Article
Chemistry, Medicinal
Dehui Zhang, David A. Perrey, Ann M. Decker, Tiffany L. Langston, Vijayakumar Mavanji, Danni L. Harris, Catherine M. Kotz, Yanan Zhang
Summary: The study identified a promising dual small molecule agonist that can increase wakefulness and alleviate narcolepsy symptoms, with positive effects demonstrated in experiments on elderly mice, supporting the development of orexin agonists as potential treatments for orexin-deficient disorders in the future.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Marieke Vringer, Birgitte Rahbek Kornum
Summary: Narcolepsy type 1 and type 2 are characterized by excessive daytime sleepiness and reduced quality of life, with current treatments focused on improving daytime sleepiness and reducing cataplexy. Targeting Hcrt receptors shows promise in alleviating symptoms, but careful consideration of potential side effects is required. Immunotherapies may target the core pathophysiology of narcolepsy, but further research is needed to identify the optimal therapeutic target.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Review
Clinical Neurology
Jari K. Gool, Eva M. van Heese, Mink S. Schinkelshoek, Aniek Remmerswaal, Gert Jan Lammers, Karin D. van Dijk, Rolf Fronczek
Summary: This study assessed the effect of opioid use on narcolepsy type 1 symptom severity through a literature review and questionnaire study. The results showed that opioids could improve narcolepsy symptom severity, with the most significant improvements seen in sleep quality and excessive daytime sleepiness.
Editorial Material
Clinical Neurology
Tomi Sarkanen, Gabriele Sved, Maria Juujarvi, Anniina Alakuijala, Markku Partinen
Summary: This article reports four cases of false positives and misdiagnosis of narcolepsy due to measurement of orexin levels using enzyme immune assay (EIA), therefore strongly discouraging the use of orexin EIA measurement in a clinical setting.
JOURNAL OF CLINICAL SLEEP MEDICINE
(2022)
Article
Multidisciplinary Sciences
Guo Luo, Jing Zhang, Ling Lin, Emmanuel Jean-Marie Mignot
Summary: This study replicated the data from 77 cases and 44 controls and further investigated the reactivity of CD4+ T cells associated with HCRT. The results showed lower activation of TCRs associated with HCRTNH2 compared to flu antigens, and no significant phenotypic differences were found between the two types of T cells. In addition, the analysis of TCRs did not find evidence of molecular mimicry between HCRT and flu antigens.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
Melanie Strauss, Lucie Griffon, Maxime Elbaz, Isabelle Arnulf, Mounir Chennaoui, Damien Leger
Summary: This study examines decision-making impairments in individuals with central disorders of hypersomnolence (CDH), specifically narcolepsy type 1 (NT1). The results suggest that both NT1 and other CDH patients have decreased learning abilities to avoid losses, which is associated with alterations in vigilance. The study provides new insights into the nature of decision-making impairments in CDH and suggests the potential for minimizing these alterations by restoring adequate vigilance.
Review
Clinical Neurology
Ryan K. Tisdale, Akihiro Yamanaka, Thomas S. Kilduff
Summary: Animal models have played a crucial role in investigating the etiology and phenotype of narcolepsy, revealing the relationship between the hypocretin/orexin system and narcolepsy. Additionally, these models have helped us understand the mechanisms of sleep/wake regulation.
Article
Clinical Neurology
Sara Alvente, Chiara Berteotti, Stefano Bastianini, Viviana Lo Martire, Gabriele Matteoli, Alessandro Silvani, Giovanna Zoccoli
Summary: The study found that in orexin-deficient mouse models, higher arterial pressure during sleep and smaller differences in arterial pressure between sleep and wakefulness are mediated by alterations in cardiovascular sympathetic control.
Article
Multidisciplinary Sciences
Takuya Ogawa, Yuta Kajiyama, Hideaki Ishido, Shigeru Chiba, Gajanan S. Revankar, Tomohito Nakano, Seira Taniguchi, Takashi Kanbayashi, Kensuke Ikenaka, Hideki Mochizuki
Summary: This study investigated the association between cerebrospinal fluid (CSF) orexin levels and sleep disturbances in patients with Parkinson's disease (PD). The results showed decreased CSF orexin levels in patients with PD, but these levels did not correlate with any clinical characteristics. The study suggests that understanding the reciprocal role of orexin among other neurotransmitters may provide a better treatment strategy for sleep disturbance in patients with PD.
Article
Clinical Neurology
Ming-Fung Wu, Thomas C. Thannickal, Songlin Li, Ronald McGregor, Yuan-Yang Lai, Jerome M. Siegel
Summary: Long-term use of sodium oxybate (SXB) can alleviate cataplexy and sleepiness in narcolepsy. However, unlike opioids, SXB increases the size of Hcrt neurons, decreases Hcrt levels in the hypothalamus, and reduces tyrosine hydroxylase levels in the locus coeruleus. Although there are some similar effects on narcoleptic symptoms, SXB does not produce anatomical changes similar to opioids.
Article
Clinical Neurology
Geoffroy Vellieux, Justine Frija-Masson, Anny Rouvel-Tallec, Xavier Drouot, Marie-Pia D'ortho
Summary: The case describes a male patient diagnosed with narcolepsy type 1 based on sleep and wake symptoms and various investigations. Despite receiving treatment with stimulants and anti-cataplectic drugs for several years without significant improvement, the patient experienced spontaneous remission of the disease after 15 years.
NATURE AND SCIENCE OF SLEEP
(2021)
Article
Pharmacology & Pharmacy
Takashi Ishikawa, Hiroe Hara, Ayumi Kawano, Kimio Tohyama, Yuichi Kajita, Yuhei Miyanohana, Tatsuki Koike, Haruhide Kimura
Summary: The loss of orexin neurons is associated with NT1, and a new OX2R agonist called TAK-994 shows potential in promoting wakefulness and improving narcolepsy-like symptoms in mouse models.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Review
Neurosciences
Sachin Kumar, Tapan Behl, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Saurabh Bhatia, Ahmed Al-Harassi, Mohammed M. Abdel-Daim, Simona Bungau
Summary: This study reviewed the changes in the orexinergic system in parkinsonian subjects and found dysfunctioning of this system to be linked with non-motor symptoms (sleep abnormalities) in PD. Orexinergic neurons' behavior is modulated by various factors, and orexin antagonists have been shown to improve abnormal sleep patterns. Since the orexinergic system plays a role in several psychological and neurological disorders, targeting this system could potentially help manage these disorders.
NEUROTOXICITY RESEARCH
(2021)
Article
Clinical Neurology
Lucie Barateau, Regis Lopez, Sofiene Chenini, Anna Laura Rassu, Lytissia Mouhli, Cloe Dhalluin, Isabelle Jaussent, Yves Dauvilliers
Summary: This study aimed to determine the factors associated with disrupted nocturnal sleep (DNS) in patients with narcolepsy type 1 (NT1) and evaluate the effect of medication on DNS and its severity. The results showed that DNS severity was associated with disease severity, sleep quality, and sleep instability. Treatment led to improvements in DNS and reduced sleepiness and depressive symptoms.
Article
Cell Biology
Matthew Dawson, Dylan J. Terstege, Naila Jamani, Mio Tsutsui, Dmitrii Pavlov, Raluca Bugescu, Jonathan R. Epp, Gina M. Leinninger, Derya Sargin
Summary: The hypothalamus is crucial in regulating social behavior by encoding internal states. Hypocretin/orexin neurons in the hypothalamus, initially known for their role in sleep and appetite regulation, also play a key role in emotional and motivated behaviors. However, their involvement in social behavior is still not well understood.
Article
Toxicology
Meng Liu, Ling Zhao, Jin-Tao Wei, Yu-Xuan Huang, Mahmoud Mohamed Khalil, Wen-Da Wu, Kamil Kuca, Lv-Hui Sun
Summary: This study explored the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating advanced microbiomic, metabolomic, and transcriptomic technologies. The results showed that T-2 toxin exposure at different doses reduced feed intake, body weight gain, and induced histopathological lesions in the small intestine. T-2 toxin also affected antioxidant enzyme activities, oxidative stress markers, and was associated with nucleotide and glycerophospholipid metabolism, inflammation, and apoptosis. In conclusion, this study provides novel insights into the toxic mechanisms of T-2 toxin in the small intestine of broilers and suggests potential detoxification strategies.
ARCHIVES OF TOXICOLOGY
(2023)
Review
Toxicology
Li You, Eugenie Nepovimova, Marian Valko, Qinghua Wu, Kamil Kuca
Summary: Mycotoxins induce oxidative stress, hypoxia, and cellular senescence, which are involved in immunosuppressive effects. Activation of senescence markers and cell cycle arrest pathways by mycotoxins further contribute to immunomodulatory effects.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Milan Jokanovic, Patrik Oleksak, Kamil Kuca
Summary: This article examines the potential link between organophosphorus (OP) pesticides and neurological disorders, including dementia, attention deficit hyperactivity disorder, neurodevelopment, autism, cognitive development, Parkinson's disease, and chronic organophosphate-induced neuropsychiatric disorder. These effects are primarily observed after chronic exposure to low doses of OP pesticides. The article also discusses three well-defined neurotoxic effects in humans resulting from single doses of OP compounds. These effects include the cholinergic syndrome, the intermediate syndrome, and organophosphate-induced delayed polyneuropathy. Poisoning can generally be prevented through improved administrative control, restricted access to OP pesticides, effective personal protection measures, and education for OP pesticide applicators and medical staff.
Review
Toxicology
Ying Deng, Vojtech Adam, Eugenie Nepovimova, Zbynek Heger, Marian Valko, Qinghua Wu, Wei Wei, Kamil Kuca
Summary: Cellular senescence leads to reduced tissue regeneration and increased inflammation, and is associated with diseases like diabetes, neurodegenerative diseases, and tumorigenesis. The signaling pathway c-Jun N-terminal kinase (JNK) is involved in the regulation of cellular senescence. JNK can accelerate hypoxia-induced neuronal cell senescence by downregulating hypoxia inducible factor-1 alpha. It can also promote cellular senescence by inhibiting mTOR activity and triggering autophagy.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Medicine, Research & Experimental
Martin Valis, Alzbeta Dlabkova, Jakub Hort, Francesco Angelucci, Jaroslav Pejchal, Kamil Kuca, Zbysek Pavelek, Jana Zdarova Karasova, Michal Novotny
Summary: This study examined the differences in plasma and cerebrospinal fluid (CSF) levels of donepezil among Alzheimer's disease patients receiving a standard dose of 10 mg/day. The results showed that the CSF/plasma donepezil concentration ratio increased significantly in the 24 h group compared to the 6 h and 12 h groups. This finding suggests that measuring the CSF/plasma donepezil concentration ratio could help determine the optimal dose of donepezil.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Plant Sciences
Ying-Ning Zou, Qiu-Yun Qin, Wen-Ya Ma, Li-Jun Zhou, Qiang-Sheng Wu, Yong-Jie Xu, Kamil Kuca, Abeer Hashem, Al-Bandari Fahad Al-Arjani, Khalid F. Almutairi, Elsayed Fathi Abd-Allah
Summary: Metabolomic analysis revealed the metabolic mechanisms of mycorrhiza-enhanced drought tolerance in walnuts. The results showed that AMF inoculation increased biomass production and leaf water potential in walnut under drought stress, accompanied by regulation of numerous metabolic pathways. Furthermore, the regulation of walnut metabolites by AMF exhibited differences under different stress conditions.
Article
Chemistry, Medicinal
Ondrej Benek, Michaela Vaskova, Marketa Miskerikova, Monika Schmidt, Rudolf Andrys, Aneta Rotterova, Adam Skarka, Jana Hatlapatkova, Jana Zdarova Karasova, Matej Medvecky, Lukas Hroch, Lucie Vinklarova, Zdenek Fisar, Jana Hroudova, Jiri Handl, Jan Capek, Tomas Rousar, Tereza Kobrlova, Rafael Dolezal, Ondrej Soukup, Laura Aitken, Frank Gunn-Moore, Kamil Musilek
Summary: In this study, new benzothiazolylurea-based inhibitors were developed for 17 beta-HSD10, a potential drug target for Alzheimer's disease and hormone-dependent cancer. The most potent compounds within this class were identified, showing submicromolar inhibitory activity and cell penetrability. These compounds also showed no off-target effects, cytotoxicity, or neurotoxicity. Compound 9, one of the most potent inhibitors, was found to be bioavailable and able to penetrate the blood-brain barrier.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Filip Pidany, Jana Kroustkova, Abdullah Al Mamun, Daniela Suchankova, Xavier Brazzolotto, Florian Nachon, Fabien Chantegreil, Rafael Dolezal, Lenka Pulkrabkova, Lubica Muckova, Martina Hrabinova, Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniel Jun, Jaroslav Jenco, Jiri Kunes, Lucie Novakova, Jan Korabecny, Lucie Cahlikova
Summary: This study focuses on the design, synthesis, and in vitro evaluation of novel hBChE inhibitors for the treatment of late-stage AD. Compound 87 exhibits promising BChE inhibitory activity and low cytotoxicity, making it a potential lead compound for further development. Crystallographic and QSAR analyses provide insights into the binding mode and structure-activity relationship of these compounds.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Yihao Li, Haoyu Gao, Eugenie Nepovimova, Qinghua Wu, Vojtech Adam, Kamil Kuca
Summary: Recombinant ferritins play a crucial role in maintaining iron homeostasis in living organisms. They have found wide application in multimodal nanomedicine, particularly in anticancer treatment and vaccination. The fusion of viral proteins and ferritin subunits in recombinant particles has been shown to enhance the immune response and antibody production. Targeted ferritin nanoparticles can specifically deliver drugs to tumor tissue, while ferritin linked with contrast agents or fluorescent dyes has potential use in cancer theranostics. This review provides a comprehensive summary of the utilization of recombinant ferritins in multimodal nanomedicine, with emphasis on their role as nanovaccines, nanozymes, and targeted therapy carriers for bioimaging.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Agriculture, Multidisciplinary
Ci Deng, Ying-Ning Zou, Abeer Hashem, Kamil Kuca, Elsayed Fathi Abd-Allah, Qiang-Sheng Wu
Summary: This study visually analyzed the literature on GRSP in the C field from 1999 to 2022 using CiteSpace software and the core collection of Web of Science. The study found that research on GRSP in the C field could be divided into an initial stage, a steady stage, and an explosive stage. The Chinese Academy of Sciences had the most publications, and the United States, China, and India were the leading nations in the C field of GRSP.
CHEMICAL AND BIOLOGICAL TECHNOLOGIES IN AGRICULTURE
(2023)
Article
Biochemistry & Molecular Biology
Tanos Celmar Costa Franca, Jorge Alberto Valle da Silva, Marcelo Carneiro dos Santos, Samir Frontino de Almeida Cavalcante, Kamil Kuca
Summary: The Near Attack Conformation (NAC) approach emphasizes the importance of optimal conditions for substrate atom organization and positioning in enzyme-catalyzed reactions. This approach has been successfully applied to investigate the reactivation mechanism of acetylcholinesterase inhibited by nerve agents, providing a better understanding of this mechanism and consistent corroboration with experimental data. This article summarizes the achievements so far and outlines future perspectives.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Environmental Sciences
Jiefeng Li, Ying Deng, Yating Wang, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca
Summary: Mycotoxins can cause immune dysfunction and diseases in animals and humans. The mechanisms by which mycotoxins induce immunotoxicity involve cellular senescence, activation of signaling pathways, and secretion of senescence-associated secretory phenotype (SASP) cytokines. Cellular senescence is triggered by DNA damage, which also leads to cell cycle arrest and chronic inflammation, eventually leading to immune exhaustion.
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Vladimir Finger, Tomas Kucera, Radka Kafkova, Lubica Muckova, Rafael Dolezal, Jan Kubes, Martin Novak, Lukas Prchal, Levente Lakatos, Martin Andrs, Michaela Hympanova, Jan Marek, Martin Kufa, Vojtech Spiwok, Ondrej Soukup, Eva Mezeiova, Jiri Janousek, Lenka Nevosadova, Marketa Benkova, Russell R. A. Kitson, Martin Kratky, Szilvia Bosze, Katarina Mikusova, Ruben Hartkoorn, Jaroslav Roh, Jan Korabecny
Summary: Phenotypic screening of a small molecule purine derivatives library led to the discovery of compound 10 as a potent antimycobacterial agent. Further structure-activity relationship studies identified compounds 56 and 64 with improved antimycobacterial activity. Mechanism of action studies revealed inhibition of the enzyme DprE1 as the target of these compounds, essential for the biosynthesis of arabinose in the mycobacterial cell wall.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Summary: Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are important kinases in cell growth and DNA damage repair, and their dysfunction and aberrant activation are linked to various diseases including cancer. Inhibitors targeting the PI3K/AKT/mTOR pathway and PIKK inhibitors related to DNA damage response have shown promise in cancer treatment. However, combination therapies are needed to overcome drug resistance and improve efficacy.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Klaudia Jomova, Marcel Cvik, Peter Lauro, Marian Valko, Erik Cizmar, Suliman Y. Alomar, Saleh H. Alwasel, Patrik Oleksak, Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca, Christopher J. Rhodes
Summary: The antioxidant properties of flavonoids with hydroxyl groups allow them to chelate redox active metals and scavenge free radicals. This paper studies the antioxidant and prooxidant properties of baicalein and its complexes with Cu(II) under different conditions. The results show that baicalein and Cu(II)-baicalein complexes have moderate ROS scavenging efficiency and can protect DNA from damage caused by ROS. These findings suggest that baicalein could be a therapeutic agent for diseases involving disrupted metabolism of copper, while low concentrations of baicalein may not inhibit the pro-oxidant effect of copper ions and ascorbate in cancer cells, leading to effective DNA damage.
JOURNAL OF INORGANIC BIOCHEMISTRY
(2023)
