bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence Of Foreign Direct Investment, Wage Level, Tourism Industry and Regional Native Income on Products Domestic Regional Bruto
Authors: Asmara Puja Dego
Published: September 2024

Background. High GRDP (Gross Regional Domestic Product) growth can attract investor interest, stimulate investment, and encourage infrastructure development, leading to increased connectivity and economic efficiency. Furthermore, strong GRDP growth can create additional labor demand, potentially reducing poverty and raising income levels.
Purpose. This research aims to examine the factors influencing GRDP in Indonesia, specifically focusing on foreign direct investment (FDI), wage levels, the tourism industry, and regional original income (PAD), using data from 2020 to 2022.
Method. The study employs a quantitative approach, utilizing panel data obtained from the Indonesian Central Statistics Agency (BPS) from 2020 to 2022. Multiple Linear Regression analysis is applied to assess the relationship between GRDP and the selected independent variables: FDI, wage levels, tourism, and PAD.
Results. The results indicate that FDI has a significant positive effect on GRDP, with a t-value of 6.264, which is greater than the critical value of 1.66196. Conversely, wage levels and the tourism industry do not show a significant impact on GRDP, with respective probability values of 0.39 and 0.254, both below the threshold. Meanwhile, PAD has a significant positive effect on GRDP, with a t-value of 4.904, also exceeding the critical value of 1.66196.
Conclusion. This study concludes that FDI and regional original income (PAD) are significant contributors to GRDP growth in Indonesia, while wage levels and the tourism sector do not have a notable impact on regional economic performance during the observed period.
Tracing the Development of Santri Proficiency in Reading The Book of Fathul Qarib With A Mathematical Model
Authors: Ulfiyati Nur Shofa , Yahadiana Fahdina , Hidayat Rahmat
Published: September 2024

Background. Santri are the main object in the learning process of the yellow book. The success of the yellow book education cannot be separated from the aspect of the ability of the students to read and understand the book. One of the yellow books that are widely studied in all pesantren is the book of Fathul Qarib.
Purpuse. This study seeks to trace developments in learning to read and understand the yellow book with a mathematical model approach. Mathematical models are a branch of mathematics that attempts to photograph and translate a phonomene in life into a representation of mathematical equations that describe this phenomenon.
Method. This research is a combination of fieldwork and literature study. This research was conducted at Pondok Pesantren Al Munawwir Krapyak Komplek Q in Krapyak Hamlet, Panggung Harjo Village, Sewon District, Bantul Regency, Yogyakarta Special Region Province. The object of this research is the students of Al Munawwir Krapyak Islamic Boarding School Komplek Q Awwal Class, Tsani and Tsalis who are studying the book of Fathul Qarib.
Results. This research results that the mathematical model of the development of the students' ability to read the Fathul Qarib book at the Al-Munawwir Q Krapyak Islamic Boarding School, Yogyakarta is: K (t) = 55e^((0.1447) t) and based on parameter estimates from year 0 of 55, Year 1 is 63.563, year 2 is 73.459, and year 3 is 84.897.
Conclusion. This means that the development of the students' ability in reading the book Fathul Qarib will continue to increase until the students can really master and understand the book.
The Effect of Using Digital Learning Applications on Student Achievement in Elementary Schools
Authors: Asta Ngr. Putu Raka Novandra , Aribowo Aribowo , Saputra Memed , Najmuddin Najmuddin , Pahmi Pahmi
Published: September 2024

Background. Every digital technology will be able to influence its users. The response to incoming digital technology has pros and cons. The use of technology in education can no longer be avoided. The use of learning media in the form of applications will have a new impact on the world of education. Learning sometimes has to be done online due to some natural conditions that cannot be denied. Therefore, it is important to be able to use learning applications for education today.
Purpose This study aims to determine the benefits of using learning applications. It is also useful to measure how influential the use of digital learning applications is on student achievement in elementary schools. The use of digital learning applications at the education level will have a significant impact on the success of education.
Method. The method used in this research is a qualitative method. Qualitative method is a data that will be presented in the form of numbers. Data collection is in the form of distributing questionnaires to teachers and also parents whose children are at the elementary school level. In this case the statement is presented in google from. The statement contains matters relating to the influence of the use of digital learning applications on student achievement in education. This research is more focused on the elementary school level.
Results. The results of this study explain that positive effects are obtained in the use of digital learning applications. However, there are also obstacles in using digital applications for learning at the elementary school level. Students who are still classified as underage must be extra supervised so as not to make mistakes in the use of technology. In addition, the use of technology that is influenced by the internet will also affect. This is due to some areas that are constrained by internet networks. In fact, there are still students in whose homes there is no digital technology.
Conclusion This research can be concluded that the use of digital technology will have a significant and effective effect on student achievement at the elementary school level if done with the right method. Other supports are the internet and also tools as a medium to facilitate the use of learning applications. Every influence will certainly also experience challenges and obstacles as well as negative influences in its use.
The Impact of Using a Cloud-Based Learning Management System on Access and Quality of Education
Authors: Rijal Syamsu , Zou Guijiao , Jie Lie , Demsky Caitlin
Published: September 2024

Background:The use of a cloud-based learning management system is the use of cloud computing technology to manage and access the online education system. By using this technology, educational institutions can provide learning materials, manage courses, and interact with students digitally via the internet.
Research purposes:This research was conducted with the aim of seeing how the use of a cloud-based learning management system can improve access and quality of education by creating an online learning management system that can be accessed anytime and anywhere, as well as making it easier to manage learning materials, course management and digital interaction with students. .
Method:The method used in this research is quantitative methods.This method is a way of collecting data and numbers that can be tested. Data was collected through distributing questionnaires addressed to students. Furthermore, the data that has been collected from the results of distributing the questionnaire will be accessible in Excel format which can then be processed using SPSS.
Results:From the research results, it can be seen that the impact of using a cloud-based learning management system can improve access and quality of learning. Apart from that, the use of a Cloud-Based Learning Management System can also improve the competitive performance of teachers in schools.
Conclusion:From this research, researchers can conclude that the impact of using a cloud-based learning management system helps people acquire the skills needed to meet the demands of an ever-changing job market. However, LMS use must be done carefully and incorporated well into an institution's educational strategy to create an inclusive, adaptive, and sustainable learning experience.
The Impact of Using Mobile Learning Applications on the Development of Students' Digital Literacy
Authors: Ramadhona Rossa , Oscar Schersclight , Kathryn Morse , Cale Wolnough
Published: September 2024

Background:The use of mobile learning applications has influenced students' digital literacy levels. The use of information technology as a learning medium, including mobile learning, can influence students' motivation to learn and make learning easier and faster. Using mobile learning applications can also increase students' digital literacy, especially in terms of connections.
Research Objectives:The aims of this research are to identify the impact of using mobile learning applications on the development of students' digital literacy, assess students' abilities in using mobile learning applications, determine how the use of mobile learning applications is effective and efficient in increasing students' digital literacy, and assess the impact of using mobile learning applications on the development of digital literacy student.
Method:The method used in this research is a quantitative method.This method is a way of collecting numerical data that can be tested. Data was collected through distributing questionnaires addressed to students. Furthermore, the data that has been collected from the results of distributing the questionnaire will be accessible in Excel format which can then be processed using SPSS.
Results:From the research results, it can be seen thatMobile learning apps can help students learn more about digital literacy. This application can offer a variety of learning materials and information related to digital literacy, so that students can better understand and expand their knowledge.
Conclusion:From this research, researchers can conclude that the impact of using mobile learning applications on the development of students' digital literacy can increase students' interest in learning, help them learn digital literacy and students' learning resilience.
The Impact of Applying Augmented Reality Technology in Learning on Student Learning Experiences
Authors: Meriyati Meriyati , Nitin Mahon , Bradford Snyder , Wiliyanti Vandan
Published: September 2024

Background:Augmented Reality AR technology is a technology that combines information from the real world with computer technology, so that the learning process can provide varied learning experiences to students.
Research purposes:This research was conducted with the aim of understanding the impact of applying Augmented Reality technology in learning on students' learning experiences. Apart from that, to be able to find out the impact of applying Augmented Reality technology to make learning more interesting for students, the use of Augmented Reality can help teachers and parents learn.
Method:The method used in this research is a quantitative method.This method is a way of collecting numerical data that can be tested. Data was collected through distributing questionnaires addressed to students. Furthermore, the data that has been collected from the results of distributing the questionnaire will be accessible in Excel format which can then be processed using SPSS.
Results:From this research, researchers were able to obtain research results on the impact of applying Augmented Reality technology in learning, showing that using Augmented Reality technology as a learning medium greatly facilitates learning and has the ability to change the way students think. In addition, by using Augmented Reality Technology in Learning, teachers can facilitate the exchange of information between recipients and senders or educators and students.
Conclusion:Based on the results of this research, it can be concluded that the impact of applying Augmented Reality Technology in Learning on Student Learning Experiences has a number of quite large benefits, such as providing an immersive learning experience, an interesting learning environment, and an easier learning process. Apart from that, the application of Augmented Reality Technology can also make learning more fun, increase students' interest and desire to learn, and increase students' interest in learning.
Influence of the Blended Learning Method on Student Achievement in Mathematics Lessons
Authors: Sappaile Baso Intang , Mayadiana Dina , Lengam Rino , Guilin Xie , Abda Muhammad Ichsan
Published: September 2024

Background. The characteristics and achievements of each student are different. This is influenced by the methods, interests, talents, media, sources, environment, and even strategies of the students themselves. A blanded learning method that combines traditional classroom learning with online-based learning can make a big impact in the world of education. It will provide opportunities for students to learn with more flexibility. It also creates a more engaging learning experience.
Purpose This study aims to find out how much the use of blended learning method affects students' achievement. This achievement is more specific to mathematics learning. This is because there are often difficulties in understanding mathematics learning by students. Therefore, the blended learning method is considered to be able to influence learning, especially mathematics.
Method. The method used in this research is quantitative. This method is considered suitable as a measuring tool. This is because the effect of using the blanded learning method on student achievement can be measured by a number scale. So that it can be read or understood through graphs, percentages, or data processing. Research using quantitative methods that have the characteristics of using numbers will be more in line with this research.
Results. The result of this study explains that the use of blanded learning method will affect students' achievement in learning mathematics. The blanded learning method that combines traditional and online-based learning will enrich the learning experience. Not only that, this method will also provide a combination of different methods, media, sources, environments, and even learning strategies.
Conclusion This research can be concluded that the use of blanded learning method will provide innovation in learning. It will support different ways of learning from students. In addition, it will also help teachers in the flexibility of organising learning time. On the other hand, it will also help students who have difficulty in following face-to-face learning.
Enhancing Higher Education Pedagogy with ChatGPT: Leveraging the Power of Generative AI
Authors: Sain Zohaib Hassan , Baharun Hasan , Abdullah Nurulannisa Binti
Published: September 2024

Background. The prevalence of burnout among students at madrasas has reached a critical level, highlighting the need for efficient administration of counselling services to tackle this issue. Understanding how counselling may mitigate student burnout is crucial for improving educational achievements and promoting student welfare.
Purpose. This research investigates the efficacy of counselling service administration in mitigating burnout among students in madrasas. The study aims to analyse the effects of these services and provide not just valuable insights, but practical, actionable suggestions for enhancing counselling practices in educational institutions, making the research directly applicable to the field.  
Method. This research employs a qualitative approach, using a case study technique to assess the function of counselling services in the school setting. Data were gathered via comprehensive interviews, participatory observations, and documentation studies involving students, counsellors, and instructors. Thematic analysis was used to identify the primary themes that arose from the data.
Results. The study results indicate that doing a thorough evaluation of student requirements has a substantial impact on reducing the likelihood of burnout by facilitating the development of more suitable remedies. Appointing qualified counsellors improves the efficacy of counselling services by fostering a more profound comprehension of student concerns. Continuous mentorship programs provide crucial emotional and practical assistance, aiding students in cultivating appropriate coping mechanisms. Moreover, including student input enhances the quality of counselling services.  
Conclusion. This research provides a substantial advancement in understanding counselling service administration. It introduces intervention models that may be used in different educational institutions to address student burnout effectively. The results provide pragmatic advice for other academic environments, including strategies to improve their counselling services and effectively tackle student burnout.
Application of the Multi-Representative Discourse Learning Model (DMR) to Numeracy Literacy Ability
Authors: Nari Nola , Akila Nisa
Published: September 2024

Background: The general issue in mathematics education is the suboptimal numeracy literacy skills of students, which adversely affects their learning outcomes. Improving these skills is essential for enhancing students' overall academic performance in mathematics.
Purpose: This study aims to maximize students' numeracy literacy skills through the application of the Multi-Representation Discourse (DMR) learning model. The research seeks to evaluate the effectiveness of the DMR model in improving students' numeracy literacy compared to conventional teaching methods.
Methods: The research methodology employs a quantitative approach using a quasi-experimental design. The instrument used in this study is a numeracy literacy skills test, with a sample consisting of two classes: an experimental group and a control group. Preliminary tests confirmed that the data met the criteria for normality and homogeneity, allowing hypothesis testing to be conducted using the t-test.
Results: The research findings show that tcalculate>ttablet_{calculate} > t_{table}tcalculate?>ttable? or 3.03695 > 1.67792, leading to the rejection of H0H_0H0?. This indicates that at a 5% significance level, the numeracy literacy skills of students using the cooperative learning model type Multi-Representation Discourse (DMR) are significantly better than those of students using conventional teaching methods.
Conclusion: The study concludes that the application of the DMR learning model significantly enhances students' numeracy literacy skills compared to conventional teaching methods. These results suggest that implementing the DMR model in mathematics education can lead to better learning outcomes for students.
REDOX AND METABOLIC REPROGRAMMING OF BREAST CANCER CELLS AND ASSOCIATED ADIPOSE TISSUE - THE CORNERSTONES OF ADAPTIVE TUMOUR BEHAVIOUR
Authors: Jankovic Aleksandra , Zakic Tamara , Srdic-Galic Biljana , Korac Aleksandra , Korac Bato
Published: September 2024

A high proliferation rate and the malignancy of cancer cells are favoured by redox and metabolic plasticity, which is determined by the co-evolution of cancer cells with their host microenvironment. The tight functional connections between the mammary glands' epithelium and adipose tissue (AT) allow breast cancer cells to subjugate the AT and form a protumorigenic cancer-associated adipose tissue (CAAT). Our findings in luminal invasive ductal carcinomas in premenopausal women confirmed key cancer cell strategies - the Warburg effect, increased mitochondrial metabolism and redox adaptability, which are associated with a specific shift in the metabolic and redox phenotype of CAAT. Notably, the upregulated master redox-sensitive transcription factor Nrf2 appears to be responsible for the cancer cell-induced redox and metabolic shift of CAAT. We also investigated the role of Nrf2 in the metabolic co-evolution of cancer cells and CAAT during disease progression. Our results in the orthotopic breast cancer mouse model and in the co-culture of breast cancer cells with adipocytes confirmed the different spatiotemporal redox and metabolic properties of cancer cells and CAAT, established with respect to the Nrf2-coupled/uncoupled tumour microenvironment. The uncovered metabolic and redox strategies adopted by breast cancer cells according to CAAT properties and at different disease stages have helped to better understand the biology of the aggressive disease and to identify breast cancer vulnerabilities that could become therapeutic targets.

This research was supported by the Science Fund of the Republic of Serbia, #7750238, Exploring new avenues in breast cancer research: Redox and metabolic reprogramming of cancer and associated adipose tissue - REFRAME.
DIETARY NITRATE AS PIVOT ON THE GUT MICROBIOTA-HOST REDOX COMMUNICATION
Authors: S. Rocha Bárbara , Laranjinha João
Published: September 2024

Humans are complex holobionts in which many physiological functions are ensured by the gut microbiota. The communication between the microbiota and its human host relies on immune, neural, metabolic and endocrine pathways and the derailment of this interaction can lead to gastrointestinal and systemic diseases. Here, we propose a novel form of communication between the microbiota and the host, based on the production of redox species by gut bacteria and the activation of signaling cascades in host mucosa. The biological significance of such a pathway is further highlighted by the observation that these inter-kingdom interactions are modulated by dietary nitrate, the major precursor of nitrite and NO in vivo. We demonstrate that nitrate has a positive metabolic effect in a murine model of antibiotic-induced dysbiosis by regulating cecum morphology and body weight (p<0.05). In agreement with these observations, shallow shotgun sequencing analysis showed that nitrate modulates the metabolic function of bacteria involved in the metabolism of carbohydrates, likely aiding in food digestion and substrate delivery to the host. Furthermore, we observed that the exposure to antibiotics decreases the expression of tight junction proteins in the colon and that nitrate recovers the expression of both occludin (p<0.05) and claudin-5 (p<0.01). The activation of the Nrf2/ARE pathway was also investigated by the downstream expression of detoxifying enzymes including NQO1 and GCLM/GCLC. Here, dietary nitrate emerges as a pivot regulating microbiota-host interactions through redox pathways. Nitrate modulates the function of gut microbiota during dysbiosis by enhancing bacterial metabolic performance with positive effects on host body weight and prevents the loss of tight junction proteins likely reinforcing gut barrier integrity. Given that increased epithelial permeability may lead to leaky gut syndrome, triggering local and systemic disorders, this study has the potential to transform the way Redox Biology expands from the bench to patient's bedside.   
NUTRIGENOMICS OF VITAMIN E AND FATTY ACID METABOLISM IN LIPOTOXICITY AND OXIDATIVE STRESS-RELATED DISEASES
Authors: Galli Francesco
Published: September 2024

Vitamin E (alpha-tocopherol, VE) is essential to prevent severe neurological symptoms and even death of a genetic form of ataxia associated with vitamin deficiency or AVED. Its essentiality is also proven in secondary deficiencies associated with malnutrition and/or malabsorption syndromes that besides moderate to severe neurological abnormalities can contribute to induce metabolic, musculoskeletal, hematological, and immune dysfunctions, especially in the elderly. VE is the most abundant and ubiquitous fat-soluble nutrient with hydrogen atom donating properties (often described as “antioxidant”) of the plasmalemma; its relative abundance with respect to phospholipid residues is by far the highest among other H donors and its membrane levels influence the flux of lipoperoxyl radicals during both enzymatic and non-enzymatic processes of lipid peroxidation. Consequently, VE directly affects the metabolism and function of membrane fatty acids, also playing a key role in lipid signaling and thus in the indirect control of different enzymes, signal transduction, and transcriptional proteins that connect, under a functional point of view, the VE levels in human tissues with many pathophysiological aspects and deficiency symptoms. Recent evidence strongly supports the participation of the long-chain metabolites of VE in at least some of its “non-antioxidant” properties. Altogether these aspects depict the biological complexity of this vitamin which is far from being comprehensively understood. Last-generation omics technologies make it possible to face such a complexity to represent with unprecedented efficacy both the essentiality aspects and the health-promoting potential of this vitamin in human nutrition studies and clinical trials on deficiency syndromes and other human diseases that may benefit from its biological properties. Transcriptomics and especially metabolomics protocols have been utilized in our laboratories, either separate or in multiomics mode, to develop personalized and precision nutrition (i.e. nutrigenomics) platforms of investigation dedicated to this vitamin, and examples of their potential for innovation in VE research will be given in this presentation, including in vitro studies and clinical trials on hepatic fatty acid metabolism and lipotoxicity, the etiologic factor of non-alcoholic fatty liver disease, and studies in kidney disease patients that develop secondary VE deficiency in the context of severe oxidative stress and lipid peroxidation symptoms.
OXYGEN, SULFUR, SELENIUM AND LIPID PEROXIDATION: HOW GPx4 CONTROLS LIFE AND DEATH
Authors: Ursini Fulvio
Published: September 2024

The selenoperoxidase GPx4, discovered in 1982, plays a pivotal role in preventing ferroptosis. In a moonlighting function, GPx4, in its mitochondrial and nuclear forms, also contributes to spermatogenesis. The critical advantage of Selenium vs. Sulfur catalysis is the stability of the oxidized form of the chalcogen in the catalytic cycle. While the mechanisms of catalytic cycle are understood, its regulation remains largely unknown. Existing evidence supports the notion that ferroptosis is activated when GPx4 is inhibited, glutathione (GSH) concentration is lowered, or the labile iron pool is expanded. The outcome is framed in the context of oxygen toxicity playing the physiological function of controlling cell death. GPx4 stands out as the sole peroxidase indispensable to aerobic life. Moreover, a recent study exploring the role of the residue Arg152 in GPx4, linked to a fatal although not embryonically lethal disease, revealed that the wild-type enzyme exhibits surface-sensing and positive cooperativity in the presence of cardiolipin. This adds complexity to the mechanism of physiological function encompassing the interaction with acidic phospholipids in mitochondrial membranes. Ferroptosis is implicated in both physio-pathological conditions, including embryogenesis, cancer suppression, neurodegenerations, inflammatory disorders, metabolic syndrome, heart and kidney diseases. No antioxidant enzymatic system can substitute for GPx4 in inhibiting ferroptosis, emphasizing the vital role of selenium. Phenolic antioxidants, which reduce lipid hydroperoxyl radicals, can only inhibit lipid peroxidation under physiological conditions, and thus ferroptosis, when the lipid hydroperoxides formed are immediately reduced by GPx4. In contrast, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) proves to be significantly more efficient than phenolic antioxidants. Analytical and computational evidence supports the notion of a pseudo-catalytic cycle where the ferrostatin-iron complex, both produces and reduces lipid alkoxyl radicals from lipid hydroperoxides. This discloses the roadmap for the identification of innovative antioxidants competent for preventing ferroptosis.
CO3•−, THE RADICAL THAT CONNECTS PEROXYNITRITE AND FENTON CHEMISTRY
Authors: H Koppenol Willem
Published: September 2024

Oxidative biochemistry centered about 35 years ago on the one-electron reduction of H2O2 by Fe2+, the Fenton reaction, to yield HO· and a Fe(III)-complex. The discovery that NO· is formed in vivo and that it reacts with O2·− at a diffusion-controlled rate led to ONOO− as an additional oxidant. The rate constant of the Fenton reaction is 53 M−1s−1 up to about pH 4, but above it the rate constant increases linearly with pH.  This acceleration of the Fenton reaction led to the hypothesis that above pH 5 formation of FeO2+ predominates.  Thermodynamically, this species is comparable to HO· as an oxidant.  HCO3− accelerates the reaction even more, and convincing evidence has been presented that the complex of Fe2+ with CO32− reacts with H2O2 to form CO3·− and a Fe(III)-complex, conceivably via FeO2+ as an intermediate. The rapid reaction of ONOO− with CO2 (k > 107 M−1s−1) leads to ONOOCO2− that, depending on the CO2 concentration, yields varying amounts of NO2· and CO3·−.  These two oxidizing radicals together nitrate aromatic residues. Compared to 35 years ago, oxidative biochemistry is no longer concerned with the indiscriminate oxidations and additions of HO·, but with the more selective reactions of CO3·− and NO2·.
MITOCHONDRIAL TESTS THAT EXPOSE DISEASE CLUES AND LIFESTYLE EFFECTS
Authors: Vujacic-Mirski Ksenija , Sudowe Stephan
Published: September 2024

The impairment of mitochondrial respiration, observed in neurodegenerative and cardiovascular disease, diabetes, cancer, and migraine headaches, has emerged as a biomarker of mitochondrial dysfunctions. Chronic fatigue, depression, and other behavior/mood disorders are also associated with mitochondrial malfunctioning, but so is our lifestyle! Our lab offers tests for insight into mitochondrial fitness, linking not only diseases but also behaviors and modern lifestyles that lead to health damage. Firstly, we focused on 88 (relatively) healthy volunteers, of which 32% were taking some medication (such as for high blood pressure or mood disorders), however, they considered themselves fit and healthy.  The blood was drawn 3h before PBMC (peripheral blood mononuclear cells) isolation, followed by an immediate Seahorse XF Cell Mito Stress Test (Agilent) on the SeahorseXF96e instrument (Agilent). Parameters of mitochondrial respiration were carefully examined. There was a significant difference between BHI (bioenergetic health index), reserve capacity, coupling efficiency, and proton leak, between people who took medication for chronic but manageable comorbidities and completely healthy individuals. Later, in another group we examined the alterations in NAD+ levels (by Q-NADMED Blood NAD+ assay kit, NADMED) and mitochondrial respiration parameters in a binge-drinking session (consuming 10 or more units of alcohol in less than three days). The decrease in NAD+ levels was positively correlated with the amount of alcohol consumed. Additionally, total NAD+ levels positively correlated with the BHI.  In another experiment, supplementation with niacin for 20 days, did not increase NAD+ levels in (relatively) healthy individuals. Apart from mitochondrial respiration and NAD+ levels, we focus on optimizing tests for mtDNA count and mitochondrial potential. All of these tests not only explore disease but also serve to monitor behaviors that lead to health damage or improvements.
NEUROPEPTIDE Y DISRUPTS REDOX BALANCE IN HUMAN EXTRAVILLOUS TROPHOBLASTS
Authors: H Zupic Nejla , C Dolicanin Zana , Z Djordjevic Natasa
Published: September 2024

Human extravillous trophoblasts play a key role in implantation, placentation, and successful pregnancy outcomes due to their ability to migrate and invade through the uterine spiral arteries. Abnormalities in the trophoblasts' migratory and invasive abilities may result in insufficient remodeling of the uterine spiral arteries. This leads to the development of preeclampsia, a syndrome in pregnancy. Neuropeptide Y (NPY) is a sympathetic neurotransmitter that plays a significant role in the adaptive stress response as well as in the regulation of body energy balance. This study was designed with the aim of investigating whether preeclampsia is associated with NPY-induced disruption of trophoblast migration and redox balance. For this purpose, the concentration of NPY was determined in the plasma of 20 healthy and 20 preeclamptic pregnant women. The obtained results demonstrated that in preeclampsia, the concentration of NPY is significantly lower (190 pg/mL) than in a healthy pregnancy (260 pg/mL). After that, NPY in concentrations of 190 pg/mL and 260 pg/mL was used to treat the human extravillous trophoblast cell line HTR-8/SVneo for ten weeks. The effect of NPY on trophoblast proliferation was determined by counting cells during each passage. After the end of the treatment, the effect of NPY on migration and intracellular concentrations of superoxide anion radical (O2.-), hydrogen peroxide (H2O2), and nitric oxide (NO) were examined. The obtained results show that NPY induces changes in trophoblast proliferation and reduces their migration at both applied doses. In addition, both doses of NPY induce a decrease in intracellular concentrations of O2.-, H2O2, and NO. The NPY concentration of 190 pg/mL significantly decreased O2.- in trophoblasts in comparison to the concentration of 260 pg/mL. This study demonstrates that NPY affects the migration and redox balance regulation of trophoblasts. It also disrupts the trophoblast redox balance at a level characteristic of preeclamptic pregnancy.
VITAMIN MISUSE DURING THE COVID-19 PANDEMIC – SINGLE CENTER EXPERIENCE
Authors: Petrushevska Marija , Zendelovska Dragica , Atanasovska Emilija
Published: September 2024

The global pandemic crisis affected almost every society and economy, challenged almost every health system worldwide. Above all, governments and non-governmental organizations had to fight the misinformation and conspiracy theories placed by the social and mass media. All of this had a profound impact on the public in terms of vaccine safety and the advantages of vitamin use in fighting the virus. This fear has opened doors to alternative medicines such as supplements (vitamins, minerals, herbal products, oils) that may have profound effects on the immune system. To determine the pattern of use of supplements during the pandemic in healthy individuals who tested negative for SARS-CoV-2. The 33 healthy individuals tested negative for SARS-CoV-2 in the pandemic period were included (Group 1). Total antioxidant power, iron-reducing (PAT), and plasma peroxides (d-ROMs) were measured using FRAS5 analytical photometric system and are reported in equivalents of ascorbic acid and H2O2, respectively. The oxidative stress index (OSI) was automatically calculated by the software. The obtained values were compared with 30 healthy individuals analyzed prior to the pandemic (Group 2). The mean values for oxidative stress parameters in Group 1 vs Group 2 were: d-ROMs 418 vs 266 U. Carr, PAT 3862 vs 2554 U. Carr, and OSI 111 vs 36. In all comparisons, a statistically significant difference was obtained (p<0.05, t-test). Individuals belonging to Group 1 had reported that they have consumed daily doses of Zinc (30 mg), Vitamin C (at least 1000 mg) and Vitamin D (at least 2000 IU) in a period of >1 month. Several of them have also used Isoprinosine, magnesium, and selenium. Uncontrolled intake of supplements can have a profound effect on the pro- and antioxidant balance resulting in interruption of the phycological balance and leading to increased oxidative stress index in otherwise healthy individuals. 
THE ROLE OF NRF2-DEPENDENT METABOLIC REPROGRAMMING OF BROWN ADIPOSE TISSUE IN ORTHOTOPIC BREAST CANCER MODEL
Authors: Vukobratovic Maja , Djuric Strahinja , Jevtic Jelena , Zakic Tamara , Korac Aleksandra , Jankovic Aleksandra , Korac Bato
Published: September 2024

Breast cancer is characterized by specific metabolic changes that support tumorigenesis, highlighting the emerging appreciation of cancer as a metabolic disease. These metabolic changes are simultaneous with redox reprogramming with nuclear factor erythroid 2-related factor 2 (Nrf2) representing their master integrator. Given that interscapular brown adipose tissue (IBAT) influences whole-body metabolism, our goal was to investigate the redox-metabolic crosstalk between the tumor and the host at the systemic level by exploring Nrf2-driven metabolic changes that occur in IBAT in the orthotopic model of breast cancer in wild-type (WT) and mice lacking functional Nrf2 (Nrf2KO). We analyzed the protein expression of key enzymes involved in glucose and lipid metabolism in control groups and at different points during tumor growth (10 mg, 50 mg, 100 mg, 200 mg, and 400 mg). In both WT and Nrf2KO mice, the results indicated a transient induction of hexokinase 2 expression during the early phase of tumor growth (<100 mg). Accordingly, pyruvate dehydrogenase expression followed the same profile. In Nrf2KO mice, a general decline in glyceraldehyde 3-phosphate dehydrogenase, phosphofructokinase-1, and glucose-6-phosphate dehydrogenase expression was detected during the late phase of tumor growth (>100 mg). Since no changes in WT mice occurred, these findings are considered Nrf2-dependent. Concomitantly, a decrease in protein expression of fatty acid synthase and acetyl-CoA carboxylase in Nrf2KO mice was observed. These observations correspond to decreased levels of 5'-AMP-activated protein kinase and hypoxia-inducible factor 1 during the late-phase (>100 mg) of tumor growth in Nrf2KO mice which suggests their involvement in transcriptional regulation. Our results revealed that IBAT metabolism responds to tumor growth and underscored that this communication is Nrf2-dependent giving implications for further understanding of breast cancer in the light of systemic metabolic disease.

This research was supported by the Science Fund of the Republic of Serbia, #7750238, Exploring new avenues in breast cancer research: Redox and metabolic reprogramming of cancer and associated adipose tissue - REFRAME.
THE ROLE OF MACROPHAGE MIGRATION INHIBITORY FACTOR IN LIVER INFLAMMATION, OXIDATIVE STRESS, AND APOPTOSIS IN MICE ON A FRUCTOSE DIET
Authors: Gligorovska Ljupka , Teofilovic Ana , Vrataric Milos , Velickovic Natasa , Vojnovic Milutinovic Danijela , Kovacevic Sanja , Djordjevic Ana
Published: September 2024

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays an essential role in the inflammatory response and various other biological effects such as activation of apoptosis and oxidative stress. Fructose-enriched diets have previously been associated with the development of low-grade inflammation leading to metabolic stress. The aim of the present study was to investigate the combined effects of deletion of the Mif gene and a 9-week 20% fructose-enriched diet on metabolic inflammation, apoptosis, and oxidative stress in the liver of wild-type (WT) and Mif knockout (MIF−/−) male C57Bl/6J mice. We analyzed liver histology and expression of pro-inflammatory genes: Tumor necrosis factor (TNF), interleukin 1β (IL-1β), and IL-6. Antioxidant activity was estimated by the protein levels of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD1), mitochondrial MnSOD (SOD2), glutathione reductase (GR) and glutathione peroxidase (GPX). The results showed that antioxidant protection was activated in the liver of MIF-deficient mice. Increased hepatic expression of the cytokines IL-6 and IL-1β was observed in the same animals. Histologic analysis confirmed the presence of apoptosis, inflammation, enlarged Kupffer cells, and regenerative changes, such as binucleated hepatocytes, anisonucleosis, and anisocytosis. In addition, confluent and focal necrosis was observed in the liver of MIF−/− mice, which was even more pronounced in the animals consuming fructose. In conclusion, MIF may play a protective role in metabolic stress, as inflammation, oxidative stress, apoptotic and necrotic changes occur in the liver in its absence.
ADJUVANT TREATMENT WITH POLYPHENOLS REDUCES OXIDATIVE STRESS PARAMETERS IN IMATINIB TREATED PATIENTS WITH CHRONIC MYELOID LEUKEMIA
Authors: Zendelovska Dragica , Petrushevska Marija , Labachevski Bojan , Popova-Labachevska Marija , Atanasovska Emilija
Published: September 2024

Imatinib, a tyrosine kinase inhibitor (TKI) is used as a standard treatment in chronic myeloid leukemia (CML) patients. Increased levels of BCR-ABL1 expression in CML cells are associated with oxidative stress induction due to overproduction of reactive oxygen species (ROS) or by deficient antioxidant system, disease progression, and imatinib resistance. Current scientific research confirms that oxidative stress is involved in CML pathogenesis and response to TKI treatment. Moreover, recent findings suggest that the antioxidant properties of some natural compounds can provide benefits to patients with CML. To determine the effect of adjuvant treatment with polyphenols on the oxidative stress markers in imatinib-treated CML patients. 40 CML patients at the University Clinic of Hematology, Skopje, who received imatinib longer than 1 month were included in the study. 20 patients were additionally treated with Aronia melanocarpa extract and 20 patients received only imatinib (control group). Besides the regular clinical laboratory analysis for these patients, total antioxidant power (PAT) and plasma peroxides (d-ROMs) were measured at initial visit and after 21 and 42 days of treatment using FRAS5 analytical photometric system and the oxidative stress index (OSI) was automatically calculated. Oxidative stress parameters (d-ROM and OSI) were significantly higher at initial visit in both groups. In group of patients who received adjuvant polyphenols values for d-ROM and OSI were significantly lower after 21 and 42 days of treatment (p<0.05). Also, total antioxidant capacity (PAT) was significantly higher after 21 and 42 days of treatment initiation in comparison with the pretreatment values. In the control group, no significant differences were obtained between investigated parameters at any time of measurement. Adjuvant treatment with Aronia melanocarpa extract after 21 and 42 days led to significant reduction of oxidative stress parameters in patients with CML treated with imatinib. 
MITOCHONDRIAL TARGETING AS A MEANS OF OVERCOMING CANCER DRUG RESISTANCE
Authors: Uslu Cemile , Kapan Eda , Fadda Hagar , Hassan Khan Raheema , Shqair Yara , Ülker Zeynep , Tunçay Can , Abad Etna , Lyakhovich Alex
Published: September 2024

Our recent observations show that both resistant and stem-like cancer cells predominantly responsible for metastasis differ from chemotherapy-sensitive cells. We have shown bioinformatically and experimentally that mitochondria of such cells are much more prone to oxidative phosphorylation (OXPHOS) than radio- or chemotherapy-sensitive cancer cells from which they evolved during therapeutic interventions. Specifically, in triple-negative breast cancer models, we observed that such resistant cells exhibit higher mitochondrial membrane potential, higher OXPHOS and respiration, and increased resistance to oxidative stress, allowing them to survive chemo-radiotherapy.  These findings of increased expression of OXPHOS-associated genes and proteins in chemoresistant cells and biopsies of relapsed tumors suggest an alternative druggable target. Our in vitro and in vivo (nude mice and Artemia salina) data suggest that certain antibiotics, inducers of mitochondrial dysfunction, create additive oxidative stress and can reduce the growth rate of tumors developed from resistant or stem-like cancer cells. Such repurposed drugs, selected from a chemical library, are also able to resensitize resistant tumors, allowing reuse of chemotherapeutic agents. In addition, their modification with a specific moiety (TPP) allows for increased delivery to mitochondria to reduce cytotoxic pressure on normal cells. Thus, research from our laboratory offers an alternative strategy for anticancer therapy of resistant tumors.
FMP40 AMPYLASE REGULATES CELL SURVIVAL UPON OXIDATIVE STRESS BY CONTROLLING PRX1 AND TRX3 OXIDATION
Authors: Suchismita Masanta , Wiesyk Aneta , Panja Chiranjit , Pilch Sylwia , Ciesla Jaroslaw , Sipko Marta , De Abhipsita , Enkhbaatar Tuguldur , Maslanka Roman , Skoneczna Adrianna , Kucharczyk Roza
Published: September 2024

AMPylation (adenylation) is one of the post-translational protein modifications (PTM) leading to the diversification of protein functions and activity. With our collaborators, we discovered that the SelO family members of humans, yeast, and E. coli have AMPylase activity. The yeast SelO – Fmp40 – was identified in the proteome of the inter-membrane space of mitochondria. We have shown that Fmp40 is involved in the response of cells to hydrogen peroxide (H2O2) and menadione treatment: cells lacking the Fmp40 AMPylase grow sensitivity upon H2O2 and menadione treatment. E. coli SelO AMPylates glutaredoxin GrxA and the s-glutathionylation level of proteins is reduced in bacterial and yeast cells lacking SelO1. The objective of the study is to reveal the biological functions of Fmp40 in mitochondrial redox regulation. The decreased survival of fmp40Δ cells, observed in survival tests, depends on the oxidation of Trx3 upon oxidative stress. In contrast, we verified that fmp40Δ cells are resistant upon exposure to high concentrations of the hydrogen peroxide - phenotype dependent on the presence of the Glutaredoxin Grx2, Thioredoxin Trx3, Peroxiredoxin Prx1, Oxidation Resistance Oxr1, and Apoptotic inducing factor Aif1 basing on qPCR analysis. We found multidimensional genetic interactions of FMP40 with other known redox genes upon low or high oxidative stress. We revealed that Fmp40 AMPylates Prx1, Trx3, and Grx2 in vitro and it has a matrix-localized echo form. We discovered that Fmp40 is critical for the efficient reduction of Prx1 upon high oxidative stress. Moreover, Grx2 is involved in the Prx1 reduction directly and at the level of Trx3 reduction in vivo. Fmp40 regulates its function on Trx3 protein, most probably through Threonine66 which is AMPylated in vivo. In addition, Fmp40 is necessary to maintain the balance of cellular redox buffers GSH and NADPH. Overall Fmp40 regulates redox gene expression for efficient ROS neutralization and signaling which eventually determines the fate of cell survival upon oxidative stress.

Financed by National Science Centre of Poland: 2018/31/B/NZ3/01117.