profiles against tyrosinase (IC50 = 1.05 µM and 7.03 µM) and collagenase (IC50 = 123.4 µM and 110.4 µM); the 3-(4'-bromophenyl)-6,7-dihydroxycoumarin (4) presented a good inhibition against tyrosinase and hyaluronidase; the 3-(3'-bromophenyl)-6,7-dihydroxycoumarin (5) showed an effective tyrosinase and elastase inhibition; and 6,7-dihydroxy-3-(3'-hydroxyphenyl)coumarin (11) presented a dual profile inhibition against collagenase and hyaluronidase. Furthermore, considering the overall activities tested, compounds 1 and 2 proved to be the most promising anti-aging compounds. These compounds also showed to have a photo-protective effect, without being cytotoxic to human skin keratinocyte cells. To predict the binding site with the target enzymes, computational studies were also carried out.

Structural Characterisation and Assessment of the Novel Bacillus amyloliquefaciens RK3 Exopolysaccharide on the Improvement of Cognitive Function in Alzheimer's Disease Mice.

In this study Bacillus amyloliquefaciens RK3 was isolated from a sugar mill effluent-contaminated soil and utilised to generate a potential polysaccharide with anti-Alzheimer's activity. Traditional and molecular methods were used to validate the strain. The polysaccharide produced by B. amyloliquefaciens RK3 was purified, and the yield was estimated to be 10.35 gL-1. Following purification, the polysaccharide was structurally and chemically analysed. The structural analysis revealed the polysaccharide consists of α-d-mannopyranose (α-d-Manp) and ß-d-galactopyranose (ß-d-Galp) monosaccharide units connected through glycosidic linkages (i.e., ß-d-Galp(1→6)ß-d-Galp (1→6)ß-d-Galp(1→2)ß-d-Galp(1→2)[ß-d-Galp(1→6)]ß-d-Galp(1→2)α-d-Manp(1→6)α-d-Manp (1→6)α-d-Manp(1→6)α-d-Manp(1→6)α-d-Manp). The scanning electron microscopy and energy-dispersive X-ray spectroscopy imaging of polysaccharides emphasise their compactness and branching in the usual tubular heteropolysaccharide structure. The purified exopolysaccharide significantly impacted the plaques formed by the amyloid proteins during Alzheimer's disease. Further, the results also highlighted the potential applicability of exopolysaccharide in various industrial and pharmaceutical applications.

Monitoring Indoor People Presence in Buildings Using Low-Cost Infrared Sensor Array in Doorways.

We propose a device for monitoring the number of people who are physically present inside indoor environments. The device performs local processing of infrared array sensor data detecting people's direction, which allows monitoring users' occupancy in any space of the building and also respects people privacy. The device implements a novel real-time pattern recognition algorithm for processing data sensed by a low-cost infrared (IR) array sensor. The computed information is transferred through a Z-Wave network. On-field evaluation of the algorithm has been conducted by placing the device on top of doorways in offices and laboratory rooms. To evaluate the performance of the algorithm in varying ambient temperatures, two groups of stress tests have been designed and performed. These tests established the detection limits linked to the difference between the average ambient temperature and perturbation. For an in-depth analysis of the accuracy of the algorithm, synthetic data have been generated considering temperature ranges typical of a residential environment, different human walking speeds (normal, brisk, running), and distance between the person and the sensor (1.5 m, 5 m, 7.5 m). The algorithm performed with high accuracy for routine human passage detection through a doorway, considering indoor ambient conditions of 21-30 °C.

Synthesis and in vitro study of nitro- and methoxy-2-phenylbenzofurans as human monoamine oxidase inhibitors.

A new series of 2-phenylbenzofuran derivatives were designed and synthesized to determine relevant structural features for the MAO inhibitory activity and selectivity. Methoxy substituents were introduced in the 2-phenyl ring, whereas the benzofuran moiety was not substituted or substituted at the positions 5 or 7 with a nitro group. Substitution patterns on both the phenyl ring and the benzofuran moiety determine the affinity for MAO-A or MAO-B. The 2-(3-methoxyphenyl)-5-nitrobenzofuran 9 was the most potent MAO-B inhibitor (IC50 = 0.024 µM) identified in this series, whereas 7-nitro-2-phenylbenzofuran 7 was the most potent MAO-A inhibitor (IC50 = 0.168 µM), both acting as reversible inhibitors. The number and position of the methoxyl groups on the 2-phenyl ring, have an important influence on the inhibitory activity. Molecular docking studies confirmed the experimental results and highlighted the importance of key residues in enzyme inhibition.

A new biological prospective for the 2-phenylbenzofurans as inhibitors of α-glucosidase and of the islet amyloid polypeptide formation.

In this study, we have investigated a series of hydroxylated 2-phenylbenzofurans compounds for their inhibitory activity against α-amylase and α-glucosidase activity. Inhibitors of carbohydrate degrading enzymes seem to have an important role as antidiabetic drugs. Diabetes mellitus is a wide-spread metabolic disease characterized by elevated levels of blood glucose. The most common is type 2 diabetes, which can lead to severe complications. Since the aggregates of islet amyloid polypeptide (IAPP) are common in diabetic patients, the effect of compounds to inhibit amyloid fibril formation was also determined. All the compounds assayed showed to be more active against α-glucosidase. Compound 16 showed the lowest IC50 value of the series, and it is found to be 167 times more active than acarbose, the reference compound. The enzymatic activity assays showed that compound 16 acts as a mixed-type inhibitor of α-glucosidase. Furthermore, compound 16 displayed effective inhibition of IAPP aggregation and it manifested no significant cytotoxicity. To predict the binding of compound 16 to IAPP and α-glucosidase protein complexes, molecular docking studies were performed. Altogether, our results support that the 2-phenylbenzofuran derivatives could represent a promising candidate for developing molecules able to modulate multiple targets involved in diabetes mellitus disorder.

Looking for new xanthine oxidase inhibitors: 3-Phenylcoumarins versus 2-phenylbenzofurans.

Overproduction of uric acid in the body leads to hyperuricemia, which is also closely related to gout. Uric acid production can be lowered by xanthine oxidase (XO) inhibitors. Inhibition of XO has also been proposed as a mechanism for improving cardiovascular health. Therefore, the search for new efficient XO inhibitors is an interesting topic in drug discovery. 3-Phenylcoumarins and 2-phenylbenzofurans are privileged scaffolds in medicinal chemistry. Their structural similarity makes them interesting molecules for a comparative study. Methoxy and nitro substituents were introduced in both scaffolds. The current study gives some insights into the synthesis and biological activity of these molecules against this important target. For the best compound of the series, the 3-(4-methoxyphenyl)-6-nitrocoumarin (4), the IC50 value, type of inhibition, cytotoxicity on B16F10 cells and ADME theoretical properties, were determined. Docking studies were also performed in order to better understand the interactions of this molecule with the XO binding pocket. This work is a preliminary screening for further design and synthesis of new non-purinergic derivatives as potential compounds involved in the inflammatory suppression, specially related to gout.

Inhibition of CD44 sensitizes cisplatin-resistance and affects Wnt/ß-catenin signaling in HNSCC cells.

CD44 is one of the key cancer stem-like cell (CSC) marker and may have a potential role in tumorigenesis. In this study, we investigated the role of CD44 in prognosis of HNSCC patients, its possible crosstalk with Wnt/ß-catenin signaling and modulating cisplatin resistance. We observed increased expression of CD44 in the cut margin of recurrent HNSCC patients were associated with poor prognosis. We observed that inhibition of CD44 by using 1,2,3,4 tetrahydroisoquinoline (THIQ) modulates the expression of Wnt/ ß-catenin signaling proteins and further silencing of ß-catenin also decreases the expression of CD44. This led us to investigate the possible protein-protein interaction between CD44 and ß-catenin. Co-immunoprecipitation study illustrated possible interaction between CD44 and ß-catenin which was further confirmed by molecular docking and molecular dynamic (MD) simulation studies. Molecular docking study revealed that one interface amino acid residue Glu642 of ß -catenin interacts with Lys92 of CD44 which was also present for 20% of simulation time. Furthermore, we observed that inhibition of CD44 chemosensitizes cisplatin-resistant HNSCC cells towards cisplatin. In conclusion, this study investigated the possible role of CD44 along with Wnt/ ß-catenin signaling and their possible therapeutic role to abrogate cisplatin resistance.

The impact of missense mutation in PIGA associated to paroxysmal nocturnal hemoglobinuria and multiple congenital anomalies-hypotonia-seizures syndrome 2: A computational study.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The disease is caused by the deficiency of two glycosylphosphatidylinositols (GPI)-anchored proteins (CD55 and CD59) in the hemopoietic stem cells. The deficiency of GPI-anchored proteins has been associated with the somatic mutations in phosphatidylinositol glycan class A (PIGA). However, the mutations that do not cause PNH is associated with the multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2). To best of our knowledge, no computational study has been performed to explore at an atomistic level the impact of PIGA missense mutations on the structure and dynamics of the protein. Therefore, we focused our study to provide molecular insights into the changes in protein structural dynamics upon mutation. In the initial step, screening for the most pathogenic mutations from the pool of publicly available mutations was performed. Further, to get a better understanding, pathogenic mutations were mapped to the modeled structure and the resulting protein was subjected to 100 ns molecular dynamics simulation. The residues close to C- and N-terminal regions of the protein were found to exhibit greater flexibility upon mutation. Our study suggests that four mutations are highly effective in altering the structural conformation and stability of the PIGA protein. Among them, mutant G48D was found to alter protein's structural dynamics to the greatest extent, both on a local and a global scale.

Antibacterial Activity and Molecular Docking Studies of a Selected Series of Hydroxy-3-arylcoumarins.

Antibiotic resistance is one of the main public health concerns of this century. This resistance is also associated with oxidative stress, which could contribute to the selection of resistant bacterial strains. Bearing this in mind, and considering that flavonoid compounds are well known for displaying both activities, we investigated a series of hydroxy-3-arylcoumarins with structural features of flavonoids for their antibacterial activity against different bacterial strains. Active compounds showed selectivity against the studied Gram-positive bacteria compared to Gram-negative bacteria. 5,7-Dihydroxy-3-phenylcoumarin (compound 8) displayed the best antibacterial activity against Staphylococcus aureus and Bacillus cereus with minimum inhibitory concentrations (MICs) of 11 g/mL, followed by Staphylococcus aureus (MRSA strain) and Listeria monocytogenes with MICs of 22 and 44 g/mL, respectively. Moreover, molecular docking studies performed on the most active compounds against Staphylococcus aureus tyrosyl-tRNA synthetase and topoisomerase II DNA gyrase revealed the potential binding mode of the ligands to the site of the appropriate targets. Preliminary structure-activity relationship studies showed that the antibacterial activity can be modulated by the presence of the 3-phenyl ring and by the position of the hydroxyl groups at the coumarin scaffold.