bluuebunny/crossref_metadata_2025 huggingface dataset:
A Crystal Mush Perspective Explains Magma Variability at La Fossa Volcano (Vulcano, Italy)
Authors: Costa Simone , Masotta Matteo , Gioncada Anna , Pistolesi Marco
Published: October 2021

The eruptive products of the last 1000 years at La Fossa volcano on the island of Vulcano (Italy) are characterized by abrupt changes of chemical composition that span from latite to rhyolite. The wide variety of textural features of these products has given rise to several petrological models dealing with the mingling/mixing processes involving mafic-intermediate and rhyolitic magmas. In this paper, we use published whole-rock data for the erupted products of La Fossa and combine them in geochemical and thermodynamic modelling in order to provide new constrains for the interpretations of the dynamics of the active magmatic system. The obtained results allow us to picture a polybaric plumbing system characterized by multiple magma reservoirs and related crystal mushes, formed from time to time during the differentiation of shoshonitic magmas, to produce latites, trachytes and rhyolites. The residing crystal mushes are periodically perturbated by new, fresh magma injections that, on one hand, induce the partial melting of the mush and, on the other hand, favor the extraction of highly differentiated interstitial melts. The subsequent mixing and mingling of mush-derived melts ultimately determine the formation of magmas erupted at La Fossa, whose textural and chemical features are otherwise not explained by simple assimilation and fractional crystallization models. In such a system, the compositional variability of the erupted products reflects the complexity of the physical and chemical interactions among recharging magmas and the crystal mushes.
Apatite U-Pb Thermochronology: A Review
Authors: Chew David M. , Spikings Richard A.
Published: October 2021

The temperature sensitivity of the U-Pb apatite system (350–570 °C) makes it a powerful tool to study thermal histories in the deeper crust. Recent studies have exploited diffusive Pb loss from apatite crystals to generate t-T paths between ~350–570 °C, by comparing apatite U-Pb ID-TIMS (isotope dilution-thermal ionisation mass spectrometry) dates with grain size or by LA-MC-ICP-MS (laser ablation-multicollector-inductively coupled plasma-mass spectrometry) age depth profiling/traverses of apatite crystals, and assuming the effective diffusion domain is the entire crystal. The key assumptions of apatite U-Pb thermochronology are discussed including (i) that Pb has been lost by Fickian diffusion, (ii) can experimental apatite Pb diffusion parameters be extrapolated down temperature to geological settings and (iii) are apatite grain boundaries open (i.e., is Pb lost to an infinite reservoir). Particular emphasis is placed on detecting fluid-mediated remobilisation of Pb, which invalidates assumption (i). The highly diverse and rock-type specific nature of apatite trace-element chemistry is very useful in this regard—metasomatic and low-grade metamorphic apatite can be easily distinguished from sub-categories of igneous rocks and high-grade metamorphic apatite. This enables reprecipitated domains to be identified geochemically and linked with petrographic observations. Other challenges in apatite U-Pb thermochronology are also discussed. An appropriate choice of initial Pb composition is critical, while U zoning remains an issue for inverse modelling of single crystal ID-TIMS dates, and LA-ICP-MS age traverses need to be integrated with U zoning information. A recommended apatite U-Pb thermochronology protocol for LA-MC-ICP-MS age depth profiling/traverses of apatite crystals and linked to petrographic and trace element information is presented.
Prereduction of Nchwaning Ore in CO/CO2/H2 Gas Mixtures
Authors: Schanche Trygve Lindahl , Tangstad Merete
Published: October 2021

Prereduction of Nchwaning manganese ore was investigated by isothermal reduction between 600 and 800 °C to optimize the conditions for industrial pretreatment of manganese ores. Experiments were conducted in CO/CO2 gas mixtures with and without hydrogen at two different oxygen partial pressures. Ore in the size fraction 9.52–15 mm was reduced in a thermogravimetric furnace, and the O/Mn ratio from the chemical analysis was used to determine the extent of prereduction. The samples were investigated by X-ray diffraction to investigate the evolution of phases under the course of reduction. The X-ray diffraction revealed that bixbyite and braunite (I and II) were reduced to manganosite with no or limited formation of hausmannite. Reduction of iron oxides subsided with wüstite, which is stabilized by manganese in the monoxide phase, and hydrogen was seen to improve the reduction of iron oxides. Modeling revealed that the reduction rate increased 2.8-fold upon increasing the CO content from 30% to 70% in a CO/CO2 gas mixture. The addition of hydrogen improved the reduction rate with factors of 1.3 and 2.6 for the low and the high oxygen partial pressures, respectively. Hence, the optimal conditions for pretreatment can be achieved by keeping the oxygen partial pressure as low as possible while adding hydrogen to the reducing gas and ensuring a high reduction temperature. Successful pretreatment limits the extent of the Boudouard reaction in the submerged arc furnace, reducing the amount of CO produced and, thus, reducing the CO available for pretreatment. Hydrogen is a useful addition to the pretreatment unit since it lowers the oxygen partial pressure and improves the kinetics of prereduction.
In-Situ LA-ICP-MS Uraninite U–Pb Dating and Genesis of the Datian Migmatite-Hosted Uranium Deposit, South China
Authors: Cheng Long , Zhang Chengjiang , Song Hao , Cheng Qian
Published: October 2021

The Datian uranium deposit is a migmatite-hosted, high temperature, hydrothermal deposit in the Kangdian region. Detailed information on the chemical composition and formation age of the uraninite remains lacking, which impedes our understanding of uraninite genesis. Two phases of uraninite have been identified according to their relationships with other minerals and their field relationships. The phase 1 (Ur1) uraninite is characterized by local development of microfractures and pores in the crystal of uraninite, a scattered distribution, and irregular crystal shapes, and it is associated with ilmenite, biotite, and rare earth element (REE) minerals (monazite and xenotime). The phase 2 uraninite (Ur2) has anhedral crystal shapes with well-developed microfractures and pores and is associated with pyrite, albite, pyrrhotite, molybdenite, zircon, and chlorite. X-ray element mapping revealed that the distributions of U, Th, and Pb in the Ur1 uraninite are homogeneous, whereas those in the Ur2 uraninite are heterogeneous. The results of the electron microprobe analysis (EMPA) show that the UO2 and PbO contents of the Ur1 and Ur2 uraninite do not vary significantly. The high ThO2 contents of the Ur1 (1.08–1.68 wt %) and Ur2 uraninite (3.41–4.83 wt %) indicate that they formed at different temperatures. The laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) analysis results show that the ∑REE of the Ur1 uraninite (3747.5–7032.3 ppm) is lower than that of the Ur2 uraninite (8369.2–11,484.3 ppm), and the REE patterns of the Ur1 and Ur2 uraninite are sickle-shaped with large negative Eu anomalies. The LA-ICP-MS U–Pb dating results revealed that the ages of the Ur1 (841.4 ± 4.0 Ma) and Ur2 (834.5 ± 4.1 Ma–837.2 ± 4.5 Ma) uraninite are in consistent with that of the migmatite. Thus, the Datian uranium deposit underwent at least two hydrothermal events, and the uraninite was formed due to the migmatization.
Convertible and Constrained Nucleotides: The 2’-Deoxyribose 5’-C-Functionalization Approach, a French Touch
Authors: Chardet Crystalle , Payrastre Corinne , Gerland Béatrice , Escudier Jean-Marc
Published: October 2021

Many strategies have been developed to modulate the biological or biotechnical properties of oligonucleotides by introducing new chemical functionalities or by enhancing their affinity and specificity while restricting their conformational space. Among them, we review our approach consisting of modifications of the 5’-C-position of the nucleoside sugar. This allows the introduction of an additional chemical handle at any position on the nucleotide chain without disturbing the Watson–Crick base-pairing. We show that 5’-C bromo or propargyl convertible nucleotides (CvN) are accessible in pure diastereoisomeric form, either for nucleophilic displacement or for CuAAC conjugation. Alternatively, the 5’-carbon can be connected in a stereo-controlled manner to the phosphate moiety of the nucleotide chain to generate conformationally constrained nucleotides (CNA). These allow the precise control of the sugar/phosphate backbone torsional angles. The consequent modulation of the nucleic acid shape induces outstanding stabilization properties of duplex or hairpin structures in accordance with the preorganization concept. Some biological applications of these distorted oligonucleotides are also described. Effectively, the convertible and the constrained approaches have been merged to create constrained and convertible nucleotides (C2NA) providing unique tools to functionalize and stabilize nucleic acids.
Total Syntheses of Pladienolide-Derived Spliceosome Modulators
Authors: Sim Jaehoon , Jang Eunbin , Kim Hyun Jin , Jeon Hongjun
Published: October 2021

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.
Quassinoids from the Roots of Eurycoma longifolia and Their Anti-Proliferation Activities
Authors: Yang Wei-Qun , Tang Wei , Huang Xiao-Jun , Song Jian-Guo , Li Yue-Yue , Xiong Yu , Fan Chun-Lin , Wu Zhen-Long , Wang Ying , Ye Wen-Cai
Published: October 2021

A phytochemical investigation on the roots of medicinal plant Eurycoma longifolia resulted in the isolation of 10 new highly oxygenated C20 quassinoids longifolactones G‒P (1–10), along with four known ones (11–14). Their chemical structures and absolute configurations were unambiguously elucidated on the basis of comprehensive spectroscopic analysis and X-ray crystallographic data. Notably, compound 1 is a rare pentacyclic C20 quassinoid featuring a densely functionalized 2,5-dioxatricyclo[5.2.2.04,8]undecane core. Compound 4 represents the first example of quassinoids containing a 14,15-epoxy functionality, and 7 features an unusual α-oriented hydroxyl group at C-14. All isolated compounds were evaluated for their anti-proliferation activities on human leukemia cells. Among the isolates, compounds 5, 12, 13, and 14 potently inhibited the in vitro proliferation of K562 and HL-60 cells with IC50 values ranging from 2.90 to 8.20 μM.
Novel Boronate Probe Based on 3-Benzothiazol-2-yl-7-hydroxy-chromen-2-one for the Detection of Peroxynitrite and Hypochlorite
Authors: Modrzejewska Julia , Szala Marcin , Grzelakowska Aleksandra , Zakłos-Szyda Małgorzata , Zielonka Jacek , Podsiadły Radosław
Published: October 2021

Derivatives of coumarin, containing oxidant-sensitive boronate group, were recently developed for fluorescent detection of inflammatory oxidants. Here, we report the synthesis and the characterization of 3-(2-benzothiazolyl)-7-coumarin boronic acid pinacol ester (BC-BE) as a fluorescent probe for the detection of peroxynitrite (ONOO–), with high stability and a fast response time. The BC-BE probe hydrolyzes in phosphate buffer to 3-(2-benzothiazolyl)-7-coumarin boronic acid (BC-BA) which is stable in the solution even after a prolonged incubation time (24 h). BC-BA is slowly oxidized by H2O2 to form the phenolic product, 3-benzothiazol-2-yl-7-hydroxy-chromen-2-one (BC-OH). On the other hand, the BC-BA probe reacts rapidly with ONOO−. The ability of the BC-BA probe to detect ONOO– was measured using both authentic ONOO– and the system co-generating steady-state fluxes of O2•– and •NO. BC-BA is oxidized by ONOO– to BC-OH. However, in this reaction 3-benzothiazol-2-yl-chromen-2-one (BC-H) is formed in the minor pathway, as a peroxynitrite-specific product. BC-OH is also formed in the reaction of BC-BA with HOCl, and subsequent reaction of BC-OH with HOCl leads to the formation of a chlorinated phenolic product, which could be used as a specific product for HOCl. We conclude that BC-BA shows potential as an improved fluorescent probe for the detection of peroxynitrite and hypochlorite in biological settings. Complementation of the fluorescence measurements by HPLC-based identification of oxidant-specific products will help to identify the oxidants detected.
Modulation of the NOTCH1 Pathway by LUNATIC FRINGE Is Dominant over That of MANIC or RADICAL FRINGE
Authors: Pennarubia Florian , Nairn Alison V. , Takeuchi Megumi , Moremen Kelley W. , Haltiwanger Robert S.
Published: October 2021

Fringes are glycosyltransferases that transfer a GlcNAc to O-fucose residues on Epidermal Growth Factor-like (EGF) repeats. Three Fringes exist in mammals: LUNATIC FRINGE (LFNG), MANIC FRINGE (MFNG), and RADICAL FRINGE (RFNG). Fringe modification of O-fucose on EGF repeats in the NOTCH1 (N1) extracellular domain modulates the activation of N1 signaling. Not all O-fucose residues of N1 are modified by all Fringes; some are modified by one or two Fringes and others not modified at all. The distinct effects on N1 activity depend on which Fringe is expressed in a cell. However, little data is available on the effect that more than one Fringe has on the modification of O-fucose residues and the resulting downstream consequence on Notch activation. Using mass spectral glycoproteomic site mapping and cell-based N1 signaling assays, we compared the effect of co-expression of N1 with one or more Fringes on modification of O-fucose and activation of N1 in three cell lines. Individual expression of each Fringe with N1 in the three cell lines revealed differences in modulation of the Notch pathway dependent on the presence of endogenous Fringes. Despite these cell-based differences, co-expression of several Fringes with N1 demonstrated a dominant effect of LFNG over MFNG or RFNG. MFNG and RFNG appeared to be co-dominant but strongly dependent on the ligands used to activate N1 and on the endogenous expression of Fringes. These results show a hierarchy of Fringe activity and indicate that the effect of MFNG and/or RFNG could be small in the presence of LFNG.
β-Cyclodextrin Derivative Grafted on Silica Gel Represents a New Polymeric Sorbent for Extracting Nitisinone from Model Physiological Fluids
Authors: Danek Magdalena , Korytkowska-Wałach Anna , Barchańska Hanna
Published: October 2021

Nitisinone (NTBC) is used in the treatment of disorders affecting the tyrosine pathway, including hereditary tyrosinemia type I, alkaptonuria, and neuroblastoma. An inappropriate dosage of this therapeutic drug causes side effects; therefore, it is necessary to develop a rapid and sensitive method to monitor the content of NTBC in patients’ blood. This study aimed to develop anew polymeric sorbent containing β-cyclodextrin (β-CD) derivatives grafted on silica gel to effectively extract NTBC from model physiological fluids. The inclusion complex formed between β-CD and NTBC was examined by proton nuclear magnetic resonance spectroscopy. The novel sorbents with derivatives of β-CD were prepared on modified silica gel using styrene as a comonomer, ethylene glycol dimethacrylate as a crosslinking agent, and 2,2′-azo-bis-isobutyronitrile as a polymerization initiator. The obtained products were characterized via Fourier transform infrared spectroscopy and then used as sorbents as part of a solid phase extraction technique. High NTBC recovery (70%indicated that the developed polymeric sorbent may be suitable for extracting this compound from patients’ blood samples.
Discovery of Active Ingredients Targeted TREM2 by SPR Biosensor-UPLC/MS Recognition System, and Investigating the Mechanism of Anti-Neuroinflammatory Activity on the Lignin-Amides from Datura metel Seeds
Authors: Wang Si-Yi , Liu Yan , Li Xiao-Mao , Algradi Adnan Mohammed , Jiang Hai , Sun Yan-Ping , Guan Wei , Pan Juan , Kuang Hai-Xue , Yang Bing-You
Published: October 2021

As a new target protein for Alzheimer’s disease (AD), the triggering receptor expressed on myeloid Cells 2 (TREM2) was expressed on the surface of microglia, which was shown to regulate neuroinflammation, be associated with a variety of neuropathologic, and regarded as a potential indicator for monitoring AD. In this study, a novel recognition system based on surface plasmon resonance (SPR) for the TREM2 target spot was established coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-MS), in order to screen the active ingredients targeting TREM2 from Datura metel seeds. The results showed that four lignan-amides were discovered as candidate compounds by SPR biosensor-UPLC/MS recognition analysis. According to the guidance of the active ingredients discovered by the system, the lignin-amides from Datura metel seeds (LDS) were preliminarily identified as containing 27 lignan-amides, which were enriched compositions by the HP-20 of Datura metel seeds. Meanwhile, the anti-inflammatory activity of LDS was evaluated in BV2 microglia induced by LPS. Our experimental results demonstrated that LDS could reduce NO release in LPS-treated BV2 microglia cells and significantly reduce the expression of the proteins of inducible Nitric Oxide Synthase (iNOS), cyclooxygenase 2 (COX-2), microtubule-associated protein tau (Tau), and ionized calcium-binding adapter molecule 1 (IBA-1). Accordingly, LDS might increase the expression of TREM2/DNAX-activating protein of 12 kDa (DAP12) and suppress the Toll-like receptor SX4 (TLR4) pathway and Recombinant NLR Family, Pyrin Domain Containing Protein 3 (NLRP3)/cysteinyl aspartate specific proteinase-1 (Caspase-1) inflammasome expression by LDS in LPS-induced BV2 microglial cells. Then, the inhibitory release of inflammatory factors Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNFα) inflammatory cytokines were detected to inhibit neuroinflammatory responses. The present results propose that LDS has potential as an anti-neuroinflammatory agent against microglia-mediated neuroinflammatory disorders.
Cellular and Molecular Engineering of Glycan Sialylation in Heterologous Systems
Authors: Hombu Ryoma , Neelamegham Sriram , Park Sheldon
Published: October 2021

Glycans have been shown to play a key role in many biological processes, such as signal transduction, immunogenicity, and disease progression. Among the various glycosylation modifications found on cell surfaces and in biomolecules, sialylation is especially important, because sialic acids are typically found at the terminus of glycans and have unique negatively charged moieties associated with cellular and molecular interactions. Sialic acids are also crucial for glycosylated biopharmaceutics, where they promote stability and activity. In this regard, heterogenous sialylation may produce variability in efficacy and limit therapeutic applications. Homogenous sialylation may be achieved through cellular and molecular engineering, both of which have gained traction in recent years. In this paper, we describe the engineering of intracellular glycosylation pathways through targeted disruption and the introduction of carbohydrate active enzyme genes. The focus of this review is on sialic acid-related genes and efforts to achieve homogenous, humanlike sialylation in model hosts. We also discuss the molecular engineering of sialyltransferases and their application in chemoenzymatic sialylation and sialic acid visualization on cell surfaces. The integration of these complementary engineering strategies will be useful for glycoscience to explore the biological significance of sialic acids on cell surfaces as well as the future development of advanced biopharmaceuticals.
Monitoring of Polycyclic Aromatic Hydrocarbon Levels in Mussels (Mytilus galloprovincialis) from Aquaculture Farms in Central Macedonia Region, Greece, Using Gas Chromatography–Tandem Mass Spectrometry Method
Authors: Grigoriou Constantina , Costopoulou Danae , Vassiliadou Irene , Chrysafidis Dimitrios , Tzamtzis Vassilios , Bakeas Evangelos , Leondiadis Leondios
Published: October 2021

A new sensitive and selective gas chromatography tandem mass spectrometry (GC-MS/MS) method was developed for the analysis of 26 polycyclic aromatic hydrocarbons (PAHs), including 16 Environmental Protection Agency (EPA) and 15 + 1 European Union (EU) PAHs, in mussel samples from aquaculture farms in Thermaikos and Strymonian Gulf, Central Macedonia Region, in three sampling periods. Concentrations were found at moderate to low values at all sampling sites, without exceeding maximum levels set by EU. Low molecular weight PAHs were predominant in all samples. Seasonal variation of the concentrations was observed; values were slightly higher in the winter period. Use of diagnostic ratios for potential sources of PAHs showed both petrogenic and pyrolitic origin. In comparison to other related studies of mussels from the Mediterranean Sea, Greek mussels cultivated in the studied gulfs are low in contaminants due to minimal environmental pollution effects. Low concentrations of PAHs are in compliance with the low values of other POPs which were found in the mussels.
Synthesis and Characterization of Manganese Dithiocarbamate Complexes: New Evidence of Dioxygen Activation
Authors: Martini Petra , Boschi Alessandra , Marvelli Lorenza , Uccelli Licia , Carli Stefano , Cruciani Giuseppe , Marzola Erika , Fantinati Anna , Esposito Juan , Duatti Adriano
Published: October 2021

(1) Background: Metal dithiocarbamate compounds have long been the subject of research due to their ease of formation, excellent properties and potential applications. However, manganese complexes with dithiocarbamates, to our knowledge, have never been used for medical imaging applications. With the aim of developing a new class of mononuclear manganese(II)-based agents for molecular imaging applications, we performed a specific investigation into the synthesis of mononuclear bis-substituted Mn(II) complexes with dithiocarbamate ligands. (2) Methods: Synthesis in either open or inert atmosphere at different Mn(II) to diethyldithiocarbamate molar ratios were performed and the products characterized by IR, EA, ESI-MS and XRD analysis. (3) Results: We found that only under oxygen-free atmospheric conditions the Mn(II) complex MnL2, where L = diethyldithiocarbamate ligand, is obtained, which was further observed to react with dioxygen in the solid state to form the intermediate superoxo Mn(III) complex [MnL2(η2-O2)]. The existence of the superoxo complex was revealed by mass spectroscopy, and this species was interpreted as an intermediate step in the reaction that led the bis-substituted Mn(II) complex, MnL2, to transform into the tris-substituted Mn(III) complex, MnL3. A similar result was found with the ligand L’ (= bis(N-ethoxyethyl)dithiocarbamate). (4) Conclusions: We found that in open atmosphere and in aqueous solution, only manganese(III) diethyldithiocarbamate complexes can be prepared. We report here a new example of a small-molecule Mn(II) complex that efficiently activates dioxygen in the solid state through the formation of an intermediate superoxide adduct.
Grape Extract Promoted α-MSH-Induced Melanogenesis in B16F10 Melanoma Cells, Which Was Inverse to Resveratrol
Authors: Zhou Siqi , Riadh Drira , Sakamoto Kazuichi
Published: October 2021

Melanin is a natural pigment produced by cells to prevent damage caused by ultraviolet radiation. Previously, resveratrol was shown to reduce melanin synthesis. As a natural polyphenol with various biological activities, resveratrol occurs in a variety of beverages and plant foods, such as grapes. Therefore, we investigated whether grape extracts containing resveratrol also had the ability to regulate melanin synthesis. In this study, we used mouse B16F10 melanoma cells as a model for melanin synthesis with the melanogenesis-inducing α-melanocyte-stimulating hormone (α-MSH) as a positive control. Our results confirmed previous reports that resveratrol reduces melanin synthesis by reducing the activity of the rate-limiting enzyme tyrosinase. In contrast, the grape extract could not reduce melanin synthesis, and in fact promoted melanogenesis in the presence of α-MSH. The expression of genes related to melanin synthesis, such as tyrosinase, tyrosinase-related protein-1, tyrosinase-related protein-2, and microphthalmia-associated transcription factor, also supports these phenomena, which means that even in the presence of resveratrol, grape extract will strengthen the function of α-MSH in promoting melanin synthesis. Therefore, these results also provide a point of view for research on cosmetics.
Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small Cell Lung Cancer
Authors: Hsu Jui-Ling , Leu Wohn-Jenn , Zhong Nan-Shan , Guh Jih-Hwa
Published: October 2021

Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action.
Evidence for an Ordering Transition near 120 K in an Intrinsically Disordered Protein, Casein
Authors: Maslennikova Natalya A. , Golysheva Elena A. , Dzuba Sergei A.
Published: October 2021

Intrinsically disordered proteins (IDPs) are proteins that possess large unstructured regions. Their importance is increasingly recognized in biology but their characterization remains a challenging task. We employed field swept Electron Spin Echoes in pulsed EPR to investigate low-temperature stochastic molecular librations in a spin-labeled IDP, casein (the main protein of milk). For comparison, a spin-labeled globular protein, hen egg white lysozyme, is also investigated. For casein these motions were found to start at 100 K while for lysozyme only above 130 K, which was ascribed to a denser and more ordered molecular packing in lysozyme. However, above 120 K, the motions in casein were found to depend on temperature much slower than those in lysozyme. This abrupt change in casein was assigned to an ordering transition in which peptide residues rearrange making the molecular packing more rigid and/or more cohesive. The found features of molecular motions in these two proteins turned out to be very similar to those known for gel-phase lipid bilayers composed of conformationally ordered and conformationally disordered lipids. This analogy with a simpler molecular system may appear helpful for elucidation properties of molecular packing in IDPs.
Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells
Authors: Panwong Suthida , Wathikthinnakon Methi , Kaewkod Thida , Sawasdee Nunghathai , Tragoolpua Yingmanee , Yenchitsomanus Pa-thai , Panya Aussara
Published: October 2021

Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a lethal cancer, cholangiocarcinoma (CCA), to natural killer (NK) cells. Treatment with cordycepin prior to and during co-culturing with NK-92 cells significantly increased cell death of KKU-213A as compared to solitary cordycepin or NK treatment. Moreover, sensitization activity was also observed in the combination of NK-92 cells and Cordyceps militaris extract that contained cordycepin as a major component. The cordycepin treatment remarkably caused an increase in TRAIL receptor (DR4 and DR5) expression in KKU-213A, suggesting the possible involvement of TRAIL signaling in KKU-213A sensitization to NK-92 cells. In conclusion, this is the first report on the sensitization activity of cordycepin on CCA cells to NK cytotoxicity, which supports that cordycepin can be further developed as an alternate immunomodulating agent.
Are Point Mutations in HMG-CoA Reductases (Hmg1 and Hmg2) a Step towards Azole Resistance in Aspergillus fumigatus?
Authors: Gonzalez-Jimenez Irene , Lucio Jose , Roldan Alejandra , Alcazar-Fuoli Laura , Mellado Emilia
Published: October 2021

Invasive aspergillosis, mainly caused by Aspergillus fumigatus, can lead to severe clinical outcomes in immunocompromised individuals. Antifungal treatment, based on the use of azoles, is crucial to increase survival rates. However, the recent emergence of azole-resistant A. fumigatus isolates is affecting the efficacy of the clinical therapy and lowering the success rate of azole strategies against aspergillosis. Azole resistance mechanisms described to date are mainly associated with mutations in the azole target gene cyp51A that entail structural changes in Cyp51A or overexpression of the gene. However, strains lacking cyp51A modifications but resistant to clinical azoles have recently been detected. Some genes have been proposed as new players in azole resistance. In this study, the gene hmg1, recently related to azole resistance, and its paralogue hmg2 were studied in a collection of fifteen azole-resistant strains without cyp51A modifications. Both genes encode HMG-CoA reductases and are involved in the ergosterol biosynthesis. Several mutations located in the sterol sensing domain (SSD) of Hmg1 (D242Y, G307D/S, P309L, K319Q, Y368H, F390L and I412T) and Hmg2 (I235S, V303A, I312S, I360F and V397C) were detected. The role of these mutations in conferring azole resistance is discussed in this work.
Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy
Authors: Chis Adriana Aurelia , Dobrea Carmen Maximiliana , Rus Luca-Liviu , Frum Adina , Morgovan Claudiu , Butuca Anca , Totan Maria , Juncan Anca Maria , Gligor Felicia Gabriela , Arseniu Anca Maria
Published: October 2021

Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.
Thiol-Responsive Gold Nanodot Swarm with Glycol Chitosan for Photothermal Cancer Therapy
Authors: Jo SeongHoon , Sun In-Cheol , Yun Wan Su , Kim Jinseong , Lim Dong-Kwon , Ahn Cheol-Hee , Kim Kwangmeyung
Published: October 2021

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.
Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner
Authors: Komorowska-Müller Joanna Agnieszka , Rana Tanushka , Olabiyi Bolanle Fatimat , Zimmer Andreas , Schmöle Anne-Caroline
Published: October 2021

Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB2R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB2R in physiological brain aging. We used CB2R−/− mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB2R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB2R−/− mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB2R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB2R−/− microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB2R−/− microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB2Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself.
Photodegradation of Anti-Inflammatory Drugs: Stability Tests and Lipid Nanocarriers for Their Photoprotection
Authors: Ioele Giuseppina , Grande Fedora , De Luca Michele , Occhiuzzi Maria Antonietta , Garofalo Antonio , Ragno Gaetano
Published: October 2021

The present paper provides an updated overview of the methodologies applied in photodegradation studies of non-steroidal anti-inflammatory drugs. Photostability tests, performed according to international standards, have clearly demonstrated the photolability of many drugs belonging to this class, observed during the preparation of commercial forms, administration or when dispersed in the environment. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques and in many studies the analytical data are processed by chemometric procedures. The application of multivariate analysis in the resolution of often-complex data sets makes it possible to estimate the pure spectra of the species involved in the degradation process and their concentration profiles. Given the wide use of these drugs, several pharmaceutical formulations have been investigated to improve their photostability in solution or gel, as well as the pharmacokinetic profile. The use of lipid nanocarriers as liposomes, niosomes or solid lipid nanoparticles has demonstrated to both minimize photodegradation and improve the controlled release of the entrapped drugs.
Roles of Organic Fragments in Redirecting Crystal/Molecular Structures of Inorganic–Organic Hybrids Based on Lacunary Keggin-Type Polyoxometalates
Authors: Khajavian Ruhollah , Jodaian Vida , Taghipour Fatemeh , Mague Joel T. , Mirzaei Masoud
Published: October 2021

Lacunary polyoxometalates (LPOMs) are key precursors for the synthesis of functional POMs. To date, reviews dedicated to behavioral studies of LPOMs often comprise the role of metal ions, including transition metal (TM) and rare earth (RE) ions, in extending and stability of high-nuclearity clusters. In contrast, the role of organic ligands in the structures and properties of lacunary-based hybrids has remained less explored. In this review, we focus on the role of organic fragments in the self-assembling process of POM-based architectures and discuss relationships between the nature and structure of organic ligand and properties such as the topology of hybrid inorganic–organic material in RE and TM-RE heterometallic derivatives of lacunary Keggin-type POMs. The effects of organic fragment in mixed ligand hybrids are also briefly reviewed.
RETRACTED: Potential Role of Natural Products to Combat Radiotherapy and Their Future Perspectives
Authors: Akter Rokeya , Najda Agnieszka , Rahman Md. , Shah Muddaser , Wesołowska Sylwia , Hassan Syed , Mubin Sidra , Bibi Parveen , Saeeda Saeeda
Published: October 2021

Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy (RT) are the common cancer treatments. In addition to these limitations, the development of adverse effects from chemotherapy and RT reduces the quality of life for cancer patients. Cellular radiosensitivity, or the ability to resist and overcome cell damage caused by ionizing radiation (IR), is directly related to cancer cells’ response to RT. Therefore, radiobiological research is emphasizing chemical compounds ’radiosensitization of cancer cells so that they are more reactive in the IR spectrum. Recent years researchers have seen an increase in interest in natural products that have antitumor effects with minimal side effects. Natural products, on the other hand, are easy to recover and therefore less expensive. There have been several scientific studies done based on these compounds that have tested their ability in vitro and in vivo to induce tumor radiosensitization. The role of natural products in RT, as well as their usefulness and potential applications, is the goal of this current review.
The Reactions of 6-(Hydroxymethyl)-2,2-dimethyl-1-azaspiro[4.4]nonanes with Methanesulfonyl Chloride or PPh3-CBr4
Authors: Khoroshunova Yulia V. , Morozov Denis A. , Taratayko Andrey I. , Dobrynin Sergey A. , Eltsov Ilia V. , Rybalova Tatyana V. , Sotnikova Yulia S. , Polovyanenko Dmitriy N. , Asanbaeva Nargiz B. , Kirilyuk Igor A.
Published: October 2021

Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh3-CBr4 system is a commonly used pathway to various functional derivatives. The reactions of (5R(S),6R(S))-1-X-6-(hydroxymethyl)-2,2-dimethyl- 1-azaspiro[4.4]nonanes 1a–d (X = O·; H; OBn, OBz) with MsCl/NR3 or PPh3-CBr4 were studied. Depending on substituent X, the reaction afforded hexahydro-1H,6H-cyclopenta[c]pyrrolo[1,2-b]isoxazole (2) (for X = O), a mixture of 2 and octahydrocyclopenta[c]azepines (4–6) (for X = OBn, OBz), or perhydro-cyclopenta[2,3]azeto[1,2-a]pyrrol (3) (for X = H) derivatives. Alkylation of the latter with MeI with subsequent Hofmann elimination afforded 2,3,3-trimethyl-1,2,3,4,5,7,8,8a-octahydrocyclopenta[c]azepine with 56% yield.
Olive Pomace Phenolic Compounds Stability and Safety Evaluation: From Raw Material to Future Ophthalmic Applications
Authors: Katsinas Nikolaos , Enríquez-de-Salamanca Amalia , Bento da Silva Andreia , Bronze Maria Rosário , Rodríguez-Rojo Soraya
Published: October 2021

Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive’s industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.
Altered Glycosylation of Human Alpha-1-Acid Glycoprotein as a Biomarker for Malignant Melanoma
Authors: Virág Dávid , Kremmer Tibor , Lőrincz Kende , Kiss Norbert , Jobbágy Antal , Bozsányi Szabolcs , Gulyás Lili , Wikonkál Norbert , Schlosser Gitta , Borbély Adina , Huba Zsófia , Dalmadi Kiss Borbála , Antal István , Ludányi Krisztina
Published: October 2021

A high-resolution HILIC-MS/MS method was developed to analyze anthranilic acid derivatives of N-glycans released from human serum alpha-1-acid glycoprotein (AGP). The method was applied to samples obtained from 18 patients suffering from high-risk malignant melanoma as well as 19 healthy individuals. It enabled the identification of 102 glycan isomers separating isomers that differ only in sialic acid linkage (α-2,3, α-2,6) or in fucose positions (core, antenna). Comparative assessment of the samples revealed that upregulation of certain fucosylated glycans and downregulation of their nonfucosylated counterparts occurred in cancer patients. An increased ratio of isomers with more α-2,6-linked sialic acids was also observed. Linear discriminant analysis (LDA) combining 10 variables with the highest discriminatory power was employed to categorize the samples based on their glycosylation pattern. The performance of the method was tested by cross-validation, resulting in an overall classification success rate of 96.7%. The approach presented here is significantly superior to serological marker S100B protein in terms of sensitivity and negative predictive power in the population studied. Therefore, it may effectively support the diagnosis of malignant melanoma as a biomarker.
Photodegradation of Riboflavin under Alkaline Conditions: What Can Gas-Phase Photolysis Tell Us about What Happens in Solution?
Authors: Wong Natalie G. K. , Rhodes Chris , Dessent Caroline E. H.
Published: October 2021

The application of electrospray ionisation mass spectrometry (ESI-MS) as a direct method for detecting reactive intermediates is a technique of developing importance in the routine monitoring of solution-phase reaction pathways. Here, we utilise a novel on-line photolysis ESI-MS approach to detect the photoproducts of riboflavin in aqueous solution under mildly alkaline conditions. Riboflavin is a constituent of many food products, so its breakdown processes are of wide interest. Our on-line photolysis setup allows for solution-phase photolysis to occur within a syringe using UVA LEDs, immediately prior to being introduced into the mass spectrometer via ESI. Gas-phase photofragmentation studies via laser-interfaced mass spectrometry of deprotonated riboflavin, [RF − H]−, the dominant solution-phase species under the conditions of our study, are presented alongside the solution-phase photolysis. The results obtained illustrate the extent to which gas-phase photolysis methods can inform our understanding of the corresponding solution-phase photochemistry. We determine that the solution-phase photofragmentation observed for [RF − H]− closely mirrors the gas-phase photochemistry, with the dominant m/z 241 condensed-phase photoproduct also being observed in gas-phase photodissociation. Further gas-phase photoproducts are observed at m/z 255, 212, and 145. The value of exploring both the gas- and solution-phase photochemistry to characterise photochemical reactions is discussed.