Semenogelins armed in Zn(II) and Cu(II): may bioinorganic chemistry help nature to cope with Enterococcus faecalis?

Antimicrobial fragments of semenogelinsfrom the human semen(peptides: SgIIA, SgI-29, and their common 15 amino acid fragment,Sg-15) bind Zn(II) and Cu(II) ions via a [NH2, 3Nim] donorset at physiological pH, and metal binding enhances their antimicrobialactivity. In the case of the two native semenogelin fragment metalcomplexes, the strong local positive charge in the metal-bound HHmotif correlates well with their antimicrobial activity.Proteolytic degradation of semenogelins, the most abundantproteinsfrom human semen, results in the formation of 26- and 29-amino acidpeptides (SgIIA and SgI-29, respectively), which share a common 15amino acid fragment (Sg-15). All three ligands are effective Zn(II)and Cu(II) binders; in solution, a variety of differently metalatedspecies exist in equilibrium, with the [NH2, 3N(im)] donor set prevailing at physiological pH in the case of both metals.For the first time, the Cu(II)-induced antimicrobial activity of Sg-15against Enterococcus faecalis is shown. In the caseof the two native semenogelin fragment metal complexes, the stronglocal positive charge in the metal-bound HH motif correlates wellwith their antimicrobial activity. A careful analysis of semenogelins'metal coordination behavior reveals two facts: (i) The histamine-likeCu(II) binding mode of SgI-29 strongly increases the stability ofsuch a complex below pH 6 (with respect to the non-histamine-likebinding of SgIIA), while in the case of the SgI-29 Zn(II)-histamine-likespecies, the stability enhancement is less pronounced. (ii) The HHsequence is a more tempting site for Cu(II) ions than the HXH one

The impact of new research technologies on our understanding of environmental causes of disease: the concept of clinical vulnerability

In spite of decades of epidemiological research, the etiology and causal patterns for many common diseases, such as breast and colon cancer or neurodegenerative diseases, are still largely unknown. Such chronic diseases are likely to have an environmental origin. However, "environmental" risks have been often elusive in epidemiological studies. This is a conundrum for current epidemiological research. On the other side, the relative contribution of genes to chronic diseases, as emerging from GWAS, seems to be modest (15-50% increase in disease risk). What is yet to be explored extensively is a model of disease based on long-term effects of low doses of environmental exposures, incorporating both genetic and acquired susceptibility ("clinical vulnerability"), and the cumulative effects of different exposures. Such a disease model would be compatible with the weak associations found by GWAS and the still elusive role of many (low-level) environmental exposures. We also propose that the introduction of "-omic" high-throughput technologies, such as transcriptomics, proteomics and metabolomics, may provide, in the next years, powerful tools to investigate early effects of environmental exposures and understand the etiology of common diseases better, according to the "clinical vulnerability model". The development of "-omics", in spite of current limitations and lack of sound validation, could greatly contribute to the elucidation of the disease model we propose

Southern African Large Telescope Spectroscopy of BL Lacs for the CTA project

In the last two decades, very-high-energy gamma-ray astronomy has reached maturity: over 200 sources have been detected, both Galactic and extragalactic, by ground-based experiments. At present, Active Galactic Nuclei (AGN) make up about 40% of the more than 200 sources detected at very high energies with ground-based telescopes, the majority of which are blazars, i.e. their jets are closely aligned with the line of sight to Earth and three quarters of which are classified as high-frequency peaked BL Lac objects. One challenge to studies of the cosmological evolution of BL Lacs is the difficulty of obtaining redshifts from their nearly featureless, continuum-dominated spectra. It is expected that a significant fraction of the AGN to be detected with the future Cherenkov Telescope Array (CTA) observatory will have no spectroscopic redshifts, compromising the reliability of BL Lac population studies, particularly of their cosmic evolution. We started an effort in 2019 to measure the redshifts of a large fraction of the AGN that are likely to be detected with CTA, using the Southern African Large Telescope (SALT). In this contribution, we present two results from an on-going SALT program focused on the determination of BL Lac object redshifts that will be relevant for the CTA observatory

Dicarboxylic Acid-Based Co-Crystals of Pyridine Derivatives Involving Structure Guiding Unconventional Synthons: Experimental and Theoretical Studies

Four co-crystals involving dicarboxylic acids and pyridine derivatives, viz. (ox)0.5(2-CNpy) (1), (adp)(4-CNpy)2 (2), (tp)(4-CNpy)2 (3) and (adp)(3-CNpy)2 (4) (ox = oxalic acid, tp = terephthalic acid, adp = adipic acid, CNpy = cyanopyridine), have been synthesized at room temperature in water medium. Crystal-structure analysis of co-crystal 1 reveals the presence of unconventional O···π(oxalic acid)-hole interaction with the C-C bond of ox moiety, along with parallel nitrile–nitrile interactions. The structural topologies of co-crystals 2–4 unfold the presence of antiparallel nitrile–nitrile interactions involving the CNpy moieties. The molecular associations involving the H-bonds and other unconventional contacts among the co-formers of the multicomponent co-crystals are analyzed using density functional theory (DFT) calculations combined with molecular electrostatic potential (MEP) surface, quantum theory of atoms-in-molecules (QTAIM) and noncovalent interaction (NCI) plot computational tools. The computational studies revealed the presence of unconventional O···π-hole interaction in 1 and the H-bonded synthons with π-stacked nitrile contacts involving CNpy moieties in co-crystals 2–4. The energetic features of the noncovalent contacts reveal the crucial roles of the H-bonding synthons and π-stacking interactions in the multicomponent compounds

Dicarboxylic Acid-Based Co-Crystals of Pyridine Derivatives Involving Structure Guiding Unconventional Synthons: Experimental and Theoretical Studies

Four co-crystals involving dicarboxylic acids and pyridine derivatives, viz. (ox)0.5(2-CNpy) (1), (adp)(4-CNpy)2 (2), (tp)(4-CNpy)2 (3) and (adp)(3-CNpy)2 (4) (ox = oxalic acid, tp = terephthalic acid, adp = adipic acid, CNpy = cyanopyridine), have been synthesized at room temperature in water medium. Crystal-structure analysis of co-crystal 1 reveals the presence of unconventional O···π(oxalic acid)-hole interaction with the C-C bond of ox moiety, along with parallel nitrile–nitrile interactions. The structural topologies of co-crystals 2–4 unfold the presence of antiparallel nitrile–nitrile interactions involving the CNpy moieties. The molecular associations involving the H-bonds and other unconventional contacts among the co-formers of the multicomponent co-crystals are analyzed using density functional theory (DFT) calculations combined with molecular electrostatic potential (MEP) surface, quantum theory of atoms-in-molecules (QTAIM) and noncovalent interaction (NCI) plot computational tools. The computational studies revealed the presence of unconventional O···π-hole interaction in 1 and the H-bonded synthons with π-stacked nitrile contacts involving CNpy moieties in co-crystals 2–4. The energetic features of the noncovalent contacts reveal the crucial roles of the H-bonding synthons and π-stacking interactions in the multicomponent compounds

‘Charge Reverse’ Halogen Bonding Contacts in Metal-Organic Multi-Component Compounds: Antiproliferative Evaluation and Theoretical Studies

Two new metal–organic multi-component compounds of Ni(II) and Co(II), viz. [Ni(3-CNpy)2(H2O)4]ADS·2.75H2O (1) and [Co(3-CNpy)2(H2O)4](4-ClbzSO3)2 (2) (3-CNpy = 3-cyanopyridine, ADS = anthraquinone-1,5-disulfonate, 4-ClbzSO3 = 4-chlorobenzenesulfonate), were synthesized and characterized using single crystal XRD, TGA, spectroscopic (IR, electronic) and elemental analyses. Both the compounds crystallize as multi-component compounds of Ni(II) and Co(II), with uncoordinated ADS and 4-ClbzSO3 moieties in the crystal lattice, respectively. Crystal structure analyses revealed the presence of antiparallel nitrile···nitrile and π-stacked assemblies involving alternate coordinated 3-CNpy and uncoordinated ADS and 4-ClbzSO3 moieties. Moreover, unconventional charge reverse Cl∙∙∙N halogen bonding contacts observed in compound 2 provide additional reinforcement to the crystal structure. Theoretical calculations confirm that the H-bonding interactions, along with anion–π(arene) and anion–π(CN) in 1 and π–π, antiparallel CN···CN and charge reverse Cl···N halogen bonds in 2, play crucial roles in the solid state stability of the compounds. In vitro anticancer activities observed through the trypan blue cell cytotoxicity assay reveal that the compounds induce significant concentration dependent cytotoxicity in Dalton’s lymphoma (DL) cancer cells, with nominal effects in normal healthy cells. Molecular docking studies reveal that the compounds can effectively bind with the active sites of anti-apoptotic proteins, which are actively involved in cancer progression

Rationalization of Noncovalent Interactions within Six New M-II/8-Aminoquinoline Supramolecular Complexes (M-II = Mn, Cu, and Cd): A Combined Experime

To examine the influence of the metal ions and their counterions on crystalline networks, we have designed and synthesized six MX2/8-aminoquinoline (8-aq) (M = Mn-II, Cu-II, Cd-II and X = Cl-, Br-, I-, NO3-, SCN-) complexes, having the formulas [Mn(8-aq)(2) I-2].(1), [Mn(8-aq)(2)(H2O)(2)](8-aq)(3).Br-2 (2), [Mn(8-aq)(2)(SCN)(2)] (3), [Cu(8-aq)(2)Cl(H2O)].Cl.H2O (4), [Cu(8-aq)(2)(NO3)(H2O)].NO3 (5), and Cd(8-aq)(2)I-2 (6). Single-crystal X-ray diffraction analyses showed that all of the complexes have a distorted octahedral geometry, in which each 8-aq molecule acts as a bidentate ligand and coordinates to the central metal ion with its common coordination mode, to form an N,N&#39; chelating motif. Remarkably, the influence of the counterion on the geometry of the complex is very significant since both I- and SCN- anions are coordinated to the metal ion in compounds 1, 3, and 6, adopting a cis configuration, while a single anion occupies an axial position in compounds 4 and 5 (Cl- and NO3-, respectively) and the other counterion is not coordinated. Finally, both Br anions are not coordinated in the cationic complex 2 (Mn metal center). In all cases, there are extended supramolecular networks due to cooperativity hydrogen-bonding and pi-pi stacking interactions that play an essential role in the formation and stability of the crystalline materials. The binding energies attributed to the different interactions have been evaluated using DFT calculations.</p

Irinotecan-induced mucositis is associated with changes in intestinal mucins

PurposeMucositis is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. Irinotecan is used to treat a variety of solid tumours, through the inhibition of DNA topoisomerase I and is linked with severe mucositis and diarrhoea. Mucus production appears to be increased, which may contribute to the development of diarrhoea.MethodsDark agouti rats were treated with irinotecan, and tissues collected at several time points up to 72 h. Goblet cells and mucin secretion were investigated, as well as mucin expression (Muc2 and Muc4) and kruppel-like factor (Klf) 4 using immunohistochemistry in the gastrointestinal tract. Both goblet cells and cells positive for Muc expression were counted, and analysed statistically using the Mann-Whitney U test with Bonferroni correction.ResultsGoblet cells decreased significantly after irinotecan treatment. However, mucin secretion increased. Mucin expression changed significantly after treatment. Muc2 and Muc4 decreased significantly in the villi of the jejunum after treatment, Muc2 and Muc4 decreased significantly in the crypts. Muc2 decreased significantly in the colon.ConclusionsIrinotecan causes an increase in mucin secretion and a net decrease in mucin-producing goblet cells, and the expression of Muc2 and Muc4 in the gastrointestinal tract is altered following treatment. Increased mucin secretion is likely to be related to altered mucin expression, and may contribute to chemotherapy-induced diarrhoea.Andrea M. Stringer, Rachel J. Gibson, Richard M. Logan, Joanne M. Bowen, Ann S. J. Yeoh, Jessica Laurence and Dorothy M. K. Keef