Effects of Lewis Basicity and Acidity on σ-Hole Interactions in Carbon-Bearing Complexes: A Comparative Ab Initio Study

The effects of Lewis basicity and acidity on σ-hole interactions were investigated using two sets of carbon-containing complexes. In Set I, the effect of Lewis basicity was studied by substituting the X₃/X atom(s) of the NC-C₆H₂-X₃ and NCX Lewis bases (LB) with F, Cl, Br, or I. In Set II, the W-C-F₃ and F-C-X₃ (where X and W = F, Cl, Br, and I) molecules were utilized as Lewis acid (LA) centers. Concerning the Lewis basicity effect, higher negative interaction energies (E_int) were observed for the F-C-F₃∙∙∙NC-C₆H₂-X₃ complexes compared with the F-C-F₃∙∙∙NCX analogs. Moreover, significant E_int was recorded for Set I complexes, along with decreasing the electron-withdrawing power of the X₃/X atom(s). Among Set I complexes, the highest negative E_int was ascribed to the F-C-F₃∙∙∙NC-C₆H₂-I₃ complex with a value of −1.23 kcal/mol. For Set II complexes, E_int values of F-C-X₃ bearing complexes were noted within the −1.05 to −2.08 kcal/mol scope, while they ranged from −0.82 to −1.20 kcal/mol for the W-C-F₃ analogs. However, V_s,max quantities exhibited higher values in the case of W-C-F₃ molecules compared with F-C-X₃; preferable negative E_int were ascribed to the F-C-X₃ bearing complexes. These findings were delineated as a consequence of the promoted contributions of the X₃ substituents. Dispersion forces (E_disp) were identified as the dominant forces for these interactions. The obtained results provide a foundation for fields such as crystal engineering and supramolecular chemistry studies that focus on understanding the characteristics of carbon-bearing complexes.     

Metal Coordination Enhances Chalcogen Bonds: CSD Survey and Theoretical Calculations

In this study the ability of metal coordinated Chalcogen (Ch) atoms to undergo Chalcogen bonding (ChB) interactions has been evaluated at the PBE0-D3/def2-TZVP level of theory. An initial CSD (Cambridge Structural Database) inspection revealed the presence of square planar Pd/Pt coordination complexes where divalent Ch atoms (Se/Te) were used as ligands. Interestingly, the coordination to the metal center enhanced the σ-hole donor ability of the Ch atom, which participates in ChBs with neighboring units present in the X-ray crystal structure, therefore dictating the solid state architecture. The X-ray analyses were complemented with a computational study (PBE0-D3/def2-TZVP level of theory), which shed light into the strength and directionality of the ChBs studied herein. Owing to the new possibilities that metal coordination offers to enhance or modulate the σ-hole donor ability of Chs, we believe that the findings presented herein are of remarkable importance for supramolecular chemists as well as for those scientists working in the field of solid state chemistry.     

On the Importance of Pnictogen and Chalcogen Bonding Interactions in Supramolecular Catalysis

In this review, several examples of the application of pnictogen (Pn) (group 15) and chalcogen (Ch) bonding (group 16) interactions in organocatalytic processes are gathered, backed up with Molecular Electrostatic Potential surfaces of model systems. Despite the fact that the use of catalysts based on pnictogen and chalcogen bonding interactions is taking its first steps, it should be considered and used by the scientific community as a novel, promising tool in the field of organocatalysis.     

TCR Recognition of Peptide–MHC-I: Rule Makers and Breakers

T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR–pMHC-I structures to date were determined within this time. Here, we review the new insights learned from these recent TCR–pMHC-I structures and their impact on T cell activation.     

Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their functional activity. An imbalance of pro- and anti-inflammatory signals can lead to the development of reproductive pathology. The aim of this study was to assess the effects of cytokines on NK cells in the presence of trophoblast cells in an in vitro model. We used TNFα, IFNγ, TGFβ and IL-10; the NK-92 cell line; and peripheral blood NK cells (pNKs) from healthy, non-pregnant women. For trophoblast cells, the JEG-3 cell line was used. In the monoculture of NK-92 cells, TNFα caused a decrease in CD56 expression. In the coculture of NK cells with JEG-3 cells, TNFα increased the expression of NKG2C and NKG2A by NK-92 cells. Under the influence of TGFβ, the expression of CD56 increased and the expression of NKp30 decreased in the monoculture. After the preliminary cultivation of NK-92 cells in the presence of TGFβ, their cytotoxicity increased. In the case of adding TGFβ to the PBMC culture, as well as coculturing PBMCs and JEG-3 cells, the expression of CD56 and NKp44 by pNK cells was reduced. The differences in the effects of TGFβ in the model using NK-92 cells and pNK cells may be associated with the possible influence of monocytes or other lymphoid cells from the mononuclear fraction.     

Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice

Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).     

Novel Synthesis Methods of New Imidazole-Containing Coordination Compounds Tc(IV,V, VII)—Reaction Mechanism,Xrd and Hirshfeld Surface Analysis

In this work, we have proposed two new methods for the synthesis of [TcO₂L₄]⁺ (where L = imidazole (Im), methylimidazole (MeIm)) complexes using thiourea (Tu) and Sn(II) as the reducing agents. The main and by-products of the reactions were determined, and possible reaction mechanisms were proposed. We have shown that the reduction of Tc(VII) with thiourea is accompanied by the formation of the Tc(III) intermediate and further oxidation to Tc(V). The reaction conditions’ changing can lead to the formation of Tc(VII) and Tc(IV) salts. Seven new crystal structures are described in this work: Tc(V) complexes, salts with Tc(VII) and Tc(IV) anions. For the halide salts of Tu the cell parameters were determined. In all of the obtained compounds, except for [TcO₂(MeIm)₄]TcO₄, there are π–stacking interactions between the aromatic rings. An increase in the anion size lead to weakening of the intermolecular interactions. The halogen bonds and anion-π interactions were also found in the hexahalide-containing compounds. The Hirshfeld surface analysis showed that the main contribution to the crystal packing is created by the van der Waals interactions of the H···H type (42.5–55.1%), H···C/C···H (17.7–21.3%) and hydrogen bonds, which contribute 15.7–25.3% in total.     

Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis

Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.     

The Intriguing Thyroid Hormones–Lung Cancer Association as Exemplification of the Thyroid Hormones–Cancer Association: Three Decades of Evolving Research

Exemplifying the long-pursued thyroid hormones (TH)–cancer association, the TH–lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH–lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.     

Tumor-Suppressor Role of the α1-Na/K-ATPase Signalosome in NASH Related Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, with an estimate of 0.84 million cases every year. In Western countries, because of the obesity epidemic, non-alcoholic steatohepatitis (NASH) has become the major cause of HCC. Intriguingly, the molecular mechanisms underlying tumorigenesis of HCC from NASH are largely unknown. We hypothesized that the growing uncoupled metabolism during NASH progression to HCC, manifested by lower cell redox status and an apoptotic ‘switch’ activity, follows a dysregulation of α1-Na/K-ATPase (NKA)/Src signalosome. Our results suggested that in NASH-related malignancy, α1-NKA signaling causes upregulation of the anti-apoptotic protein survivin and downregulation of the pro-apoptotic protein Smac/DIABLO via the activation of the PI3K → Akt pro-survival pathway with concomitant inhibition of the FoxO3 circuit, favoring cell division and primary liver carcinogenesis. Signalosome normalization using an inhibitory peptide resets apoptotic activity in malignant cells, with a significant decrease in tumor burden in vivo. Therefore, α1-NKA signalosome exercises in HCC the characteristic of a tumor suppressor, suggesting α1-NKA as a putative target for clinical therapy.     

Versatile Dicyanomethylene-Based Fluorescent Probes for the Detection of β-Amyloid in Alzheimer’s Disease: A Theoretical Perspective

Motivated by the growing demand for target chemosensors designed with diagnostic or therapeutic capability for fibrils related to amyloidosis diseases, we investigated in the present work the response mechanism of dicyanomethylene-based fluorescent probes for amyloid fibril using a combined approach, including molecular docking, quantum mechanics/molecular mechanics (QM/MM), and the quantum chemical method. Various binding modes for the probes in β-amyloid (Aβ) are discussed, and the fibril environment-induced molecular optical changes at the most stable site are compared to the fibril-free situation in aqueous environments. The results reveal that the fluorescence enhancement for the probes in Aβ observed experimentally is an average consequence over multiple binding sites. In particular, the conformational difference, including conjugation length and donor effect, significantly contributes to the optical property of the studied probes both in water and fibril. To further estimate the transition nature of the molecular photoabsorption and photoemission processes, the hole-electron distribution and the structural variation on the first excited state of the probes are investigated in detail. On the basis of the calculations, structure–property relationships for the studied chemosensors are established. Our computational approach with the ability to elucidate the available experimental results can be used for designing novel molecular probes with applications to Aβ imaging and the early diagnosis of Alzheimer’s disease.     

A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS

The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the molecular mechanisms responsible for its pathogenesis. Starting from the observation that SBDS single-point mutations, localized in different domains of the proteins, are responsible for an SDS phenotype, we carried out the first comparative Molecular Dynamics simulations on three SBDS mutants, namely R19Q, R126T and I212T. The obtained 450-ns long trajectories were compared with those returned by both the open and closed forms of wild type SBDS and strongly indicated that two distinct conformations (open and closed) are both necessary for the proper SBDS function, in full agreement with recent experimental observations. Our study supports the hypothesis that the SBDS function is governed by an allosteric mechanism involving domains I and III and provides new insights into SDS pathogenesis, thus offering a possible starting point for a specific therapeutic option.     

Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer

Glycogen synthase kinase 3 beta (GSK-3β) is a serine/threonine protein kinase involved in multiple normal and pathological cell functions, including cell signalling and metabolism. GSK-3β is highly expressed in the onset and progression of multiple cancers with strong involvement in the regulation of proliferation, apoptosis, and chemoresistance. Multiple studies showed pro- and anti-cancer roles of GSK-3β creating confusion about the benefit of targeting GSK-3β for treating cancer. In this mini-review, we focus on the role of GSK-3β in pancreatic cancer. We demonstrate that the proposed anti-cancer roles of GSK-3β are not relevant to pancreatic cancer, and we argue why GSK-3β is, indeed, a very promising therapeutic target in pancreatic cancer.     

Fatty-Acid-Based Membrane Lipidome Profile of Peanut Allergy Patients: An Exploratory Study of a Lifelong Health Condition

Peanut allergy is a lifelong, increasingly prevalent, and potentially life-threatening disease burdening families and communities. Dietary, particularly polyunsaturated fatty acids (PUFAs), intakes can exert positive effects on immune and inflammatory responses, and the red blood cell (RBC) membrane lipidome contains stabilized metabolic and nutritional information connected with such responses. The fatty-acid-based membrane lipidome profile has been exploratorily evaluated in a small cohort of patients (eight males and one female, age range 4.1–21.7 years old, body mass index BMI < 25) with angioedema and/or anaphylaxis after peanut ingestion. This analysis was performed according to an ISO 17025 certified robotic protocol, isolating mature RBCs, extracting membrane lipids, and transforming them to fatty acid methyl esters for gas chromatography recognition and quantification. Comparison with a group of age- and BMI-matched healthy individuals and with benchmark interval values of a healthy population evidenced significant differences, such as higher levels of ω-6 (arachidonic acid), lower values of ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with an increased ω-6/ω-3 ratio in allergic patients. A significant inverse correlation was also found between specific immunoglobulin E (IgE) levels and ω-6 di-homo-gamma-linolenic acid (DGLA) and total PUFAs. Results of this preliminary study encourage screenings in larger cohorts, also in view of precision nutrition and nutraceuticals strategies, and stimulate interest to expand basic and applied research for unveiling molecular mechanisms that are still missing and individuating treatments in chronic allergic disorders.     

Solvent-Induced Formation of Novel Ni(II) Complexes Derived from Bis-Thiosemicarbazone Ligand: An Insight from Experimental and Theoretical Investigations

In this work, we report solvent-induced complexation properties of a new N₂S₂ tetradentate bis-thiosemicarbazone ligand (H₂L^I), prepared by the condensation of 4-phenylthiosemicarbazide with bis-aldehyde, namely 2,2’-(ethane-1,2-diylbis(oxy)dibenzaldehyde, towards nickel(II). Using ethanol as a reaction medium allowed the isolation of a discrete mononuclear homoleptic complex [NiL^I] (1), for which its crystal structure contains three independent molecules, namely 1-I, 1-II, and 1-III, in the asymmetric unit. The doubly deprotonated ligand L^I in the structure of 1 is coordinated in a cis-manner through the azomethine nitrogen atoms and the thiocarbonyl sulfur atoms. The coordination geometry around metal centers in all the three crystallographically independent molecules of 1 is best described as the seesaw structure. Interestingly, using methanol as a reaction medium in the same synthesis allowed for the isolation of a discrete mononuclear homoleptic complex [Ni(L^II)₂] (2), where L^II is a monodeprotonated ligand 2-(2-(2-(2-(dimethoxymethyl)phenoxy)ethoxy)benzylidene)-N-phenylhydrazine-1-carbothioamide (HL^II). The ligand L^II was formed in situ from the reaction of L^I with methanol upon coordination to the metal center under synthetic conditions. In the structure of 2, two ligands L^II are coordinated in a trans-manner through the azomethine nitrogen atom and the thiocarbonyl sulfur atom, also yielding a seesaw coordination geometry around the metal center. The charge and energy decomposition scheme ETS-NOCV allows for the conclusion that both structures are stabilized by a bunch of London dispersion-driven intermolecular interactions, including predominantly N–H∙∙∙S and N–H∙∙∙O hydrogen bonds in 1 and 2, respectively; they are further augmented by less typical C–H∙∙∙X (where X = S, N, O, π), CH∙∙∙HC, π∙∙∙π stacking and the most striking, attractive long-range intermolecular C–H∙∙∙Ni preagostic interactions. The latter are found to be determined by both stabilizing Coulomb forces and an exchange-correlation contribution as revealed by the IQA energy decomposition scheme. Interestingly, the analogous long-range C–H∙∙∙S interactions are characterized by a repulsive Coulomb contribution and the prevailing attractive exchange-correlation constituent. The electron density of the delocalized bonds (EDDB) method shows that the nickel(II) atom shares only ~0.8|e| due to the σ-conjugation with the adjacent in-plane atoms, demonstrating a very weak σ-metalloaromatic character.     

alfaNET: A Database of Alfalfa-Bacterial Stem Blight Protein–Protein Interactions Revealing the Molecular Features of the Disease-causing Bacteria

Alfalfa has emerged as one of the most important forage crops, owing to its wide adaptation and high biomass production worldwide. In the last decade, the emergence of bacterial stem blight (caused by Pseudomonas syringae pv. syringae ALF3) in alfalfa has caused around 50% yield losses in the United States. Studies are being conducted to decipher the roles of the key genes and pathways regulating the disease, but due to the sparse knowledge about the infection mechanisms of Pseudomonas, the development of resistant cultivars is hampered. The database alfaNET is an attempt to assist researchers by providing comprehensive Pseudomonas proteome annotations, as well as a host–pathogen interactome tool, which predicts the interactions between host and pathogen based on orthology. alfaNET is a user-friendly and efficient tool and includes other features such as subcellular localization annotations of pathogen proteins, gene ontology (GO) annotations, network visualization, and effector protein prediction. Users can also browse and search the database using particular keywords or proteins with a specific length. Additionally, the BLAST search tool enables the user to perform a homology sequence search against the alfalfa and Pseudomonas proteomes. With the successful implementation of these attributes, alfaNET will be a beneficial resource to the research community engaged in implementing molecular strategies to mitigate the disease. alfaNET is freely available for public use at http://bioinfo.usu.edu/alfanet/.     

Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins

Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-β.