Search Results (161)

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

L-carnitine and Mildronate are substances that can significantly rearrange the energy metabolism of cells. This can potentially cause changes in the bacterial composition of the gut microbiome and affect testis functionality and male sexual health. Mice of the C57Bl/6 line were used. Sexual behavior was assessed using physiological tests, and gene expression patterns were assessed by qPCR. High-throughput sequencing of mouse fecal microbiota was performed. We showed that long-term administration of Mildronate has no significant effect on the intestinal microbiome, and there was a compensatory increase in the expression of genes involved in fatty acid and leptin metabolism. No impairment of sexual motivation in male mice was observed. Prolonged L-carnitine supplementation caused a decrease in alpha diversity of bacteria and a decrease in some groups of microorganisms that are components of a healthy gut microflora. A correlation was observed between the level of bacteria from Firmicutes phylum, indicators of sexual motivation of mice, and the dynamics of body weight gain. Our results may indicate that metabolic modulators can have a significant impact on the structure of the bacterial community of the gut microbiome, which may influence male sexual health through the gut–semen axis. Full article

Jumping translocations (JTs) are rare chromosomal abnormalities that play a crucial role in the pathogenesis of various cancer types. These rearrangements, especially those involving chromosome 1q, are frequently associated with tumor progression, therapeutic resistance, and poor prognosis. One gene of particular interest, human Jumping Translocation Breakpoint (JTB), has been identified at the site of translocation breakpoints and exhibits complex, context-dependent roles in cancer biology. JTB protein functions as a pivotal regulator in mitosis, chromosomal segregation, apoptosis, and cellular metabolism. It is functionally linked with the chromosomal passenger complex (CPC) and is implicated in processes such as epithelial–mesenchymal transition (EMT), immune evasion, and therapy resistance, especially in breast and prostate cancers. Advances in genomic, transcriptomic, and proteomic research have highlighted the significant potential of JTB as a diagnostic biomarker and a target for therapeutic interventions. This review underscores the dual role of JTB as both a tumor suppressor and oncogene, depending on the cellular context, and advocates for its continued investigation at the genomic, transcriptomic, and proteomic levels. Understanding JTB’s multifaceted contributions to tumor biology may pave the way for novel biomarkers and targeted treatments in cancer management. Full article

In recent decades, heavy metal pollution has become a significant environmental stress factor. Plants are characterized by high biochemical plasticity and can adjust their metabolism to ensure survival under a changing environment. Here we report, to our knowledge, the first gas chromatography-mass spectrometry (GC-MS)-based metabolomics study of Zn-induced stress responses in Amaranthus caudatus plants. The study was performed with root and leaf aqueous methanolic extracts after their lyophilization and sequential derivatization with methoxylamine hydrochloride and N-methyl-N-(trimethylsilyl)trifluoroacetamide. In total, 419 derivatives were detected in the samples, and 144 of them could be putatively annotated. The metabolic shifts in seven-week-old A. caudatus plants in response to a seven-day treatment with 300 µmol/L ZnSO₄·7H₂O in nutrient solution were organ-specific and more pronounced in roots. Most of the responsive metabolites were up-regulated and dominated by sugars and sugar acids. The revealed effects could be attributed to the involvement of these metabolites in osmotic regulation, antioxidant protection and Zn²⁺ complexation. A 59-fold up-regulation of gluconic acid in roots distinctly indicated enhanced glucose oxidation due to oxidative stress upon the Zn treatment. Gluconic acid might be further employed in Zn²⁺ complexation. Pronounced Zn-induced up-regulation of salicylic acid in roots and shoots suggested a key role of this hormone in stress signaling and activation of Zn stress tolerance mechanisms. Overall, our study provides the first insight into the general trends of Zn-induced biochemical rearrangements and main adaptive metabolic shifts in A. caudatus. Full article

(1) Background: Vascular mural cells reside in the media and outer layers of the vessel wall. Their ability to proliferate and migrate or to change phenotype in response to external cues is a central feature of the vascular response to injury. Genetically engineered mice are used for loss- or gain-of-function analyses or lineage tracing in vivo, their primary cells for mechanistic studies in vitro. Whether and how cultivation conditions affect their phenotype and function is often overlooked. (2) Methods: Here, we systematically studied how the cultivation of primary mural cells isolated from the aorta of adult wild-type mice in either basal medium (DMEM) or special media formulated for the cultivation of fibroblasts or pericytes affects their phenotype and function. (3) Results: Medium composition did not alter cell viability, but the mRNA levels of differentiated smooth muscle cell markers were highest in vascular mural cells expanded in DMEM. Conversely, significantly higher numbers of proliferating and migrating cells were observed in cells expanded in Pericyte medium, and cytoskeletal rearrangements supported increased migratory capacities. Significantly reduced telomere lengths and metabolic reprogramming was observed in aortic mural cells cultured in Fibroblast medium. (4) Conclusions: Our findings underline the plasticity of primary aortic mural cells and highlight the importance of the culture media composition during their expansion, which could be exploited to interrogate their responsiveness to external stimuli or conditions observed in vivo or in patients. Full article

Mesenchymal stem cells isolated from human adipose tissue (hASCs) are a promising tool for tissue repair due to their ability to differentiate into specific cell lineages. The possibility of modulating the adipogenic differentiation of hASCs is crucial in improving their therapeutic potential. This study aimed to investigate the effects of cannabidiol (CBD), a phytocannabinoid isolated from Cannabis sativa L., on hASCs. Few studies have evaluated its role in stem cell (SC) properties and their differentiation potential. hASCs were first treated with different concentrations of CBD (ranging from 0.1 to 10 μM) to assess its effects on viability, demonstrating that this molecule is non-toxic, except at the concentration of 10 μM. Subsequently, the role of CBD in the proliferation, metabolism and adipogenic potential of hASCs was analyzed. CBD promoted adipogenesis in a dose-dependent manner, even in the absence of differentiation medium. This result was evidenced by the presence of lipid vacuoles, the expression of adipogenic markers, cytoskeletal actin rearrangement and modulation in the expression of osteogenic genes. Although the results indicated a role of CBD in promoting hASC adipogenesis, further research will be needed to explore the mechanism of action of CBD in SC differentiation and to deepen its utility in SC-based approaches. Full article

Despite advances in outcome, one third of children with acute myeloid leukemia (AML) relapse, and less than half will achieve long-term survival. Relapse in AML has been shown to be driven in part by leukemic stem cells (LSCs), highlighting the unmet medical need to better characterize and target this therapy-resistant cell population. Micro-array profiling of pediatric AML subpopulations (LSCs and leukemic myeloblasts) and their healthy counterparts revealed nidogen-1 (NID1) as expressed in both leukemic subpopulations while absent in the hematopoietic stem cell. Using the TARGET dataset including pediatric AML patients (n = 1025), NID1 expression showed a correlation with worse event-free survival and KMT2A rearrangements. Drug response profiling of a NID1 knockdown model demonstrated differential sensitivity to HSP90 inhibition. RNA sequencing and gene set enrichment analysis between NID1^high and NID1^low phenotypes showed involvement of NID1 in mitochondrial metabolic pathways known to be enriched in LSCs. Altogether, this study highlights NID1 as a novel oncogene associated with worse EFS and metabolic LSC phenotype in AML. NID1 could serve as a biomarker and aid in further mapping LSCs to establish therapeutic strategies tackling the high relapse rates in pediatric AML. Full article

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have become first-line therapies for advanced non-small cell lung cancer (NSCLC) with ALK rearrangements. This study investigates ALK-TKI-associated adverse events (AEs), focusing on identifying hepatotoxicity signals and previously undocumented safety concerns. Using disproportionality analysis of 56,864 reports from the FDA Adverse Event Reporting System (FAERS) database, we systematically classified AEs via the Medical Dictionary for Regulatory Activities (MedDRA). At the System Organ Class (SOC) level, crizotinib exhibited a significantly stronger signal for eye disorders, ceritinib was uniquely linked to gastrointestinal disorders, and loratinib was predominantly associated with metabolism and nutrition disorders. Several AEs previously undocumented in drug labels were identified, including pericardial effusion, elevated C-reactive protein, hemolytic anemia, hemoptysis, and decreased hemoglobin. Furthermore, crizotinib, ceritinib, and alectinib were significantly associated with hepatotoxicity, marked by elevated alanine aminotransferase, aspartate aminotransferase, and hepatic enzyme levels. These findings highlight the need for vigilant monitoring of unlabeled AEs and potential label updates, particularly for hepatotoxicity risks associated with crizotinib, ceritinib, and alectinib. Full article

This study investigates the electrochemical oxidation mechanisms of chlorpromazine (CPZ), revealing a novel three-electron oxidation pathway that challenges the traditionally accepted two-electron paradigm, offering new insights into CPZ oxidation pathways. Using an integrated approach combining cyclic voltammetry, bulk electrolysis, UV-Vis, FT-IR, ¹H-NMR spectroscopy, and LC-MS/MS analysis, we demonstrate that CPZ undergoes sequential oxidation processes involving both the phenothiazine core and the tertiary amine-containing side chain. Our results highlight the critical role of side-chain oxidation in forming nor-CPZ sulfoxide, an often-overlooked metabolite, which may influence CPZ’s metabolic and pharmacological behaviour. Spectroelectrochemical data reveal stable intermediate species, providing insight into the structural rearrangements accompanying oxidation. This work offers a detailed mechanistic understanding of CPZ redox behaviour, contributing to improved interpretations of its pharmacological and metabolic properties. Full article

Five novel 2-methyl-4-(1-glycerol)furan (MGF) dimers, namely nocardifuran A (1), 13-acetyl-nocardifuran A (2), 15-epi-nocardifuran A (3), nocardifuran B (4), and nocardifuran C (5), were isolated from the Gause liquid fermentation of the marine-derived Nocardiopsis sp. ZSN1. Their structures were elucidated through HRESIMS, 1D and 2D NMR spectroscopic data analysis, and ECD calculations. Compounds 1–4 were identified as derivatives of MGF with its rearrangement of furan or pyran derivatives, while compound 5 was identified as the derivative of MGF with an indole derivative. These MGF dimers, representing a new structural class, were isolated from a marine microorganism for the first time, thereby enhancing chemical diversity. Screening for farnesoid X receptor (FXR) agonistic activity revealed that MGF dimers could activate FXR. Furthermore, bioactivity evaluations demonstrated that these types of compounds exhibited lipid-lowering activity with lower cytotoxicity in vitro. Consequently, our findings not only contribute to the chemical diversity of marine-derived MGF-type natural products but also offer potential insights into the development of MGF dimers as lead compounds for FXR agonists in the dysregulation of hepatic lipid metabolism. Full article

New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or “targeting kinesins”, holds great potential as an effective strategy for treating lung cancer. Full article

Infection of higher plants with agrobacteria (Agrobacterium tumefaciens) represents one of the most comprehensively characterized examples of plant–microbial interactions. Incorporation of the bacterial transfer DNA (T-DNA) in the plant genome results in highly efficient expression of the bacterial auxin, cytokinin and opine biosynthesis genes, as well as the host genes of hormone-mediated signaling. These transcriptional events trigger enhanced proliferation of plant cells and formation of crown gall tumors. Because of this, infection of plant tissues with A. tumefaciens provides a convenient model to address the dynamics of cell metabolism accompanying plant development. To date, both early and late plant responses to agrobacterial infection are well-characterized at the level of the transcriptome, whereas only little information on the accompanying changes in plant metabolism is available. Therefore, here we employ an integrated proteomics and metabolomics approach to address the metabolic shifts and molecular events accompanying plant responses to inoculation with the A. tumefaciens culture. Based on the acquired proteomics dataset complemented with the results of the metabolite profiling experiment, we succeeded in characterizing the metabolic shifts associated with agrobacterial infection. The observed dynamics of the seedling proteome and metabolome clearly indicated rearrangement of the energy metabolism on the 10th day after inoculation (d.a.i.). Specifically, redirection of the energy metabolism from the oxidative to the anaerobic pathway was observed. This might be a part of the plant’s adaptation response to tumor-induced hypoxic stress, which most likely involved activation of sugar signaling. Full article

Background: The wide variability in clinical responses to anti-tumor immunotherapy drives the search for personalized strategies. One of the promising approaches is drug screening using patient-derived models composed of tumor and immune cells. In this regard, the selection of an appropriate in vitro model and the choice of cellular response assay are critical for reliable predictions. Fluorescence lifetime imaging microscopy (FLIM) is a powerful, non-destructive tool that enables direct monitoring of cellular metabolism on a label-free basis with a potential to resolve metabolic rearrangements in immune cells associated with their reactivity. Objective: The aim of the study was to develop a patient-derived glioma explant model enriched by autologous peripheral lymphocytes and explore FLIM of the redox-cofactor NAD(P)H in living lymphocytes to measure the responses of the model to immune checkpoint inhibitors. Methods: The light microscopy, FLIM of NAD(P)H and flow cytometry were used. Results: The results demonstrate that the responsive models displayed a significant increase in the free NAD(P)H fraction α₁ after treatment, associated with a shift towards glycolysis due to lymphocyte activation. The non-responsive models exhibited no alterations or a decrease in the NAD(P)H α₁ after treatment. The FLIM data correlated well with the standard assays of immunotherapy drug response in vitro, including morphological changes, the T-cells activation marker CD69, and the tumor cell proliferation index Ki67. Conclusions: The proposed platform that includes tumor explants co-cultured with lymphocytes and the NAD(P)H FLIM assay represents a promising solution for the patient-specific immunotherapeutic drug screening. Full article

Cisplatin-based platinum compounds are important clinical chemotherapeutic agents that participate in most tumor chemotherapy regimens. Through density-functional theory calculations, the formation and stability of the inorganic oxide carrier, the mechanisms of the hydrolysis reaction of the activated platinum compound, and its binding mechanism with DNA bases can be studied. The higher the oxidation state of Pt (II to IV), the more electrons transfer from the magnesia–gold composite material to the platinum compound. After adsorption on the composite carrier, 5d←2p coordination bonds of Pt-N are strengthened. For flat and oblique adsorption modes of cisplatin, there is no significant difference in the density of states of the gold and magnesium oxide film, indicating the maintenance of the heterojunction structural framework. However, there are significant changes in the electronic states of cisplatin itself with different adsorption configurations. In the flat configuration, the band gap width of cisplatin is larger than that of the oblique configuration. The Cl-Pt bond range in the Pt(III) compound shows a clear charge reduction on the magnesia film, indicating the Cl-Pt bond is an active site with the potential for decomposition and hydrolysis. The substitution of chloride ions by water can lead to hydrolysis products, enhancing the polarization of the composite and showing strong charge separation. The hydrolysis of the free platinum compound is endothermic by 0.309 eV, exceeding the small activation energy barrier of 0.399 eV, indicating that hydrolysis of this platinum compound is easily achievable. ADME (absorption, distribution, metabolism, and excretion) prediction parameters indicate that hydrolysis products have good ESOL (Estimated SOLubility) solubility and high gastrointestinal absorption, consistent with Lipinski’s rule. During the coordination reaction process, there are significant changes in the distribution of frontier molecular orbitals, with the HOMO (highest occupied molecular orbital) of the initial state primarily located on the purine base, providing the possibility for electron transfer to the empty orbitals of the platinum compound in the LUMO (lowest unoccupied molecular orbital). The HOMO and HOMO-1 of the transition state and product are mainly distributed on the platinum compound, indicating clear electron transfer and orbital rearrangement. The activation energy barrier for the purine coordination reaction with the hydrolysis products is reduced to 0.61 eV, and the dipole moment gradually decreases to 6.77 Debye during the reaction, indicating a reduction in the system’s charge separation and polarization. This contribution is anticipated to provide a new theoretical clue for developing inorganic oxide carriers of platinum compounds. Full article

Tobacco BY-2 cell culture is one of the most widely used models in plant biology. The main advantage of BY-2 suspension cultures is the synchronization of cell development and the appearance of polar elongation. In batch culture, BY-2 cells passed through the lag, proliferation, elongation, and stationary phases. During this process, the composition of the growth medium changed dramatically. Sucrose was rapidly eliminated; hexose first accumulated and then depleted. The medium’s pH initially decreased and then rose with aging. As a result of the crosstalk between the internal and external stimuli, cells pass through complicated systemic rearrangements, which cause metabolomic alterations. The early stages were characterized by high levels of amino acids and sterols, which could be interpreted as the result of synthetic activity. The most intense rearrangements occurred between the proliferation and active elongation stages, including repression of amino acid accumulation and up-regulation of sugar metabolism. Later stages were distinguished by higher levels of secondary metabolites, which may be a non-specific response to deteriorating conditions. Senescence was followed by some increase in fatty acids and sterols as well as amino acids, and probably led to self-destructive processes. A correlation analysis revealed relationships between metabolites’ covariation, their biochemical ratio, and the growth phase. Full article