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Determination of oxidative stress markers in liver and kidney tissue, TBARS, sulfhydryl (SH) groups
No full textMale Wistar rats were divided in 4 groups: I) control; II) physical activity (PA, swimming exercise lasting for 60 minutes); III) hyperbaric oxygenation (HBO, exposed to 100% oxygen in a hyperbaric chamber) and IV) PA following HBO exposure (HBO+PA). Swimming was performed individually in cylindrical containers (depth 50 cm, diameter 30 cm) filled with water maintained at 37 °C. The HBO protocol consisted of a gradual compression phase lasting 10 minutes, followed by exposure at 2.0 atmospheres absolute (ATA) for 60 minutes, and a subsequent decompression period of 10 minutes. The intensity of lipid peroxidation was estimated by measuring the MDA concentration in liver and kidney. The concentrations of total and nonprotein-SH groups were also measured
Cultivar-Specific Responses in Postharvest Strategies to Preserve Phytochemical Profile in Traditional Serbian Peppers (Capsicum annuum L.)
No full textTraditional Serbian pepper cultivars ‘Kurtovska ajvaruša’, ‘Grkinja babura’, and ‘Duga bela ljuta’
were stored under different conditions (10 ◦C, 4 ◦C, and 4 ◦C with pre-storage hot water
dipping-HWD) for 21 days plus a 3-day shelf life. The main quality parameters measured
included mineral content, total soluble solids (TSS), titratable acidity (TA),sugar content
(glucose, fructose), organic (ascorbic and citric) acid content, and total phenolic content
(TPC). Principal component analysis (PCA) revealed cultivar-specific responses to storage
treatments. Cultivar specificity is a crucial determinant in defining optimal conditions for
the preservation of phytochemical composition. The cultivar ‘Kurtovska ajvaruša’ showed
the highest retention of phenolic compounds when stored at 4 ◦C following hot water
treatment (HWD), whereas ‘Grkinja babura’ should be stored at 4 ◦C (without hot water
treatment, as it provides no additional benefits) for up to 21 days, as this ensures balanced
preservation of sugar and organic acid contents while maintaining high sensory quality of
the fruit. ‘Duga bela ljuta’ exhibited superior ascorbic acid preservation at 10 ◦C, reaching
104.4 mg/100 g. Optimizing postharvest storage conditions is essential for maintaining the
nutritional quality of traditional pepper cultivars intended for both fresh consumption and
processing
Effects of hibernation temperature and duration on oxidative status in the common wall lizard (Podarcis muralis)
No full textGlobal warming is expected to alter phenology in temperate ectotherms by advancing spring arousal and delaying autumn entry into hibernation. However, the physiological consequences of such shifts remain poorly understood in reptiles, particularly with respect to oxidative balance. We investigated the effects of hibernation temperature and duration on oxidative status in the common wall lizard ( Podarcis muralis ). Oxidative markers were measured in the liver and tail during the pre-hibernation period and after exposure to laboratory-simulated winter regimes differing in temperature (∼2.5 °C vs. 5.5 °C) and duration (three vs. four months), representing short-cold, short-mild, long-cold, and long-mild winter scenarios. Hibernation duration exerted generally inconsistent effects on antioxidant defenses, with changes detected in liver superoxide dismutase, catalase, and glutathione, as well as in tail superoxide dismutase and glutathione. Temperature effects were modest, manifesting as upward trends in liver glutathione content and tail catalase activity, without significant interactions with hibernation duration. Cold-winter regimes were associated with increased lipid oxidative damage in the liver, although this response was not consistent across all treatments. Importantly, most oxidative parameters remained comparable to pre-hibernation values, with a significant reduction in glutathione levels observed only under short-cold conditions. Overall, the maintenance of redox homeostasis across contrasting thermal and temporal winter regimes indicates substantial physiological plasticity and resilience of P. muralis to altered thermal environments during hibernation, highlighting the capacity of reptiles to buffer oxidative challenges imposed by climate-driven changes in winter conditions
Assessment of the Type and Degree of Genomic Instability in Gliomas
No full textGlial brain tumours, including astrocytoma IDH (Isocitrate Dehydrogenase) mutant and glioblastoma IDH wild-type, are highly malignant brain tumours with poor clinical outcomes. Genomic instability, encompassing microsatellite (MIN) and chromosomal instability (CIN), drives tumour heterogeneity and evolution. In this study, genomic instability was analysed in 85 patients using AP-PCR (Arbitrarily Primed Polymerase Chain Reaction) by comparing tumour and normal tissue (blood) DNA profiles of the same patient. Both types of alterations were present in all analysed samples, contributing almost equally to the total level of genomic instability. The dominant pattern of genomic instability in our cohort was low overall instability, predominantly manifesting as low-degree microsatellite instability. A general decrease in genomic instability was observed with increasing tumour grade. Glioblastoma IDH wild-type was more prevalent in older patients, whereas astrocytoma IDH mutant predominated in younger individuals. Notably, low genomic instability (both MIN and CIN) was associated with poorer survival in patients over 50 years of age. Females, compared to males, exhibited higher MIN in grade 2 tumours and elevated CIN in grade 4 tumours. Our results confirm that genomic instability contributes to tumour progression, MIN being the pivotal factor, and could serve as a prognostic biomarker in malignant gliomas
Molecular basis of iridoid biosynthesis in Nepeta nuda L.
No full textIridoidi predstavljaju biciklične monoterpenoide koji se kod vrsta roda Nepeta (Lamiaceae) mogu naći u formi aglikona, kao i u formi glikozida, pri čemu njihova biosinteza još uvek nije u potpunosti razjašnjena. Sposobnost sinteze velikog broja iridoidnih jedinjenja i izražena varijabilnost u pogledu njihovog kvantitativnog sadržaja, čini vrstu Nepeta nuda L. idealnim model sistemom za proučavanje njihve biosinteze. U potrazi za izvorom hemijske varijabilnosti koja bi omogućila rasvetljavanje molekularnih osnova biosinteze iridoida kod N. nuda i ukazala na faktore koji određuju produktivnost biljaka, u okviru ove doktorske disertacije je diverzitet iridoida ispitan na različitim nivoima organizacije (inter- i intra-populacionom, intra-individualnom), u prirodnim populacijama i u eksperimentalnim uslovima. Analiza hemijske varijabilnosti u prirodnim populacijama N. nuda upotrebom savremenih analitičkih tehnika uz istovremenu procenu genetičkog diverziteta pomoću mikrosatelita (EST-SSR), implicira da su hemijski i genetički diverzitet između analiziranih populacija niski, dok postoji značajan nivo varijabilnosti unutar populacija. Ovakav rezultat ukazuje da u prirodnim populacijama genetička raznovrsnost može imati veći uticaj na varijabilnost metaboloma N. nuda u odnosu na sredinske faktore. Uporedno metaboličko profilisanje vegetativnih i reproduktivnih biljnih organa jasno je ukazalo na njihovu hemijsku diferenciranost što je objašnjeno razlikama u ekspresiji gena kandidata uključenih u iridoidni biosintetski put, pri čemu se listovi karakterišu većom metaboličkom varijabilnošću u odnosu na cvasti. U eksperimentalnim uslovima je ispitan uticaj različitih uslova gajenja, elicitora (metil-jasmonat, salicilna kiselina, vodonik peroksid) i stresnih faktora (UV-B zračenje, anaerobni stres) na metabolizam iridoida u listovima N. nuda, u cilju optimizacije produkcije ovih jedinjenja, ali i u cilju rasvetljavanja molekularnih mehanizama koji određuju produktivnost biljaka. Primećene razlike u akumulaciji iridoida u listovima N. nuda su u slučaju svih primenjenih uslova gajenja, stresnih faktora i elicitora, rezultat pojačane ekspresije gena kandidata uključenih u biosintezu iridoida, na prvom mestu onih koji kodiraju nepetalaktolu bliske kratkolančane dehidrogenaze/reduktaze (NEPS), a u slučaju UV-B zračenja i glukozil transferazu 7-deoksiloganetinske kiseline (Nn7DLGT). Kombinovana folijarna primena vodonik peroksida i izlaganje anaerobnom stresu u nivou korenova, pokazala se posebno efikasnom u indukciji biosinteze iridoidnih aglikona kod N. nuda, utičući na kvalitativni i kvantitativni sastav nepetalaktona u listovima. U slučaju salicilne kiseline, pokazano je da dužina trajanja tretmana i primenjena koncentracija određuju intenzitet pozitivnih ili negativnih promena u sadržaju nepetalaktona, što je uslovljeno nivoima ekspresije nekih od ranih gena u biosinteskom putu, geraniol-8-hidroksilaze (NnG8O) i 8-hidroksigeraniol-oksidoreduktaze (Nn8HGO). Doprinos ove doktorske disertacije razumevanju mehanizama koji leže u pozadini biosinteze iridoida kod vrsta roda Nepeta, dalje se ogleda kroz pružanje novih dokaza o esencijalnom značaju geraniol sintaze (GES) u regulaciji metaboličkog fluksa kroz iridoidni biosintetski put. Prekomerna ekspresija NnGES u klijancima N. nuda dovela je do indukcije, a njegovo utišavanje do redukcije sadržaja iridoidnih jedinjenja u listovima, što je ukazalo na potencijal ovog gena kao vrednog biotehnološkog alata za modifikaciju produkcije iridoida kod vrsta roda Nepeta. Rezultati ukazuju na mogućnost metaboličkog inženjeringa uz istovremeno ciljanje većeg broja biosintetskih gena, na prvom mestu GES i izomera NEPS, u cilju modifikacije kvalitativnog i kvantitativnog sastava iridoida, a samim tim i bioaktivnih svojstava N. nuda.Iridoids are bicyclic monoterpenoids that can be found in Nepeta species (Lamiaceae) in both aglycone and glycoside forms. However, their biosynthesis has not yet been fully elucidated. The ability to synthesize a large number of iridoid compounds and the variation in their quantitative content points out Nepeta nuda L. as an ideal model system for studying iridoid biosynthesis. In the search for a source of chemical variability that would allow the elucidation of the molecular basis of iridoid biosynthesis in N. nuda, and reveal the factors that determine plant productivity, this dissertation investigated iridoid diversity at different levels of organization (inter- and intra-population, intra-individual), in natural populations and in experimental conditions. The analysis of chemical variability in natural populations of N. nuda using modern analytical techniques, accompanied by the analysis of genetic diversity using microsatellites (EST-SSR), indicates that chemical and genetic diversity between the analyzed populations are low, although a significant level of variability exists within populations. This result suggests that, in natural populations, genetic diversity may have a stronger impact on shaping the metabolome of N. nuda compared to environmental factors. Comparative metabolic profiling of vegetative and reproductive plant organs clearly demonstrated their chemical differentiation, which was explained by the differences in the expression of iridoid biosynthetic genes, with leaves showing greater metabolic variability compared to inflorescences. Under experimental conditions, the influence of different cultivation conditions, elicitors (methyl jasmonate, salicylic acid, hydrogen peroxide), and stress factors (UV-B radiation, anaerobic stress) on iridoid metabolism in the leaves of N. nuda was examined, with the aim of optimizing the iridoid production, as well as to elucidate the molecular mechanisms determining plant productivity. The observed differences in iridoid accumulation in N. nuda leaves, under different growth conditions, stress factors, and elicitors, were the result of enhanced expression of genes potentially involved in iridoid biosynthesis, primarily those coding for short-chain dehydrogenases/reductases related to nepetalactol (NEPS), and in the case of UV-B radiation, also 7-deoxyloganetic acid glucosyltransferase (Nn7DLGT). Combined foliar application of hydrogen peroxide and exposure to anaerobic stress at the root level proved particularly effective in inducing the biosynthesis of iridoid aglycones in N. nuda, affecting the qualitative and quantitative composition of nepetalactone in the leaves. In the case of salicylic acid, it was shown that treatment duration and applied concentration determine the intensity of positive or negative changes in nepetalactone content, driven by the expression levels of some early iridoid biosynthetic genes, such as geraniol-8-hydroxylase (NnG8O) and 8-hydroxygeraniol oxidoreductase (Nn8HGO). The contribution of this dissertation to a better understanding of mechanisms underlying iridoid biosynthesis in Nepeta species is further reflected in providing new evidence for the essential role of geraniol synthase (GES) in regulating metabolic flux through the iridoid biosynthetic pathway. Overexpression of NnGES in N. nuda seedlings led to an increase, while its silencing caused a reduction in iridoid content in leaves, indicating the potential of this gene as a valuable biotechnological tool for modifying iridoid production in Nepeta species. The results indicate the possibility of metabolic engineering targeting multiple biosynthetic genes simultaneously, primarily GES and NEPS isomers, to modify the qualitative and quantitative composition of iridoids, and consequently the bioactive properties of N. nuda
Regulation of lipid metabolism, inflammation, and insulin sensitivity in white adipose tissue, liver, and intestine of mice resistant to diet-induced obesity
No full textGojaznost je hronični metabolički poremećaj koji povećava rizik od dislipidemije, insulinske rezistencije, metaboličke inflamacije i steatoze. Kliničke i animalne studije ukazuju da, uprkos povećanom energetskom unosu, ne razvijaju sve jedinke gojazni fenotip. Cilj ove doktorske disertacije bio je da se identifikuju molekularni mehanizmi rezistencije na gojaznost ispitivanjem molekularnih adaptacija u metabolizmu lipida, insulinskoj signalizaciji i inflamaciji u jetri i belom masnom tkivu, kao i sastava crevne mikrobiote miševa rezistentnih na gojaznost pri ishrani obogaćenoj mastima.
Nakon 14 nedelja konzumiranja hrane sa 60% masti, miševi rezistentni na gojaznost imali su nižu telesnu masu i mase visceralnog masnog tkiva i jetre, niže koncentracije glukoze, insulina i triglicerida, kao i očuvanu sistemsku toleranciju na glukozu. Adipociti u oba depoa belog masnog tkiva nisu bili hipertrofirani i imali su očuvanu ekspresiju PPARγ, adiponektina i lipolitičkih enzima. U visceralnom depou nivoi inflamatornih markera bili su smanjeni, dok je osetljivost na insulin bila poboljšana. Rezistentne životinje su imale povećanu zastupljenost rodova Lactobacillus i RF39, dok je prisustvo rodova Helicobacter i Rothia bilo smanjeno. Proteinski nivoi transportera masnih kiselina bili su sniženi u tankom crevu i jetri, što je rezultovalo odsustvom steatoze kod životinja rezistentnih na gojaznost.
Rezultati ove doktorske disertacije su pokazali da rezistentni fenotip ima povoljniji metabolički profil zahvaljujući usklađenim adaptacijama u masnom tkivu, crevu i jetri. Upravo ove adaptacije predstavljaju osnovu za razvoj personalizovanih pristupa usmerenih na očuvanje funkcionalne adipogeneze u visceralnom masnom tkivu, modulaciju crevne mikrobiote i ciljanu regulaciju apsorpcije masnih kiselina u tankom crevu i jetri.Obesity is a chronic metabolic disorder that increases the risk of dyslipidaemia, insulin resistance, metabolic inflammation and steatosis. Clinical and animal studies indicate that, despite increased energy intake, not all individuals develop an obese phenotype. The aim of this doctoral dissertation was to identify molecular mechanisms underlying resistance to obesity by examining molecular adaptations in lipid metabolism, insulin signalling and inflammation in the liver and white adipose tissue, as well as the composition of the gut microbiota in obesity resistant mice fed a high-fat diet.
After 14 weeks of consuming a diet containing 60% fat, obesity resistant mice showed lower body mass and reduced masses of visceral adipose tissue and liver, lower circulating glucose, insulin and triglyceride concentrations, as well as preserved systemic glucose tolerance. Adipocytes in both white adipose depots were not hypertrophic and displayed preserved expression of PPARγ, adiponectin and lipolytic enzymes. In the visceral depot, levels of inflammatory markers were reduced, whereas insulin sensitivity was improved. Obesity resistant animals had a higher relative abundance of the genera Lactobacillus and RF39, while the presence of the genera Helicobacter and Rothia was decreased. Protein levels of fatty acid transporters were reduced in the small intestine and liver, which was associated with the absence of steatosis in obesity resistant animals.
The results of this doctoral dissertation show that the resistant phenotype has a more favourable metabolic profile due to coordinated adaptations in adipose tissue, gut and liver. These adaptations form the basis for the development of personalised approaches aimed at preserving functional adipogenesis in visceral adipose tissue, modulating the gut microbiota and selectively regulating fatty acid absorption in the small intestine and liver
Hormonal and Environmental Factors Influencing Secondary Somatic Embryogenesis
No full textSecondary somatic embryogenesis (SSE) represents a powerful tool for clonal propagation, efficient genetic modification, and plant conservation, enabling the continuous production of secondary somatic embryos (SSEs) from previously formed embryogenic tissues. The efficiency of SSE is determined both by external factors such as exogenous hormonal and environmental conditions and internal cues such as explant type and genotype. Auxins, particularly synthetic 2,4-dichlorophenoxyacetic acid (2,4-D), represent key factors in inducing and maintaining embryogenic competence, while cytokinins often modulate the differentiation and proliferation of SSEs. The interplay of plant growth regulators (PGRs) not only affects the frequency of SSE induction, but also the morphology and proper development of the resulting embryos. Here, we provide a comprehensive review on hormonal treatments, especially the role of auxins and cytokinins and environmental factors such as temperature, light, and culture medium composition, that shape the embryogenic potential in SSE, with species-specific responses frequently being observed. The importance of primary explant selection, as well as the liquid phase and potential scale-up with bioreactors, are also discussed. Other challenges related to genotype recalcitrance, limited efficiency, maturation and conversion rates, and the lack of an advanced molecular approach are further addressed, providing a framework for improved regeneration and reliability across diverse species
Tissue-specific changes in antioxidant defence during ageing: the effect of chronic cold exposure
No full textAgeing is a multifactorial process characterised by the progressive dysregulation of redox homeostasis in different organs. Although various endogenous and exogenous factors influencing ageing have been identified, limited evidence exists regarding the effects of chronic cold exposure on aged rats. To address this, we investigated interscapular brown (iBAT) and retroperitoneal white (rWAT) adipose tissue, skeletal muscle, and liver in rats (3-, 6- and 24-month-old) at 22 ± 1 °C, alongside a cohort of 24-month-old rats kept at 4 ± 1 °C from 6 to 24 months of age. We measured antioxidant defence (AD) components: the activity of copper zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutase, catalase, glutathione peroxidase (GSH-Px), glutathione reductase (GR), thioredoxin reductase (TR), glutathione S-transferase (GST), and total glutathione (GSH) content. With chronological ageing, enzyme activity decreased in rWAT (catalase, GSH-Px, GR, TR, GST) and iBAT (GSH-Px). Conversely, aged rats exposed to 4 ± 1 °C showed an upregulation of AD components in rWAT (catalase, GSH-Px, GR, TR, GST; GSH), iBAT (catalase, GSH-Px, TR; GSH), and muscle (GSH-Px, GR, TR, GST), compared to age-matched group. However, CuZnSOD and MnSOD activities remained unchanged across all experimental groups and tissues. In addition, none of the measured AD components in the liver changed significantly across groups. Collectively, these results reveal a distinct modulation of the AD profiles in different organs, both during chronological ageing and after long-term exposure to cold, underscoring an integrated systemic responsiveness. This is most evident in the preserved AD response to prolonged cold exposure in the key thermogenic tissue, iBAT, of aged rats
Integrative lipophilicity assessment and pharmacokinetic correlation of pyrimidine precursors and artesunate–pyrimidine hybrids: development of QSAR models for anticancer activity and interaction with P -glycoprotein
No full textAims: To evaluate chromatographic lipophilicity of novel artesunate–pyrimidine hybrids and precursorsusing reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). Theimpact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principalcomponent analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemicaldescriptors. Quantitative structure–activity relationship (QSAR) and partial least squares (PLS) modelslinked molecular descriptors to cytotoxicity and resistance modulation in nonsmall cell lung cancer(NSCLC) cells.Materials and methods: Lipophilicity was measured by RP-TLC. PPB was determined using humanserum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterizedphysicochemical–pharmacokinetic correlations. Cytotoxicity in sensitive NCI-H460 and multidrug-resistant (MDR) NCI-H460/R cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. QSAR and PLS models identified key descriptors.Results: Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilichybrids showed near-complete HSA binding. Compound 2k lost cytotoxicity in the presence of albumin,whereas 4k retained potency. Models indicated steric and electronic features, alongside lipophilicity,dictate efficacy and P-glycoprotein (P-gp) interactions, particularly in resistant cells.Conclusions: Lipophilicity and steric/electronic descriptors govern distribution, protein binding, andanticancer activity. Integrating these features enables design of hybrids overcoming P-gp-mediatedmultidrug resistance, with hybrid 4k emerging as a promising candidate.This is an Accepted Manuscript of an article published by Taylor & Francis in Future Medicinal Chemistry on 13 Dec 2025, available at: [https://doi.org/10.1080/17568919.2025.2602963
Tissue-specific changes in antioxidant defence during ageing: the effect of chronic cold exposure
No full textAgeing is a multifactorial process characterised by the progressive dysregulation of redox homeostasis in different organs. Although various endogenous and exogenous factors influencing ageing have been identified, limited evidence exists regarding the effects of chronic cold exposure on aged rats. To address this, we investigated interscapular brown (iBAT) and retroperitoneal white (rWAT) adipose tissue, skeletal muscle, and liver in rats (3-, 6- and 24-month-old) at 22 ± 1 °C, alongside a cohort of 24-month-old rats kept at 4 ± 1 °C from 6 to 24 months of age. We measured antioxidant defence (AD) components: the activity of copper zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutase, catalase, glutathione peroxidase (GSH-Px), glutathione reductase (GR), thioredoxin reductase (TR), glutathione S-transferase (GST), and total glutathione (GSH) content. With chronological ageing, enzyme activity decreased in rWAT (catalase, GSH-Px, GR, TR, GST) and iBAT (GSH-Px). Conversely, aged rats exposed to 4 ± 1 °C showed an upregulation of AD components in rWAT (catalase, GSH-Px, GR, TR, GST; GSH), iBAT (catalase, GSH-Px, TR; GSH), and muscle (GSH-Px, GR, TR, GST), compared to age-matched group. However, CuZnSOD and MnSOD activities remained unchanged across all experimental groups and tissues. In addition, none of the measured AD components in the liver changed significantly across groups. Collectively, these results reveal a distinct modulation of the AD profiles in different organs, both during chronological ageing and after long-term exposure to cold, underscoring an integrated systemic responsiveness. This is most evident in the preserved AD response to prolonged cold exposure in the key thermogenic tissue, iBAT, of aged rats.This version of the article has been accepted for publication, after peer review and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: [http://dx.doi.org/10.1007/s00360-025-01646-9