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Heterogeneity of iridoid biosynthesis in catmints: Molecular background in a phylogenetic context
No full textNumerous members of the Nepeta genus (family Lamiaceae, subfamily Nepetoideae) are medicinal herbs and sources of important bioactive compounds. Most Nepeta species produce iridoids, which are monoterpenoids that deter herbivores and pathogens and are potential biopesticides. In Nepeta, some species produce iridoid aglycones and glycosylated iridoids (referred to as chemotype A), some produce only glycosylated iridoids (chemotype B), and some produce neither iridoid aglycones nor glycosylated iridoids (chemotype C). Here, we show that the observed diversity in iridoids is, at least partially, attributed to evolutionary gains and losses of key biosynthetic genes. Based on reconstructed phylogenetic relationships, we propose a scenario in which partial or complete loss of the ability to synthesize iridoids with specific stereochemistries in the taxa with chemotypes B and C resulted from independent evolutionary events. These observations improve our understanding of metabolic diversity in the Nepeta genus and may inform efforts to produce specific iridoids in plants
Combination therapies in cancer treatment: enhancing efficacy and reducing resistance
No full textCombination therapies represent a promising frontier in cancer treatment, addressing the critical need to enhance efficacy while minimizing resistance. By combining different therapeutic agents and modalities, researchers aim to exploit the synergistic effects that can arise from targeting multiple pathways simultaneously. This approach enhances the therapeutic impact and reduces the likelihood of resistance, which is a significant challenge in single-agent therapies. The rationale behind combination therapies is rooted in the complexity of cancer biology. Tumors are heterogeneous, comprising various cell types with distinct genetic and phenotypic profiles. Single-agent therapies often fail to address this complexity, leading to incomplete eradication of the cancer and subsequent resistance. Combining therapies can leverage different mechanisms of action to target various aspects of tumor growth and survival. Moreover, combination therapies can be designed to reduce the adverse effects associated with high doses of single agents. Lower doses of multiple drugs can achieve the desired therapeutic effect while minimizing toxicity. This is particularly important in cancer treatment, where the side effects of therapy can significantly impact patients' quality of life .Developing combination therapies in cancer discovery requires a robust understanding of drug action and resistance mechanisms. Preclinical studies and clinical trials are essential to identify the most effective combinations and determine the optimal dosing regimens. Integrating advanced technologies, such as high-throughput screening and computational modeling, can accelerate the identification of promising drug combinations. Additionally, personalized medicine approaches, considering the genetic and molecular characteristics of each patient's tumor, can further enhance the efficacy of combination therapies by tailoring treatment to the individual patient. By continuing to explore and refine combination therapies, the scientific community aims to provide more effective and durable treatments for cancer patients. We welcome Original Research Papers, Reviews, and Mini-Review Articles from preclinical and clinical studies that include but are not limited to the following topics:• Molecular mechanisms behind synergistic effects of two anticancer agents• Evading cancer drug resistance by combined approaches• Overcoming cancer drug resistance by combined approaches• Combining targeted therapies with immunotherapies to enhance anticancer efficacy• Impact of combination therapies on the tumor microenvironment• High-throughput screening for combined approaches in precision medicine• Role of nanotechnology in combination strategies• Artificial intelligence for optimizing combination therapies. We hope that this Research Topic can bring together studies and contributions on the subject of combination therapies in cancer treatment to enhance efficacy and reduce resistance. We expect to highlight significant and representative progress in the field to kindle further interest in focused areas by the larger anti-cancer research community. Please note that standard systematic reviews and economic evaluations that do not introduce novel methods fall outside the scope of this Research Topic
Phytochemical analysis, biological activities and molecular docking studies of black and white goji fruits of Lycium ruthenicum Murray
No full textThis study analyzes the phenolic and phenylamide composition of black and white goji berries, identifying 31 phenolics, 28 phenylamides, and 3 organic acids. Black berries contained about 10-fold higher phenolics, particularly hydroxybenzoic acid derivatives and anthocyanins, while white berries were dominated by phenolic acids and glycosylated spermidine/spermine derivatives. Glycosides of myricetin and laricitrin in black berries and caffeoyl putrescine monohexosides in both types, were identified. Phenylamide profiles differed, with N-caffeoyl-N′-dihydrocaffeoyl spermidine as the most abundant and bioactive. Both extracts showed antioxidant and enzyme-inhibitory effects. Black goji displayed stronger tyrosinase inhibition consistent with its high phenolic content and synergism among phenolics and phenylamides. Molecular docking revealed strong interactions with AChE and tyrosinase, especially for N-caffeoyl-N′-dihydrocaffeoyl spermidine, which showed higher affinity for tyrosinase than standard inhibitors. The presence of sugar moieties in some compounds reduced binding stability. These results highlight goji berries as promising sources of bioactives, for functional foods and nutraceuticals
Adolescence dietary restriction affects estrous cycle and spatial recognition memory in female Wistar rats during aging
No full textKnowing that dietary restriction (DR) during adolescence may influence age-related cognitive changes and reproductive parameters, we examined the effects of adolescent 30% DR on spatial recognition memory (SRM) and estrous cycle (EC) dynamics in female Wistar rats during aging. Control group had daily ad libitum food intake (AL), while DR groups included EADR (postnatal day (PND) 28-35), MADR (PND35–42), and EMADR (PND28–42) subgroups.
Regarding cognitive changes, 6-month-old females in proestrus (PE) and estrus (E), 9-month-old in E, and 12-month-old in PE had decreased exploratory behavior, compared to 3-month-old females in the same EC phases. EMADR females exhibited impaired SRM at 3 (PE and E) and 6 months (diestrus (DE)). Neither of DR regimens affected SRM at 9 and 12 months. At 15 months increased exploratory behavior was observed in EADR females compared to age-matched controls in extended estrus (EE), and MADR group in EE compared to extended DE MADR females.
All groups showed regular EC up to 6 months, determined by the regular occurrence of EC phases, and by a group estrous cycle ratio (ECR) of approximately 1. At 9 months, AL and 90% of MADR females had regular EC, whereas 70% of EADR and 30% of EMADR females abnormal EC. At 12 months, irregular EC was present in 30% of AL, 70% of EADR, 60% of MADR, and 40% of EMADR females, increasing further by 15 months (75% AL and 80% of each DR group). By 18 months, almost all females were acyclic regardless of treatment.Book of abstracts : Symposium Menopausal transition in medical and neuroscience research; 2026 Feb 26; Belgrade, Serbia. Belgrade: Serbian Neuroscience Society; 2026
Protein Expression Status of HTR4 and PDE4D Genes in Glial Brain Tumors Followed by the Study of Genomic Instability
No full textMalignant gliomas are the most common primary tumors of the central nervous system (CNS), originating from glial cells. They account for 30% of all CNS tumors. Among them, glioblastoma (GBM) is the most common, accounting for 45% of all glial tumors, while low-grade gliomas (LGGs) account for 31.8% of all gliomas. The aim of this study was to analyze the protein-expression profile of HTR4 and PDE4D genes in patients with glioma by immunohistochemical (IHC) analysis, to determine whether some interrelationship between them exists, to correlate their expression with clinical and histopathological parameters and therapy, and to determine their impact on patients’ survival. In addition, we analyzed the level of genomic instability (GI) (microsatellite (MIN), chromosomal (CIN) and total GI) by AP-PCR, in order to understand whether it can represent a tool for biological stratification of glioma tumors and risk assessment. Our results revealed that synchronized expression of 5-HTR4 and PDE4D proteins represents a stable modulatory signaling axis of glial-tumor biology, and reflects the activity of cAMP signaling pathway, but cannot independently stratify patients. Moreover, our study confirms that the combination of MIN, CIN and total GI represents a powerful tool for biological tumor stratification, risk assessment and understanding the pathobiological spectrum of the disease
Cellular-level imaging reveals distinct thallium detoxification strategies in Silene latifolia accessions
No full textThe facultative thallium (Tl) hyperaccumulator Silene latifolia can attain the highest known concentrations of Tl of any plant species. This trait is, however, differentiated at the population level with only two known Tl-tolerant and hyperaccumulating accessions occurring at metalliferous sites. This study aimed to reveal the internal distribution of Tl in plant organs and tissues. Silene latifolia subsp. alba from Tl-hyperaccumulating and Tl-sensitive accessions were grown hydroponically under different Tl treatments and analyzed to determine Tl accumulation. Plant organs were investigated using synchrotron X-ray fluorescence microtomography to determine cellular level distribution of Tl and other elements. The results reveal markedly different Tl distribution patterns, with mainly vacuolar localization in the epidermis of the hyperaccumulating population and a more even distribution across various cell types in the sensitive population. The differences were found even at the same applied concentrations (5 μM), being more pronounced in the Tl-hyperaccumulating plants at the highest treatment (100 µM of Tl). Elemental analysis showed Tl concentrations > 100 µg g− 1 in both accessions under all treatments, reaching up to 6910 µg g− 1 in Tl-hyperaccumulating plants treated with 100 µM of Tl. Compartmentalization in the vacuoles of epidermal cells proved to be a key mechanism for Tl hyperaccumulation in the tolerant accession, acting in both detoxification and offers protection against herbivory. In the sensitive accession, the localization of Tl in the mesophyll explains the toxic effect. Differences in Tl localization are of significant importance for deciphering the molecular and genetic bases of this extraordinary phenomenon
The interplay between phenotypic plasticity and long-term evolution in shaping life history strategy in the seed beetle
No full textPhenotypic plasticity, the capacity of organisms to adjust to varying environments, could play various roles in the evolution of phenotype development. Host shift in phytophagous insects is a perfect setting for studying the interplay between plasticity of life history traits and the evolution of life history strategies on novel plant hosts. Utilizing the benefits of a long-term laboratory evolution experiment, we used populations of seed beetle [Acanthoscelides obtectus Say (Coleoptera: Chrysomelidae)] reared on three plant hosts [common bean (Phaseolus vulgaris, L.), chickpea (Cicer arietinum, L.), and mung bean (Vigna radiata, (L.) R. Wilczek), all Fabaceae] for more than 150 generations. Reciprocal transplant experiments on inbred lines derived from these populations enabled the assessment of both long-term changes in beetles’ life history strategies and the alterations in their plastic capacity to adjust on diverse hosts. Our results demonstrate that seed beetle populations evolved distinct life history strategies, as well as different environmental sensitivity of life history traits. Beetles evolved on common beans showed stable pre-adult development within seeds of all three plant hosts but high variation in their reproductive output. On the other hand, populations adapted to chickpeas became specialised for development on chickpeas and constantly allocated more resources to reproduction. Populations evolved on mung beans were associated with high plasticity and variance in both larval survival and fecundity on all plant hosts, indicating the ongoing process of adaptation. This work is discussed in the context of how phenotypic plasticity induced by host shift can shape life history strategies, providing insights into the evolutionary and ecological dynamics of adaptation.This is the peer reviewed version of the following article: Savković U, Budečević S, Đorđević M, Vlajnić L, Predojević D, Pešić S, Stojković B. The interplay between phenotypic plasticity and long-term evolution in shaping life history strategy in the seed beetle. in Entomologia Experimentalis et Applicata. 2025, which has been published in final form at [http://dx.doi.org/10.1111/eea.70028]
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 precursors
using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The
impact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principal
component analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemical
descriptors. Quantitative structure–activity relationship (QSAR) and partial least squares (PLS) models
linked 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 human
serum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterized
physicochemical–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-diphenyltetrazolium
bromide (MTT) assay. QSAR and PLS models identified key descriptors.
Results: Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilic
hybrids 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, and
anticancer activity. Integrating these features enables design of hybrids overcoming P-gp-mediated
multidrug resistance, with hybrid 4k emerging as a promising candidate
Gene regulatory and co-expression networks reveal novel hub genes and regulatory mechanisms in rapeseed (Brassica napus L.) under drought stress
No full textRapeseed (Brassica napus L.) productivity is increasingly threatened by drought, yet coordinated regulatory programs that govern drought responses remain incompletely characterized. Here, we integrated an RNA-Seq meta-analysis with weighted gene co-expression network analysis (WGCNA)
and gene regulatory network (GRN) inference to study in depth the molecular responses of rapeseed
to drought stress. WGCNA revealed three modules: brown module enriched for upregulated genes and
two primarily downregulated modules (black and cyan). Brown-module hubs coordinate ABA signaling,
stomatal regulation, lipid mobilization, cell-wall reinforcement and protein homeostasis, whereas
black and cyan module hubs converge on suppression of growth, defense and metal-detoxification
pathways and reallocation of resources away from reproduction. Furthermore, this study identified
crucial hub transcription factors (TFs) within constructed GRNs. Upregulated TFs orchestrated the
induction of downstream genes involved in ABA signaling, protein homeostasis, antioxidant and
redox maintenance, stomatal, calcium, and ion regulation, membrane, cell wall, and lipid remodeling,
photosynthetic processes, and developmental reprogramming. Conversely, TFs in the downregulated
GRN repress growth-promoting signals, stomatal opening, and defense responses, while concurrently
regulating water use efficiency, water transport, and nutrient uptake. Our results suggest that the
ABA-mediated drought response in rapeseed involves an intricate interplay of positive and negative
regulators that prevents excessive ABA activation; concurrently, protein homeostasis is maintained by
prioritizing repair and refolding over wholesale degradation. Several TFs and hub genes identified in
this study, including BHLH122-1, HHO6, RAB18, LTP4, LEA30, DAA1, and EXLB1, represent promising
candidates for genomic selection and biotechnology approaches aimed at improving drought resilience
in rapeseed
Editorial: Redox Physiology in Fish
No full textIn recent years, ecophysiological research has focused on understanding the factors underlying variations in prooxidant/antioxidant balance and modulation of redox status, which may be the cause of many pathophysiological conditions in fish. Reactive oxygen species are known to be an important factor in oxidative cell damage through oxidation and the subsequent functional impairment of lipids, carbohydrates, proteins and DNA. Although the term oxidative stress is used as a general concept that includes all types of oxidative damage, there may be different subcategories of oxidative stress depending on which macromolecular component is damaged.
The aim of this special issue is to provide a general overview of the physiology of oxidative stress, redox signaling and the adaptations that fish have evolved to cope with oxidative stress, the environmental stressors that can induce changes in oxidative balance, the role of reactive species in transduction of environmental stimuli and cell signaling, and hormesis in response to oxidative stress.
The application of a broad spectrum of oxidative stress biomarkers may be a valuable tool to rapidly assess population dynamics under the pressure of environmental fluctuations, especially under the growing anthropogenic impact