A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. © 2021 Torsten Diesinger et al

2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)

info:eu-repo/semantics/publishe

U-Compare bio-event meta-service: compatible BioNLP event extraction services

AbstractBackgroundBio-molecular event extraction from literature is recognized as an important task of bio text mining and, as such, many relevant systems have been developed and made available during the last decade. While such systems provide useful services individually, there is a need for a meta-service to enable comparison and ensemble of such services, offering optimal solutions for various purposes.ResultsWe have integrated nine event extraction systems in the U-Compare framework, making them inter-compatible and interoperable with other U-Compare components. The U-Compare event meta-service provides various meta-level features for comparison and ensemble of multiple event extraction systems. Experimental results show that the performance improvements achieved by the ensemble are significant. ConclusionsWhile individual event extraction systems themselves provide useful features for bio text mining, the U-Compare meta-service is expected to improve the accessibility to the individual systems, and to enable meta-level uses over multiple event extraction systems such as comparison and ensemble.This research was partially supported by KAKENHI 18002007 [YK, MM, JDK, SP, TO, JT]; JST PRESTO and KAKENHI 21500130 [YK]; the Academy of Finland and computational resources were provided by CSC -- IT Center for Science Ltd [JB, FG]; the Research Foundation Flanders (FWO) [SVL]; UK Biotechnology and Biological Sciences, Research Council (BBSRC project BB/G013160/1 Automated Biological Event Extraction from the Literature for Drug Discovery) and JISC, National Centre for Text Mining [SA]; the Spanish grant BIO2010-17527 [MN, APM]; NIH Grant U54 DA021519 [AO, DRR]Peer Reviewe

Antineoplastische Wirkung des Arzneistoffkandidaten 12-Imidazolyldodecanol im Kontext des hepatozellulären Karzinoms

Das hepatozelluläre Karzinom (HCC) ist weltweit sechsthäufiges Malignom, besetzt jedoch als maligne Todesursache den dritten Rang-wirksame medikamentöse Therapien fehlen. Die meisten seiner Ursachen führen über einen chronischen Entzündungszustand zur Leberzirrhose - der wichtigsten Vorläuferläsion. Im Vorfeld dieser Arbeit wurde von unserer Arbeitsgruppe der CYP2E1-Inhibitor 12-Imidazolyldodecanol (ID-ol) als Arzneimittelkandidat zur Verhinderung der Zirrhose auf Boden chronischer Hepatitiden entwickelt. Ziel dieser Arbeit war es, die Wirkung von ID-ol auf HCC-Zellen (HepG2) und Malignome anderer Gewebe (DLD-1) in Zellkultur, im Tumormodell auf der Chorion-Allantois-Membran (CAM) des Hühnerembryos und im Xenograft mit Nacktmäusen zu prüfen. In vitro reduziert ID-ol ab einer Schwellenkonzentration zwischen 15 µM und 30 µM bis zu über 100 µM die Viabilität der Tumorzellen ohne zytotoxisch oder proapoptotisch zu sein. Basis ist ein Proliferationsstopp der Zellen durch einen phasenunspezifischen Zellzyklusarrest. Das Auftreten von Ki-67 wird unterdrückt und es kommt zur erhöhten Expression von p27. Intravenös appliziertes ID-ol reduziert im Xenograft nach 15 Tagen täglicher Injektion die Tumormasse der Mäuse signifikant und stabilisiert das Mausgewicht. Somit ist zu diskutieren, dass ID-ol durch seine Struktur den intrazellulären ROS-Stress über Destabilisierung der mitochondrialen Membran erhöht. Sobald dieser Effekt über der zellulären Kompensationsschwelle liegt, führt das zur Aktivierung von Foxo3A und zur Hemmung von Fox M1. Dazu kommt es zur Aktivierung der Protein-Phosphatase 2A. Die Summe der Effekte führt zum Arrest des Zellzyklus in allen Phasen, sowie zur vermehrten Expression und nukleären Lokalisation von p27. Aufgrund geringer Studiendichte zum medikamentösen Therapieansatz des HCC beweisen diese mit humanen Zelllinien erzielten Daten therapeutisches Potential und heben die Möglichkeit einer frühen klinischen Studie zur Wirksamkeit im Menschen hervor

The ACM Multimedia 2022 Computational Paralinguistics Challenge: Vocalisations, Stuttering, Activity, & Mosquitoes

The ACM Multimedia 2022 Computational Paralinguistics Challenge addresses four different problems for the first time in a research competition under well-defined conditions: In the Vocalisations and Stuttering Sub-Challenges, a classification on human non-verbal vocalisations and speech has to be made; the Activity Sub-Challenge aims at beyond-audio human activity recognition from smartwatch sensor data; and in the Mosquitoes Sub-Challenge, mosquitoes need to be detected. We describe the Sub-Challenges, baseline feature extraction, and classifiers based on the usual ComPaRE and BoAW features, the auDeep toolkit, and deep feature extraction from pre-trained CNNs using the DeepSpectRum toolkit; in addition, we add end-to-end sequential modelling, and a log-mel-128-BNN.Comment: 5 pages, part of the ACM Multimedia 2022 Grand Challenge "The ACM Multimedia 2022 Computational Paralinguistics Challenge (ComParE 2022)

Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis.

Background and aimsAlcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH.MethodsIn this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies.ResultsA new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol.ConclusionsDue to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH

A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD