Irina Milisav

University of Ljubljana

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Dušan Šuput

University of Ljubljana

Borut Poljšak

University of Ljubljana

Barbara Kramar

University of Ljubljana

Tinkara Pirc Marolt

University of Ljubljana

Samo Ribarič

University of Ljubljana

Vito Kovač

University of Ljubljana

Antonio Cuadrado

Biomedical Research Networking Center on Neurodegenerative Diseases

Marı́a Monsalve

Instituto de Investigaciones Biomédicas Sols-Morreale

IÁ

Ismael Álvarez‐Álvarez

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

M. Isabel Lucena

Universidad de Málaga

Cooperative Institutions

University of Ljubljana

Johannes Gutenberg University Mainz

University Medical Center of the Johannes Gutenberg University Mainz

University of Padua

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Universidad Autónoma de Madrid

Rede de Química e Tecnologia

Ljubljana University Medical Centre

National and Kapodistrian University of Athens

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Genetic variability in the cholecystokinin A receptor affects lipid profile and glucose tolerance in patients with polycystic ovary syndrome

Archives of Medical Science (2022)

Eva Drnovšek Mojca Jensterle Katja Goričar Sara Redenšek Andrej Janež

Introduction Cholecystokinin (CCK) is involved in several metabolic pathways and CCK agonist are considered as potential novel treatment option in populations with increased metabolic risk, including polycystic ovary syndrome (PCOS). As genetic variability of cholecystokinin A and B receptor genes (CCKAR and CCKBR, respectively) may modify its biological actions, we investigated the impact of CCKAR and CCKBR genetic variability on anthropometric and metabolic parameters in patients with PCOS. Material and methods Our cross-sectional study included 168 patients with PCOS and 82 healthy female controls genotyped for polymorphisms in CCKAR (rs6448456 and rs1800857) and CCKBR (rs2929180, rs1800843, rs1042047 and rs1042048) genes. Results The investigated polymorphisms were not associated with anthropometric characteristics of patients with PCOS, however, among healthy controls carriers of at least one polymorphic CCKBR rs1800843 allele had bigger waist circumference (p=0.027) and more visceral fat (p=0.046). Among PCOS patients carriers of at least one polymorphic CCKAR rs6448456 C allele had significantly higher total blood cholesterol and LDL, and significantly lower blood glucose levels after 30, 60 and 90 minutes of the oral glucose tolerance test (all p<0.05). Healthy controls with at least one polymorphic CCKAR rs1800857 C allele were less likely to have high metabolic syndrome burden (p=0.029). Conclusions Genetic variability in CCKAR affects lipid profile and post-load glucose levels in patients with PCOS and is associated with metabolic sydrome burden in healthy young women. Further investigation of the role of genetic variability in CCKAR and CCKBR could contribute to development of individually tailored treatment strategies with CCK receptor agonists.

Cholecystokinin B receptor

Lipid Profile

10.5114/aoms/150867

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Overexpression of caspase-9 triggers its activation and apoptosis in vitro.

PubMed (2006)

Mirjam Druskovic Dušan Šuput Irina Milisav

To investigate the consequences of increased expression of caspase-9: 1) whether the caspase-9 overexpression resulted in cell death through apoptosis, 2) whether apoptosis could be triggered in normal and tumor cells, and 3) what is the role of caspase-9 in the process.The caspase-9 fused to green fluorescent protein was expressed in primary cultures of anterior pituitary cells and of HeLa tumor cells. The expressed caspase-9 and the number of apoptotic and necrotic cells were determined using fluorescence microscopy.Overexpression of caspase-9 resulted in cell death of primary pituitary cells and HeLa cells. More than 94% of the cells died of apoptosis, which was triggered by the activation of caspase-9, since the cell deaths were prevented in the presence of caspase-9 specific inhibitor. HeLa cells were about 50% more resistant to apoptosis than pituitary cells.Caspase-9 overexpression and its activation leads to apoptosis. It occurs both in normal and tumor cells. Since the majority of cancer therapy treatments initiate apoptosis through the caspase-9 activation, the modulation of caspase-9 expression may be exploited in designing new ways to control apoptosis in neurodegenerative or malignant diseases.

Apoptosome

Intrinsic apoptosis

Caspase 10

NLRP1

Caspase 8

Caspase-9

Caspase 2

Zymogen

XIAP

Caspase 7

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Citations (41)

Aging, Oxidative Stress and Antioxidants

InTech eBooks (2013)

Borut Poljšak Irina Milisav

Aging is an extremely complex and multifactorial process that proceeds to the gradual dete‐ rioration in functions. It usually manifest after maturity and leads to disability and death. Traditionally researchers focused primarily on understanding how physiological functions decline with the increasing age; almost no research was dedicated to investigation of causes or methods of aging intervention. If scientists would discover a drug for healing all major chronic degenerative diseases, the average lifetime would be increased for just 12 years. Peo‐ ple would still die from complications connected with the aging process.

10.5772/51609

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The Role of Antioxidants in Cancer, Friends or Foes?

Current Pharmaceutical Design (2019)

Borut Poljšak Irina Milisav

Consumption of dietary supplements by millions of people is increasing [1]. Between 64 to 81% of cancer patients and survivors use multivitamin supplements after the cancer diagnosis [2]. The use of antioxidants during cancer therapy has been a hot topic in medical science for the last 20 years without clear answers and recommendations. It seems that antioxidants are able to I) decrease the cancer formation risk by quenching ROS that are involved in cancer initiation and progression and II) assist in survival of cancer/precancer cells once the malignant transformation already occurred. Antioxidants were shown to assist cancer initiation, interfere with cancer treatment by reducing its efficacy and patient survival, and vice versa, there are reports of beneficial antioxidant effect during the cancer treatment.

Multivitamin

Cancer Treatment

Cancer Therapy

10.2174/1381612825666190123112647

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Aripiprazole, but Not Olanzapine, Alters the Response to Oxida-Tive Stress, Reducing the Activation of Mitogen-Activated Protein Kinases (MAPKs) and Promoting Cell Survival in FAO Cells

Barbara Kramar Tinkara Pirc Marolt Ayşe Mine Yılmaz Dušan Šuput Irina Milisav

Chronic administration of atypical antipsychotics (AAPs) is commonly associated with in-creased cardiovascular disease load. Although the increase in weight gain and related dis-ease risk is generally considered the main contributing factor, direct interference with mi-tochondrial bioenergetics, particularly in the liver, where these drugs are catabolized, is emerging as an additional relevant contributor to metabolic disease risk that needs to be considered. In this study, we compared the effects of two AAPs with disparate metabolic profiles, olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not, on the response of Fao cells to oxidative stress. We found that Fao cells treated with ARI sur-vive better a challenge with H2O2 while OLA treatment has the opposite effect. This en-hanced survival is not related to a reduction in the apoptosis rate. In fact, ARI treated cells display higher apoptotic rates than control cells exposed to H2O2. Gene expression analysis of pro and anti-apoptotic factors revealed that the changes induced by H2O2 were generally dampened in ARI treated cells, but not in OLA treated cells, suggesting a reduced respon-siveness to stimuli, a notion that was consistent with a reduced activation of MAPK and STAT3 phosphorylation in response to H2O2, while OLA enhanced their activation in re-sponse to H2O2. Loss of stress response in ARI treated cells is consistent with the elevation of mitochondrial production of O2•-, a known desensitizing factor. The physiological rele-vance of the increased production of O2•- in ARI treated cells is further supported by the observed elevation of the mitophagy flux in ARI treated cells, likely related to mitochon-drial damage. An additional relevant finding was that OLA treatment protected the pro-teasome activity in Fao cells exposed to H2O2, an effect possibly related to the better preservation of stress signaling and mitochondrial function in OLA treated cells. In sum, this study highlights the underlying alterations in cell physiology derived from the inter-ference of ARI with mitochondrial function, that de-sensitize cells to stress signaling, while OLA has the opposite effect.

10.20944/preprints202407.0129.v1

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Citations (1)

Preapoptotic cell stress response

F1000Research (2011)

Irina Milisav

Open peer review

10.7490/f1000research.849.1

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Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Research Square (Research Square) (2023)

Antonio Segovia-Zafra Marina Villanueva-Paz A.S. Serras Gonzalo Matilla‐Cabello Ana Bodoque-García

Abstract Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by different drugs, herbal, and dietary supplements. The early identification of human hepatotoxicity at the preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review aims to analyse the compounds used in hepatotoxicity assays and establish a unified list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by a committee of experts from the COST Action ProEuroDILI Network (CA 17112). This systematic review was performed in accordance with the 2020 PRISMA guidelines. Original research articles focused on investigating DILI occurrence using in vitro human models performing at least one hepatotoxicity assay with positive and negative control compounds were included. A modified version of the "Toxicological Data Reliability Assessment Tool" (ToxRTool) was used to assess the bias of the included studies. A total of 2,936 studies were retrieved from the different databases. Of these, 51 met the inclusion criteria, with 30 categorized as reliable without restrictions. Diclofenac and buspirone were the most commonly used DILI-positive and DILI-negative control drugs, respectively. Although there was a broad consensus on the positive compounds, the selection of negative control compounds remained less clear. Regarding the models used, the 2D monoculture of primary human hepatocytes (PHHs) was the favoured choice. However, there was no clear consensus on the drug concentrations. Short acute exposure times were mostly utilised, and cytotoxicity was the preferred endpoint. The extensive analysis of included studies highlighted the lack of agreement on appropriate control compounds for the in vitro assessment of DILI. Therefore, following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating new in vitro models for improving preclinical drug safety testing regimes.

10.21203/rs.3.rs-3578817/v1

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Short-Term Fasting Induces Hepatocytes’ Stress Response and Increases Their Resilience

International Journal of Molecular Sciences (2025)

Patrik Prša Izak Patrik Miller Barbara Kramar Dušan Šuput Irina Milisav

Fasting leads to a range of metabolic adaptations that have developed through evolution, as humans and other mammals have unequal access to food over the circadian cycle and are therefore adapted to fasting and feeding cycles. We have investigated the role of a single fasting episode in rats in triggering the stress response of liver hepatocytes. Since the stress responses were observed in both animals and isolated cells, we investigated whether the effects of the animal stressor could persist in the cells after isolation. By measuring staurosporine-induced apoptosis, stress signalling, and oxidative and antioxidant responses in hepatocytes from fasted and ad libitum-fed animals, we found that only fasting animals elicited a stress response that prevented caspase-9 activation and persisted in isolated cells. The addition of glucose oxidase, a hydrogen peroxide-producing enzyme, to the cells from ad libitum-fed animals also led to a stress response phenotype and prevented the activation of caspase-9. A single fasting episode thus leads to a stress response in normal hepatocytes, with hydrogen peroxide as a second messenger that reduces the initiation of apoptosis. This finding is the first characterisation of a mechanism underlying the effects of fasting and provides a basis for the development of methods to increase the resilience of cells. These findings need to be taken into account when interpreting the results obtained in animal and cell research models to account for the effects of overnight fasting used in many laboratory protocols. The research results also form the basis for the development of clinical applications to increase the resistance of transplants and to improve the fitness of hepatocytes under acute stress conditions in liver and some metabolic diseases.

Staurosporine

Intermittent Fasting

10.3390/ijms26030999

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P16-38: A systematic review of control compounds tested for validation of Drug-Induced Liver Injury (DILI) in vitro models

Toxicology Letters (2023)

Antonio Segovia-Zafra Marina Villanueva-Paz A.S. Serras Gonzalo Matilla‐Cabello A. Bodoque

10.1016/s0378-4274(23)00727-0

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Aripiprazole reduces liver cell division : research data underlying the article

Tinkara Pirc Marolt Barbara Kramar Klara Bulc Rozman Dušan Šuput Irina Milisav

Effects of aripiprazole on dopamine regulation are being tested as a treatment for patients with a dual diagnosis of schizophrenia and addictions, often cocaine dependence. Aripiprazole has one of the fewest side-effects among the second-generation antipsychotics. Nevertheless, severe aripiprazole hepatotoxicity was reported in persons with a history of cocaine and alcohol abuse. Here we report that therapeutically relevant aripiprazole concentrations, equal to laboratory alert levels in patients’ serum, reduce the rate of hepatocytes’ division. This could be an underlying mechanism of severe liver injury development in the patients with a history of alcohol and cocaine abuse, the two hepatotoxic agents that require increased ability of liver self-regeneration. Monitoring liver functions is, therefore, important in the cases when aripiprazole is co-prescribed or used with drugs with potential hepatotoxic effects.

Aripiprazole

Alcohol abuse

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