Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic 'dose-dependent' Type A reactions ii) 'idiosyncratic' or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/ toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

Toxicity effects of fungicide residues on the wine-producing process

We report the detection of several fungicide residues (Dichlofluanid, Benomyl, Iprodione, Procymidone and Vinclozolin) in red and white bottled wines from two Portuguese wine-producing zones. Studies were done in order to evaluate the active compound transfer percentage from grapes to the final product along fermentation process. We also investigated their effects in Saccharomyces and non-Saccharomyces yeasts as well as their influence on the physical, chemical and organoleptic wine properties. All the tested fungicides had a negative effect on in vitro yeast growth, with Dichlofluanid and Benomyl being the most toxic. Zygosaccharomyces rouxii and Saccharomyces cerevisiae were the most resistant yeasts while Rhodotorula glutinis was the most susceptible. Microvinification experiments carried out in the presence of fungicides produced wine samples with unaltered physical, chemical and organoleptic properties, though Benomyl, a slight delay in the initiation of fermentation process was observed

Electrophysiological answer to a checkerboard stimulus: A pilot study

Electroencephalography is a clinical signal that reveals the brain's electrical activity. In this category, the Visual Evoked Potentials (VEP) is one of the most frequent measures, especially when it is necessary to assess the maturity and function of the central visual system. The Electrodermal Activity (EDA) data gives information about skin conductance, and it is used to evaluate autonomic sympathetic reactions, often related to neuropsychological states. It could be used with all ages and in young subjects with healthy development or clinical practice with children with atypical development. In this paper, we propose an experimental setup based on checkerboard stimuli to assess the evolution of visual system development of preterm infants. This experimental protocol was applied to two female preterm born infants of 4 and 6 months of corrected age. The preliminary findings show that, as expected, the P100 latencies and amplitude are still different from those expected for adults and older children. However, the older infant presents results more similar to adults, corresponding to having a more mature visual system. Concerning EDA, it was observed that the older infant presents more responses to the stimulus, a higher level of skin conductance, and a shorter latency time than the younger infant, which is congruent with what is expected, given the maturation of the nervous system. The methodology used in this pilot application and the algorithm defined seem adequate to use in a longitudinal study to follow the evolution of preterm and term infants

Infidelity in Dating Relationships: Gender-Specific Correlates of Face-to-Face and Online Extradyadic Involvement

This study examined the gender-specific correlates of face-to-face and online extradyadic involvement (EDI) in dating relationships. The sample consisted of 561 women (M age = 23.19 years) and 222 men (M age = 23.97 years), all of whom reported being in an exclusive dating relationship for an average of 35 months. Participants completed the following self-report measures: Extradyadic Behavior Inventory, Attitudes toward Infidelity Scale, and Investment Model Scale. During the current relationship, men were more likely than women to report engagement in face-to-face physical/sexual EDI (23.4 vs. 15.5 %) and online sexual EDI (15.3 vs. 4.6 %). Both men and women with a history of infidelity in a prior relationship were more likely to engage in EDI. More positive attitudes toward infidelity, lower relationship satisfaction, lower commitment, and higher quality of alternatives were significantly associated with EDI, regardless of gender. Women reporting infidelity of a partner in a prior relationship were more likely to engage in face-to-face and online emotional EDI; a longer relationship and a younger age at the first sexual encounter were significant correlates of the engagement in face-to-face emotional EDI. Women with higher education were approximately three times more likely to engage in online sexual EDI. Although men and women are converging in terms of overall EDI, men still report higher engagement in physical/sexual extradyadic behaviors, and the correlates of sexual and emotional EDI vary according to gender. This study contributes to a comprehensive approach of factors influencing the likelihood of EDI and encourages future research in this area

Patterning in time and space: HoxB cluster gene expression in the developing chick embryo

The developing embryo is a paradigmatic model to study molecular mechanisms of time control in Biology. Hox genes are key players in the specification of tissue identity during embryo development and their expression is under strict temporal regulation. However, the molecular mechanisms underlying timely Hox activation in the early embryo remain unknown. This is hindered by the lack of a rigorous temporal framework of sequential Hox expression within a single cluster. Herein, a thorough characterization of HoxB cluster gene expression was performed over time and space in the early chick embryo. Clear temporal collinearity of HoxB cluster gene expression activation was observed. Spatial collinearity of HoxB expression was evidenced in different stages of development and in multiple tissues. Using embryo explant cultures we showed that HoxB2 is cyclically expressed in the rostral presomitic mesoderm with the same periodicity as somite formation, suggesting a link between timely tissue specification and somite formation. We foresee that the molecular framework herein provided will facilitate experimental approaches aimed at identifying the regulatory mechanisms underlying Hox expression in Time and Space.Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PTDC/SAU-OBD/105111/2008, UMINHO/BI/7/2014, SFRH/BPD/65652/2009]; Ciencia Program Contract; Programa Operacional Regional do Norte (ON. 2) [NORTE-07-0124-FEDER-000017]; FCT (National and FEDER COMPETE Program) [PTDC/SAU-BID/121459/2010, PTDC/SAU-OBD/099758/2008]; [PEst-OE/EQB/LA0023/2011]info:eu-repo/semantics/publishedVersio

First Evaluation of Associated Gut Microbiota in Wild Thick-Lipped Grey Mullets (Chelon labrosus, Risso 1827)

This study aimed to characterize the intestinal microbiota of wild thick-lipped grey mullets (Chelon labrosus) and explore its potential functionality on the host. Intestinal contents of anterior and posterior sections from wild fish were collected and DNA was extracted. Subsequently, the V3–V4 regions of 16S rRNA were sequenced using the Illumina technology and results were analyzed by bioinformatics pipeline. The functional profile of the microbial community was analyzed using PICRUSt software. Shannon and Simpson diversity indices were significantly higher in the posterior section of wild specimens. The overall taxonomic composition suggests a certain homogeneity in the anterior section of the intestine and heterogeneity in the posterior section. Due to this, no statistical differences were detected at any level among both intestinal sections. Predicted functions of intestinal microbiota showed the most abundant were those related to amino acid metabolism, carbohydrate metabolism, energy metabolism, membrane transport, and cell replication and repair. Furthermore, the analysis revealed microbial functional genes related to the elimination of environmental toxins.This work was financed by the Project ‘Design and evaluation of probiotics and feed in uncoupled aquaponic system of fishes, plants and microalgae’ (grant #Agl-2017-83260R) granted by Agencia Estatal de Investigación (MINECO, Spanish Government), and by the Project Bluemaro (PID2020 116136 RB100) of the Ministry of Science and Innovation of Spain. Partial funding for open access charge: Universidad de Málag

Recreational Drugs and the Risk of Hepatocellular Carcinoma

Hepatocellular carcinoma represents an important contributor to the global cancer-related burden, and liver cirrhosis is the main risk factor for its development. Conventional or illegal drug consumption is a potential but infrequent cause of cirrhosis. However, the causal relationship between recreational drugs and the risk of developing liver cancer has not been studied in detail thus far. The aim of this review is to synthesize the available published evidence on legal and illegal recreational drug use and the risk of hepatocellular carcinoma and other liver tumors. Expanding our knowledge about the contributions of these substances to the appearance of liver cancers is important for combatting this preventable cause of cancer. Abstract Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis’ potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. (...)This research was supported by grants from Instituto de Salud Carlos III, cofounded by the Fondo Europeo de Desarrollo Regional—FEDER (contract numbers: FIS 21_01248; PI18/00901; UMA18-FEDERJA-193). CIBEREHD is funded by the Instituto de Salud Carlos III (ISCIII). All authors are members of the COST ACTION “CA-17112”, Prospective European Drug-Induced Liver Injury Network, supported by COST (European Cooperation in Science and Technology), www.cost.eu. JMPB holds a Rio Hortega contract from ISCIII. ASZ holds a Jaume Bosch Training Action 2022 from CIBEREHD (ISCIII)

Phenolics and antimicrobial activity of traditional stoned table olives alcaparra

In the present work, we report the determination of phenolic compounds in ‘alcaparra’ table olives by reversed-phase HPLC/DAD, and the evaluation of their extract in vitro activity against several microorganisms that may be causal agents of human intestinal and respiratory tract infections, namely Gram positive (Bacillus cereus, Bacillus subtilis, and Staphylococcus aureus), Gram negative bacteria (Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae) and fungi (Candida albicans and Cryptococcus neoformans). Three flavonoidic compounds were identified and quantified: luteolin 7-O-glucoside, apigenin 7-O-glucoside, and luteolin. At low concentrations (0.05 mg/mL) ‘alcaparra’ extract revealed significant inhibition of both Gram positive and Gram negative bacteria growth, with exception of P. aeruginosa. Nevertheless, no antifungal activity was observed at the tested concentrations

Phenolic compounds and antimicrobial activity of olive (Olea europaea L. Cv. Cobrancosa) leaves.

We report the determination of phenolic compounds in olive leaves by reversedphase HPLC/DAD, and the evaluation of their in vitro activity against several microorganisms that may be causal agents of human intestinal and respiratory tract infections, namely Gram positive (Bacillus cereus, B. subtilis and Staphylococcus aureus), Gram negative bacteria (Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae) and fungi (Candida albicans and Cryptococcus neoformans). Seven phenolic compounds were identified and quantified: caffeic acid, verbascoside, oleuropein, luteolin 7-O-glucoside, rutin, apigenin 7-O-glucoside and luteolin 4’-O-glucoside. At low concentrations olive leafs extracts showed an unusual combined antibacterial and antifungal action, which suggest their great potential as nutraceuticals, particulalry as a source of phenolic compounds

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratoryabnormalitiestoacuteliverfailure(ALF)anddeath.Thecellularandmolecularmecha- nisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanis- tic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.This work was supported by the MINECO Retos SAF2016-78711, EXOHEP-CM S2017/BMD- 3727, NanoLiver-CM Y2018/NMT-4949, ERAB Ref. EA 18/14, AMMF 2018/117, FIS-FEDER PI16_01748, PI19-00883, UMA18-FEDERJA-194, PY18-3364_PY19 and UCM-25-2019. FJC is a Ramón y Cajal Researcher RYC-2014-15242 and a Gilead Liver Research 2018. The research group belongs to the validated Research Groups Ref. 970935 “Liver Pathophysiology” and 920631 “Lymphocyte immunobiology” and IBL-6 (imas12-associated). This article/publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu; accessed 4 March 2021. CIBERehd is funded by ISCiii