Systematic Review of Trauma-Informed Approaches and Trauma-Informed Care for Forced Migrant Families: Concepts and Contexts.

In the past decade, there has been a significant increase in the forced migrant and refugee population in Europe. As the journey to arrive at the country of destination is mostly irregular, research has shown that forced migrants survive a number of traumatic experiences trying to reach safety and ensure the well-being of themselves and their families. Since research shows that exposure to traumatic experiences refugee and migrant families endure on their journey is severe, a systematic literature review was conducted to understand the concept of trauma-informed approaches for migrant and refugee families. A total of seven research databases have been a part of this study, and the search resulted in 45 papers that were analyzed and their results presented. The following inclusion criteria were considered: (a) migrant/refugee families living with their children and (b) migrant/refugee families approaching care (health, social, educational, legal). Inclusion criteria refer to phenomenological studies, consider trauma/resilience of migrant/refugee families, include studies that are published in English language only; published literature only; 2013 onwards, and only full-text studies. The results of this analysis imply that papers are more focused on the experiences of trauma than on the approaches to treat it. However, this analysis did result in identifying approaches, interventions, and tools in working with trauma refugee and migrant families. Trauma-informed approaches for forced migrant families require a culturally adapted response provided across all sectors of family support to refugees and migrants.

Copper(II) and Zinc(II) Complexes with Bacterial Prodigiosin Are Targeting Site III of Bovine Serum Albumin and Acting as DNA Minor Groove Binders.

The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries' approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves.

Antiviral Protein-Protein Interaction Inhibitors.

Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific antiviral drugs in a well-established and efficient manner is crucial. Taking into account the strong ability of viruses to change, therapies with diversified molecular targets must be sought. In addition to the widely explored viral enzyme inhibitor approach, inhibition of protein-protein interactions is a very valuable strategy. In this Perspective, protein-protein interaction inhibitors targeting HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses are reviewed and discussed. Antibodies, peptides/peptidomimetics, and small molecules constitute three classes of compounds that have been explored, and each of them has some advantages and disadvantages for drug development.

Peptide foldamer-based inhibitors of the SARS-CoV-2 S protein-human ACE2 interaction.

The entry of the SARS-CoV-2 virus into a human host cell begins with the interaction between the viral spike protein (S protein) and human angiotensin-converting enzyme 2 (hACE2). Therefore, a possible strategy for the treatment of this infection is based on inhibiting the interaction of the two abovementioned proteins. Compounds that bind to the SARS-CoV-2 S protein at the interface with the alpha-1/alpha-2 helices of ACE2 PD Subdomain I are of particular interest. We present a stepwise optimisation of helical peptide foldamers containing trans-2-aminocylopentanecarboxylic acid residues as the folding-inducing unit. Four rounds of optimisation led to the discovery of an 18-amino-acid peptide with high affinity for the SARS-CoV-2 S protein (Kd = 650 nM) that inhibits this protein-protein interaction with IC50 = 1.3 µM. Circular dichroism and nuclear magnetic resonance studies indicated the helical conformation of this peptide in solution.

Metal complexes with valuable biomolecules produced by Pseudomonas aeruginosa: a review of the coordination properties of pyocyanin, pyochelin and pyoverdines.

Pseudomonas aeruginosa is an opportunistic, Gram-negative bacterium, involved in severe infections associated with cystic fibrosis, pneumonia, burn wounds, ocular diseases, and immunosuppressive illnesses, and is a major cause of intrahospital infections. This bacterium is also one of the most commercially and biotechnologically significant microorganisms, since it can produce valuable biomolecules which represent a rich source of potential drug candidates. On the other hand, metal complexes have been used in medicine for both therapeutic and diagnostic purposes since ancient times. This class of compounds can adopt different geometries and generally have a three-dimensional shape, contributing to their higher clinical success compared to flat purely organic compounds. In the present review article, attention has been devoted to the three natural products derived from P. aeruginosa, namely pyocyanin, pyochelin, and pyoverdine(s) and their ability to form complexes with different metal ions, including iron(II/III), manganese(II/III), gallium(III), chromium(III), nickel(II), copper(II), zinc(II) and cadmium(II). Investigation of the coordination properties of pyocyanin, pyochelin, and pyoverdine(s) towards these metal ions is important because the resulting bacterially derived natural product-metal complex can serve as a model for the study of metal ion metabolism (transport and storage) in living systems and might also be considered as a novel therapeutic agent for potential use in medicine.

Synthesis, Biosynthesis, and Biological Activity of Diels-Alder Adducts from Morus Genus: An Update.

The plants of the Moraceae family are producers of a great variety of polyphenolic natural products. Among these, the Diels-Alder type adducts (DAAs) are endowed with a unique cyclohexene scaffold, since they are biosynthesized from [4+2] cycloaddition of different polyphenolic precursors such as chalcones and dehydroprenyl polyphenols. To date, more than 150 DAAs have been isolated and characterized from Moraceous and related plants. The main source of DAAs is the mulberry root bark, also known as "Sang-Bai-Pi" in Traditional Chinese Medicine, but they have also been isolated from root bark, stem barks, roots, stems or twigs, leaves, and callus cultures of Moraceous and other related plants. Since 1980, many biological activities of DAAs have been identified, including anti-HIV, antimicrobial, anti-inflammatory, and anticancer ones. For these reasons, natural DAAs have been intensively investigated, and a lot of efforts have been made to study their biosynthesis and to establish practical synthetic access. In this review, we summarized all the updated knowledge on biosynthesis, chemoenzymatic synthesis, racemic and enantioselective total synthesis, and biological activity of natural DAAs from Moraceous and related plants.

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors.

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies.

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.

Novel 1,3,4-thiadiazole-chalcone hybrids containing catechol moiety: synthesis, antioxidant activity, cytotoxicity and DNA interaction studies.

Hybrid compounds that combine the 1,3,4-thiadiazole-containing catechol moiety with a chalcone motif were synthesized and examined for their antioxidant activity, cytotoxicity, and DNA-binding activity. A series of thirteen compounds showed strong antioxidant and cytotoxic effects on human acute promyelocytic leukemia HL-60 cells. Several compounds exerted good cytotoxic activities on cervical adenocarcinoma HeLa cells. The treatment of HeLa cells with IC50 and double IC50 concentrations of the compounds 5a, 5c, 5f, and 5m induced a statistically significant increase in the percentage of cells within a subG1 cell cycle phase. The examined compounds caused G2/M cell cycle arrest in HeLa cells. Each of these compounds triggered apoptosis in HeLa cells through activation of caspase-3, the main effector caspase, caspase-8, which is involved in the extrinsic apoptotic pathway, and caspase-9, which is involved in the intrinsic apoptotic pathway. All of the examined compounds decreased the expression levels of MMP2 in HeLa cells and levels of protumorigenic miR-133b. Compounds 5a and 5m lowered the expression level of oncogenic miR-21 in HeLa cells. In addition, compounds 5a, 5f, and 5m decreased the expression levels of oncogenic miR-155 while the treatment of HeLa cells with compounds 5a, 5c, and 5f increased expression of tumor-suppressive miR-206. Observed effects of these compounds on expression levels of four examined miRNAs suggest their prominent cancer-suppressive activity. An investigation by absorption and fluorescence spectroscopy showed more efficient calf thymus DNA binding activity of the compound 5m in comparison to other tested compounds. Results of a pUC19 plasmid cleavage study and comet assay showed DNA damaging activities of compounds 5a and 5c.

Highly selective anthraquinone-chalcone hybrids as potential antileukemia agents.

A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway. Treatment of K562 cells with each of these four compounds caused decrease in the expression levels of MMP2, MMP9, and VEGF, suggesting their anti-invasive, antimetastatic and antiangiogenic properties. The compounds 6g and 6v downregulated expression levels of miR-155 in K562 cells, while compounds 6e and 6u upregulated miR-155 levels in treated cells, in comparison with control cells. The structure-based 3-D QSAR models for 6f, 6e, 6i and 6l describe pro-apoptotic activity against caspase-3.

Synthesis, antioxidant and antiproliferative activities of 1,3,4-thiadiazoles derived from phenolic acids.

Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and antiproliferative potential. The compound 3'c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-thiadiazole 3'h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 3'a exerted higher cytotoxic activities on A549 and HL-60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 3'c, 3'g and 3'h induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially dependent on activation of caspase-3 and caspase-8. The compounds 3c and 3'c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 3'c, 3'g and 3'h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell samples.

Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies.

A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3-thione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b, 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.

Synthesis, characterization, cytotoxicity and antiangiogenic activity of copper(II) complexes with 1-adamantoyl hydrazone bearing pyridine rings.

Three novel copper complexes with tridentate N2O ligand di(2-pyridil) ketone 1-adamantoyl hydrazone (Addpy) of the formula [Cu(II)2Cu(I)2(Addpy)2Br2(µ-Br4)] (1), catena-poly[CuCl(µ-Addpy)(µ-Cl)CuCl2]n (2) and [Cu(Addpy)(NCS)2] (3) were synthesized. Complexes are characterized by X-ray crystallography, spectral (UV-Vis, FTIR), electrochemical (CV) analyses, and magnetochemical measurements. Investigation of anticancer potential of Cu(II) complexes, mode of cell death, apoptosis, and inhibition of angiogenesis were performed. All tested malignant cell lines (HeLa, LS174, A549, K562, and MDA-MB-231) showed high sensitivity to the examined Cu(II) complexes. It has been shown that the complexes induce apoptosis in the caspase 3-dependent manner, whereas the anti-angiogenic effects of 1, 2, and 3 have been confirmed in EA.hy926 cells using a tube formation assay.

The Pictet-Spengler Reaction Still on Stage.

Today, in spite of being older than a century (born in 1911), the Pictet-Spengler two component reaction (PS-2CR) is still one of the most popular reactions, not only for the synthesis of tetrahydroisoquinolines (THIQs), tetrahydro-ß-carbolines (THBCs), or more complex structures containing these two privileged moieties, but also for the construction of novel scaffolds, available for structure-activity relationship (SAR) studies and/or for combinatorial libraries targeted at drug discovery. The prominence of the P-S cyclization is brought about by the inheritance from analogous enzyme-catalyzed reactions of the biogenetic pathways of natural products, mainly indole alkaloids, with a broad range of biological activities. This knowledge has been the starting point for the biomimetic synthesis or the bio-engineering production of pharmacologically important drugs. The long-lasting life of the P-S reaction depends on the discovery of its multiple facets, the modifications of its parameters and components, as well as the continuous renovation of solutions for the challenging stereochemical outcome of the transformation. This paper deals with an updated visit to the P-S reaction aiming to find the threads of the story without forgetting the numerous facets of the prism. It is organized as a theater piece, with a prologue and the main scene (namely, Act 1) where the readers can follow the parade of the two above-mentioned very recurring motifs (namely, THIQ and THBC) by moving from one step to another (a cyclization, an intramolecular attack, a stereoselective passage) to find the way out of the labyrinth of the P-S reaction.

Anthraquinone-chalcone hybrids: synthesis, preliminary antiproliferative evaluation and DNA-interaction studies.

Novel anthraquinone based chalcone compounds were synthesized starting from 1-acetylanthraquinone in a Claisen-Schmidt reaction and evaluated for their anticancer potential against three human cancer cell lines. Compounds 4a, 4b and 4j showed promising activity in inhibition of HeLa cells with IC50 values ranging from 2.36 to 2.73 µM and low cytotoxicity against healthy MRC-5 cell lines. The effects that compounds produces on the cell cycle were investigated by flow cytometry. It was found that 4a, 4b and 4j cause the accumulation of cells in the S and G2/M phases in a dose-dependent manner and induce caspase-dependent apoptosis. All of three compounds exhibit calf thymus DNA-binding activity. The determined binding constants by absorption titrations (2.65 × 10(3) M(-1), 1.36 × 10(3) M(-1)and 2.51 × 10(3) M(-1) of 4a/CT-DNA, 4b/CT-DNA and 4j/CT-DNA, respectively) together with fluorescence displacement analysis designate 4a, 4b and 4j as strong minor groove binders, but no cleavage of plasmid DNA was observed.

Novel anthraquinone based chalcone analogues containing an imine fragment: synthesis, cytotoxicity and anti-angiogenic activity.

A new class of imine derivatives of hybrid chalcone analogues containing anthraquinone scaffold was synthesized and evaluated for their in vitro cytotoxic activity against HeLa, LS174, and A549 cancer cells. The compound 5n with furan ring linked to imino group showed potent activity against all target cells with IC50 values ranging from 1.76 to 6.11µM. A mode of action study suggested that compounds induced changes typical for apoptosis in HeLa cells. The most active compounds inhibited tubulogenesis and 5h was found to exhibit a strong anti-angiogenic effect.

Synthesis, cytotoxic activity and DNA-interaction studies of novel anthraquinone-thiosemicarbazones with tautomerizable methylene group.

A series of novel anthraquinone-thiosemicarbazone derivatives in a tautomerizable keto-imine form was synthesized and tested for their in vitro cytotoxic activity against human cancer cells (HeLa, MDA-MB-361, MDA-MB-453, K562, A549) and human normal MRC-5 cells. Several compounds efficiently inhibited cancer cell growth at micromolar concentrations, especially against K562 and HeLa cells. As determined by flow cytometric analysis, anthraquinone-thiosemicarbazone caused significant increase in the number of sub-G1 phase of HeLa cells and apoptosis in a concentration-dependent manner. Also, inhibition of caspase-3, -8, and -9 with specific caspase inhibitors reduced the apoptosis mediated by the tested compounds in HeLa cells. All anthraquinone-thiosemicarbazones exhibit calf thymus DNA-binding activity, but no cleavage of plasmid DNA was observed.

Synthesis, characterization and antitumor activity of polymeric copper(II) complexes with thiosemicarbazones of 3-methyl-5-oxo-1-phenyl-3-pyrazolin-4-carboxaldehyde and 5-oxo-3-phenyl-3-pyrazolin-4-carboxaldehyde.

New polymeric copper(II) complexes with two tridentate ONS thiosemicarbazone ligands containing substituted pyrazolone moiety were synthesized and characterized by means of spectroscopic, electrochemical and crystallographic techniques. While both ligands exist as different tautomers in the solid state and DMSO-d(6) solution, Cu(II) ion coordinates the ligands from the same tautomeric form with square-pyramidal geometry around each Cu atom. In the crystal structures, the copper(II) complex cation forms polymeric chains {[Cu(L)Cl](+)}(n) with a bridging chlorine atom. One of the complexes was found to have a significantly higher cytotoxic potential in comparison with cisplatin in inhibition of several cell lines (HL60, REH, C6, L929 and B16). The results obtained on the basis of flow cytometry indicated that apoptosis could be possible mechanism of cell death.

Antiproliferative activity and QSAR studies of a series of new 4-aminomethylidene derivatives of some pyrazol-5-ones.

Twenty five 4-aminomethylidene derivatives obtained from 3-phenyl-2-pyrazolin-5-one and 1,3-diphenyl-2-pyrazolin-5-one were synthesized and tested for their antiproliferative activity against human breast cancer MDA-MB-361 and MDA-MB-453 cell lines. The compounds derived from 1,3-diphenyl-2-pyrazolin-5-one exhibited the most remarkable activity in the treatment of both cell lines. In vitro antiproliferative activities were accompanied by an important apoptotic fraction of both cell lines; also, compounds inhibited key endothelial cell functions implicated in invasion and angiogenesis. QSAR methods were performed in order to analyze the influence of structural features of the compounds investigated on the antiproliferative potential on MDA-MB-361 and MDA-MB-453 cancer cells. One-parameter heuristic analysis was performed and different whole molecule and fragmental descriptors were considered for rationalization of mechanism of interaction of these compounds with active place of hypothetical target included in tumorigenesis.

Synthesis, antitumor activity and QSAR studies of some 4-aminomethylidene derivatives of edaravone.

A series of aminomethylidene derivatives obtained from 4-formyledaravone were synthesized and characterized by IR, NMR and elemental analysis. All the compounds were screened for their antitumor activity. The compound containing 5-phenylpyrazole moiety (3q) exhibited remarkable antitumor activity in in vitro assays, especially against human breast cancer MDA-MB-361 and MDA-MB-453 cell lines. The most important whole-molecule descriptors for antitumor activity on MDA-MB-453 cells belong to the group of quantum-chemical descriptors.