Article
Pharmacology & Pharmacy
Liao Shen, Yadan Zhang, Qimei Cai, Jun Yang, Yongan Wang, Dongqin Quan
Summary: In this study, PEGylated liposomes loading HI-6 were prepared and evaluated in vitro and in vivo. The results showed that PEG-LP-HI-6 significantly extended the half-life and mean retention time of HI-6 in vivo, and increased the AUC of HI-6. PEG-LP-HI-6 also increased drug concentrations in the CNS. In vivo treatment experiments demonstrated that PEG-LP-HI-6 could prolong survival time and alleviate neurotoxic symptoms.
Article
Chemistry, Multidisciplinary
Qiaoli Zhang, Yang Yang, Junmei Xia, Yingying Zhang, Shilei Liu, Zhiqin Yuan
Summary: A chemiluminescence sensor array based on the organophosphorus-H2O2 reaction has been proposed in this study to effectively discriminate organophosphorus nerve agents. Experimental results demonstrate the feasibility and high accuracy of this sensor array in distinguishing the agents.
Article
Public, Environmental & Occupational Health
Ruben De Rouck, Mehdi Benhassine, Michel Debacker, Christian Dugauquier, Erwin Dhondt, Filip Van Utterbeeck, Ives Hubloue
Summary: In recent decades, there has been an increasing focus on preparedness for Chemical, Biological, Radiological, and Nuclear (CBRN) threats. Computer simulation is an effective tool for assessing contingency plans and improving response strategies. This paper presents a set of civilian nerve agent injury profiles based on military profiles, adapted for the civilian population. The methodology used can be applied to other chemical warfare agents and different exposure scenarios. These injury profiles can also be used in tabletop and live simulation exercises.
FRONTIERS IN PUBLIC HEALTH
(2023)
Article
Chemistry, Analytical
Miroslav Pohanka, Jitka Zakova
Summary: A new smartphone camera-based colorimetric assay for assessing AChE and BChE activity in biological samples was developed. The method demonstrated practical applicability and simplicity, without the need for specific manipulation or sophisticated instruments.
Review
Biochemistry & Molecular Biology
Carlos A. Valdez, Roald N. Leif
Summary: The field of gas chromatography-mass spectrometry (GC-MS) in the analysis of chemical warfare agents, particularly focusing on organophosphorus-based nerve agents, is constantly evolving and essential for the rapid and accurate detection of these lethal agents. Derivatization reactions, primarily silylations and alkylations, have played a crucial role in efficiently detecting products arising from the degradation of these nerve agents for retrospective identification.
Article
Chemistry, Analytical
Urs C. Meier
Summary: The D/H isotope ratios of sarin (5), diisopropyl methylphosphonate (3), and their precursors Isopropanol (1), methylphosphonic acid dichloride (2), and methylphosphonic acid difluoride (4) were measured using the H-2 SNIF-NMR technique. The D/H isotope ratios of compound 1 showed significant variation. However, the D/H isotope ratios of the methyl and isopropyl moieties in compounds 3, 4, and 5 remained relatively unchanged compared to compounds 1 and 2.
Article
Chemistry, Medicinal
Jack R. McGuire, Stephanie M. Bester, Mark A. Guelta, Jonah Cheung, Caroline Langley, Mark D. Winemiller, Sue Y. Bae, Vanessa Funk, James M. Myslinski, Scott D. Pegan, Jude J. Height
Summary: The study focused on the mechanism of nerve agent inhibition of human acetylcholinesterase (hAChE) and explored the differences in reactivator efficacy among various G-series nerve agents. The results revealed the impact of hAChE active site plasticity on agent selectivity, providing new insights for the development of next-generation reactivators.
CHEMICAL RESEARCH IN TOXICOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Andreia M. P. W. Da Silva, Mateus Mittersteiner, Fabio M. Da Silva, Fernanda D'Avila, Pablo A. Nogara, Karise F. Nogara, Joao B. T. Rocha, Helio G. Bonacorso, Marcos A. P. Martins, Nilo Zanatta
Summary: A chemoselective approach was used to synthesize compounds with 4-(bromo/chloro)methyl-2-methylsulfanyl-6-trihalomethyl pyrimidines, which were further substituted with aminoalcohols. The resulting choline derivatives showed potential as AChE and BChE inhibitors, with the trichloromethyl pyrimidines exhibiting the highest activity. Docking studies and ADMET properties were also reported.
Article
Chemistry, Applied
Roshan Y. Nimje, Prakasam Kuppusamy, Suresh Krishnamoorthy, Yoganand Shanmugam, Duraisamy Ramasamy, Haridhas Manoharan, Pirama Nayagam Arunachalam, Aaron Balog, Emily C. Cherney, Liping Zhang, Robert M. Borzilleri, Zhenqiu Hong, James Kempson, Richard R. Rampulla, Arvind Mathur, Anuradha Gupta
Summary: The current work presents a stereoselective and scalable route to a specific compound, achieved through an efficient synthesis of key intermediates and the use of a stereoselective methodology. This advancement provides a competent and cost-effective approach to accessing the target compound in an enantioselective, safe, and scalable manner.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Multidisciplinary Sciences
Edmond A. Lau, Heather P. Enright, Victoria M. Lao, Michael A. Malfatti, Brian Mayer, Audrey Williams, Carlos Valdez
Summary: The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade nerve agents GF, GD, and VX has been studied. It was found that 6-OxP-CD can degrade GF instantly and form an inclusion complex with GD to improve its degradation efficiency. However, no evidence of an inclusion complex between 6-OxP-CD and VX was found.
Article
Biochemistry & Molecular Biology
Yihan Liao, Yinshi Ren, Xin Luo, Anthony J. Mirando, Jason T. Long, Abigail Leinroth, Ru-Rong Ji, Matthew J. Hilton
Summary: This study reveals the role of interleukin-6 (IL-6) in regulating cartilage degradation and pain in posttraumatic osteoarthritis (PTOA). Genetic ablation of Il6 reduces cartilage catabolism, innervation of the knee joint, and nociceptive signaling in male mice with PTOA. However, it does not improve subchondral bone sclerosis or chondrocyte apoptosis. The study highlights IL-6 as a potential target for disease-modifying drugs for PTOA in a sex-specific manner.
Article
Chemistry, Multidisciplinary
Qunpeng Duan, Yibo Xing, Kainan Guo
Summary: This study investigated the host-guest complexation between the fluorescence probe TNS and the water-soluble cationic pillar[6]arene CP6. The fluorescence intensity of TNS was increased after complexation with CP6. Indicator displacement assays using the fluorescence intensity decrease of the TNS·CP6 complex in the presence of phenolic food additives were utilized for the detection of food additives in water.
FRONTIERS IN CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Hao Chen, Shanshan Deng, Najah Albadari, Mi-Kyung Yun, Sicheng Zhang, Yong Li, Dejian Ma, Deanna N. Parke, Lei Yang, Tiffany N. Seagroves, Stephen W. White, Duane D. Miller, Wei Li
Summary: The study optimized the structure of a potent tubulin inhibitor, leading to the synthesis of analogues with improved metabolic stability. High-resolution X-ray crystal structures confirmed direct binding of two compounds to tubulin. In vitro and in vivo experiments demonstrated the efficacy of one compound, 60c, as a potential anticancer agent.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Takafumi Yukawa, Tohru Yamashita, Toshihiro Imaeda, Hiroyuki Kakei, Shogo Hashizume, Minoru Nakamura, Masaki Daini, Atsutoshi Okabe, Kosuke Nakashima, Akina Harada, Naohiro Narita, Ezio Bettini, Annarosa Ugolini, Mauro Corsi, Tomoaki Hasui
Summary: We have identified a GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold through virtual ligand screening. The introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain increased the GluN2A PAM activity. Modification of the aromatic ring led to the discovery of potent and brain-penetrant 6-methylpyridin-2-one 17, which had negligible binding activity for AMPARs. Oral administration of 17 significantly enhanced rat hippocampal LTP, making it a useful tool for investigating NMDAR functions and discovering therapeutics for NMDAR dysfunction-associated diseases.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Honnalagere Mariswamy Vinusha, Shiva Prasad Kollur, Muneera Begum, Chandan Shivamallu, Ramith Ramu, Prithvi S. Shirahatti, Nagendra Prasad, Ravindra Veerapur, Joaquin Ortega-Castro, Juan Frau, Norma Flores-Holguin, Daniel Glossman-Mitnik
Summary: In this study, a new Schiff base ligand and its metal complexes were synthesized and characterized using various spectroscopic methods. Their antibacterial activities were evaluated, showing potential for future applications in medicine.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Chemistry, Multidisciplinary
M. Panic, N. Macek Hrvat, M. Stokic, I. Radojcic Redovnikovic, Z. Kovarik, K. Radosevic
Summary: This study investigates natural deep eutectic solvents (NADES) as alternative solvents for the preparation of oxime RS194B, a potent antidote for organophosphate poisoning. The aim was to enhance the solubility of RS194B by preparing oxime formulations in NADES. The study demonstrates the potential of NADES in formulating antidotes for nerve agent poisoning.
SUSTAINABLE CHEMISTRY AND PHARMACY
(2022)
Article
Chemistry, Medicinal
Tamara Zorbaz, David Malinak, Tereza Hofmanova, Nikola Marakovic, Suzana Zunec, Nikolina Macek Hrvat, Rudolf Andrys, Miroslav Psotka, Antonio Zandona, Jana Svobodova, Lukas Prchal, Sanja Fingler, Maja Katalinic, Zrinka Kovarik, Kamil Musilek
Summary: Fluorinated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation potential. Compared to non-halogenated oximes, halogenated oximes showed higher binding affinity and lower pKa values. Molecular modeling confirmed the advantage of halogen substitution in stabilizing the oxime and enhancing nucleophilic attack. In vivo administration of a highly efficient reactivator demonstrated significant protection against sarin and cyclosarin exposure.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Ante Milicevic, Goran Sinko
Summary: This study developed QSAR models based on simple descriptors to estimate BChE inhibition potency of different compounds, achieving good correlation with certain topological and constitutional descriptors.
Article
Pharmacology & Pharmacy
Giulia Palermo, Zrinka Kovarik, Peter J. Hotchkiss
Summary: In November 2019, changes were made to Schedule 1 of the Chemical Weapons Convention for the first time. This article presents a literature review on the newly scheduled carbamates, highlighting their unique chemical composition and toxicological effects. Although there is limited information on the detection of these carbamates, existing knowledge on carbamate pesticides may provide a starting point for detection methodologies. The implications of these newly scheduled carbamates for the nonproliferation and disarmament community are also discussed.
Article
Chemistry, Medicinal
Ana Matosevic, Anamarija Knezevic, Antonio Zandona, Nikola Marakovic, Zrinka Kovarik, Anita Bosak
Summary: This study synthesized 18 biscarbamates with different substituents and evaluated their inhibitory potential and selectivity towards enzymes related to Alzheimer's disease. The results showed that compounds 2 and 16 exhibited the most promising characteristics in terms of selective inhibition of cholinesterases, non-toxicity, ability to cross the blood-brain barrier, and chelation of biometals, making them suitable for the treatment of middle and late stages of Alzheimer's disease.
Article
Biochemistry & Molecular Biology
Nadav Yayon, Oren Amsalem, Tamara Zorbaz, Or Yakov, Serafima Dubnov, Katarzyna Winek, Amir Dudai, Gil Adam, Anna K. Schmidtner, Marc Tessier-Lavigne, Nicolas Renier, Naomi Habib, Idan Segev, Michael London, Hermona Soreq
Summary: This study investigated the morphology and transcriptional diversity of cortical cholinergic VIP/ChAT interneurons (VChIs) and identified two distinct morphological types. After whisker deprivation, changes in dendritic arborization, cortical depth, and distribution patterns were observed in the barrel fields. The researchers also discovered key regulatory factors involved in morphological changes using a method for isolating nuclei from fixed tissues.
Article
Clinical Neurology
Dana Shulman, Serafima Dubnov, Tamara Zorbaz, Nimrod Madrer, Iddo Paldor, David A. Bennett, Sudha Seshadri, Elliott J. Mufson, David S. Greenberg, Yonatan Loewenstein, Hermona Soreq
Summary: Females with Alzheimer's disease (AD) experience accelerated dementia and loss of cholinergic neurons compared to males, and the underlying mechanisms may involve changes in transfer RNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). The study found that NAc CholinotRFs of mitochondrial genome origin had reduced levels, which correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA sequencing in AD temporal cortices also indicated altered sex-specific levels of cholinergic transcripts in diverse cell types and sex-specific CholinotRF elevations in neuroblastoma cells under cholinergic differentiation. These findings suggest the involvement of CholinotRFs in cholinergic regulation and their potential role in AD sex-specific cholinergic loss and dementia.
ALZHEIMERS & DEMENTIA
(2023)
Article
Biochemistry & Molecular Biology
Vesna Pehar, Dora Kolic, Antonio Zandona, Goran Sinko, Maja Katalinic, Visnja Stepanic, Zrinka Kovarik
Summary: This study compared 346 herbicides currently in use and 163 no longer in use with cholinesterase inhibitors and drugs in terms of their physicochemical profile and estimated toxic effects on human health. The results showed potential adverse consequences for each herbicide class, with the classes K1, K3/N, F1, and E having the most toxic warnings. In vitro tests revealed that the organophosphate anilofos and oxyacetanilide flufenacet were the most potent inhibitors of acetylcholinesterase and butyrylcholinesterase, respectively. Some herbicides also exhibited cytotoxicity towards hepatocytes and neuroblastoma cells.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Review
Biochemistry & Molecular Biology
Zrinka Kovarik, Gilli Moshitzky, Nikolina Macek Hrvat, Hermona Soreq
Summary: This review summarizes recent studies on the chemical and molecular regulators of acetylcholine (ACh) signaling and highlights the complexity of small molecule and RNA regulators that control cholinergic functioning in health and disease. It discusses the impact of acute states, age, sex, and COVID-19 infection on ACh-mediated processes and inflammation, as well as the toxicity of organophosphorus compounds and the limitations of current treatments. The review aims to explore mechanisms of cholinergic signaling dysfunction and propose new therapeutic strategies to combat the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems, focusing on improved small molecules and RNA-based approaches.
JOURNAL OF NEUROCHEMISTRY
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
Zrinka Kovarik, Nikolina Macek Hrvat, Katarina Ilic, Dora Kolic, Palmer Taylor, Svjetlana Kalanj Bognar
JOURNAL OF NEUROCHEMISTRY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
D. Kolic, G. Sinko, L. Jean, M. Chioua, J. Dias, J. Marco-Contelles, Z. Kovarik
Meeting Abstract
Biochemistry & Molecular Biology
Z. Kovarik, V. Pehar, T. Cadez, D. Kolic, A. Zandona, A. Lulic, G. Sinko, M. Katalinic
Meeting Abstract
Biochemistry & Molecular Biology
T. Cadez, A. Zandona, M. Katalinic, Z. Kovarik