Diverse Biological Models Research Articles

Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C-2028 and C-2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass-to-charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C-2028 was gradually accumulated, while C-2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM-MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models.

Learning chemical sensitivity reveals mechanisms of cellular response

Chemical probes interrogate disease mechanisms at the molecular level by linking genetic changes to observable traits. However, comprehensive chemical screens in diverse biological models are impractical. To address this challenge, we develop ChemProbe, a model that predicts cellular sensitivity to hundreds of molecular probes and drugs by learning to combine transcriptomes and chemical structures. Using ChemProbe, we infer the chemical sensitivity of cancer cell lines and tumor samples and analyze how the model makes predictions. We retrospectively evaluate drug response predictions for precision breast cancer treatment and prospectively validate chemical sensitivity predictions in new cellular models, including a genetically modified cell line. Our model interpretation analysis identifies transcriptome features reflecting compound targets and protein network modules, identifying genes that drive ferroptosis. ChemProbe is an interpretable in silico screening tool that allows researchers to measure cellular response to diverse compounds, facilitating research into molecular mechanisms of chemical sensitivity.

Pyridine-based small molecule inhibitors of SARM1 alleviate cell death caused by NADase activity.

Our investigation has unveiled a series of pyridine-based SARM1 inhibitors, with the lead compound TH-408 exhibiting remarkable potency, achieving an IC50 value of 0.46 μM. This exceptional inhibitory effect significantly curtailed SARM1-mediated cell death across diverse biological models. This finding highlights the promising therapeutic potential for neurodegenerative disorders by disrupting SARM1 activation and advances our understanding of molecular interventions in these complex disorders, including the regulation of NAD+ metabolism.

Cocktail effects of tire wear particles leachates on diverse biological models: A multilevel analysis

Tire wear particles (TWP) stand out as a major contributor to microplastic pollution, yet their environmental impact remains inadequately understood. This study delves into the cocktail effects of TWP leachates, employing molecular, cellular, and organismal assessments on diverse biological models. Extracted in artificial seawater and analyzed for metals and organic compounds, TWP leachates revealed the presence of polyaromatic hydrocarbons and 4-tert-octylphenol. Exposure to TWP leachates (1.5 to 1000 mg peq L−1) inhibited algae growth and induced zebrafish embryotoxicity, pigment alterations, and behavioral changes. Cell painting uncovered pro-apoptotic changes, while mechanism-specific gene-reporter assays highlighted endocrine-disrupting potential, particularly antiandrogenic effects. Although heavy metals like zinc have been suggested as major players in TWP leachate toxicity, this study emphasizes water-leachable organic compounds as the primary causative agents of observed acute toxicity. The findings underscore the need to reduce TWP pollution in aquatic systems and enhance regulations governing highly toxic tire additives.

Cytoophidia: a conserved yet promising mode of enzyme regulation in nucleotide metabolism.

Nucleotide biosynthesis encompasses both de novo and salvage synthesis pathways, each characterized by significant material and procedural distinctions. Despite these differences, cells with elevated nucleotide demands exhibit a preference for the more intricate de novo synthesis pathway, intricately linked to modes of enzyme regulation. In this study, we primarily scrutinize the biological importance of a conserved yet promising mode of enzyme regulation in nucleotide metabolism-cytoophidia. Cytoophidia, comprising cytidine triphosphate synthase or inosine monophosphate dehydrogenase, is explored across diverse biological models, including yeasts, Drosophila, mice, and human cancer cell lines. Additionally, we delineate potential biomedical applications of cytoophidia. As our understanding of cytoophidia deepens, the roles of enzyme compartmentalization and polymerization in various biochemical processes will unveil, promising profound impacts on both research and the treatment of metabolism-related diseases.

Inter-species Transplantation of Blastocysts between Medaka and Zebrafish.

Transplantation of blastocysts from a donor to a host blastula constitutes a powerful experimental tool to tackle major developmental biology questions. The technique is widely implemented in diverse biological models including teleost fish, where it is typically used for intra-species blastula transplantations - i.e., labeled blastocysts into a non-labeled host to follow lineages, or mutant blastocysts into a wild-type host to address autonomous vs. non-autonomous roles of a gene of interest. We have recently implemented a protocol to transplant blastocysts between zebrafish (D. rerio) and medaka (O. latipes), two species in which blastocysts show different developmental dynamics and sizes ( Fuhrmann et al., 2020 ). We present here a detailed protocol on how to overcome the early differences in chorion structure, blastula size, and speed of development to achieve trans-species blastocyst transplantation.

Cell refractive index: Models, insights, applications and future perspectives.

Cell refractive index (RI) is an intrinsic optical parameter that governs the propagation of light (i.e., scattering and absorption) in the cell matrix. The RI of cell is sensitively correlated with its mass distribution and thereby has the capability to provide important insights for diverse biological models. Herein, we review the cell refractive index and the fundamental models for measurement of cell RI, summarize the published RI data of cell and cell organelles and discuss the associated insights. Illustrative applications of cell RI in cell biology are also outlined. Finally, future research trends and applications of cell RI, including novel imaging techniques, reshaping flow cytometry and microfluidic platforms for single cell manipulation are discussed. The rapid technological advances in optical imaging integrated with microfluidic regime seems to enable deeper understanding of subcellular dynamics with high spatio-temporal resolution in real time.

A Novel Systems-Biology Algorithm for the Analysis of Coordinated Protein Responses Using Quantitative Proteomics

The coordinated behavior of proteins is central to systems biology. However, the underlying mechanisms are poorly known and methods to analyze coordination by conventional quantitative proteomics are still lacking. We present the Systems Biology Triangle (SBT), a new algorithm that allows the study of protein coordination by pairwise quantitative proteomics. The Systems Biology Triangle detected statistically significant coordination in diverse biological models of very different nature and subjected to different kinds of perturbations. The Systems Biology Triangle also revealed with unprecedented molecular detail an array of coordinated, early protein responses in vascular smooth muscle cells treated at different times with angiotensin-II. These responses included activation of protein synthesis, folding, turnover, and muscle contraction - consistent with a differentiated phenotype-as well as the induction of migration and the repression of cell proliferation and secretion. Remarkably, the majority of the altered functional categories were protein complexes, interaction networks, or metabolic pathways. These changes could not be detected by other algorithms widely used by the proteomics community, and the vast majority of proteins involved have not been described before to be regulated by AngII. The unique capabilities of The Systems Biology Triangle to detect functional protein alterations produced by the coordinated action of proteins in pairwise quantitative proteomics experiments make this algorithm an attractive choice for the biological interpretation of results on a routine basis.

Biomineralix (COST Action TD0903), 2009-2014: An Overview

Biomineralization is the process by which living systems produce minerals. At theEuropean scale, this particular scientific field associates researchers of diverse horizons,ranging from zoology, mineralogy, palaeontology, and environmental sciences to materialssciences, dentistry and bone surgery. In this context, the COST Action TD0903, also referredas Biomineralix, was set up in November 2009 under the auspices of the COST Office inBrussels. This scientific network was active during four and half years, until May 2014. Itassociated 17 European countries, and a total of 29 laboratories. Its main objectives weremultiple: 1. To promote biochemical and proteomic research on the biomineralisationprocesses of diverse biological models, ranging from microorganisms to metazoans, such asmolluscs or sea urchins. 2. To characterize biominerals owing to the most advancedbiochemical and biophysical techniques. 3. To use natural biominerals as sentinels to recordenvironmental parameters and pollutions in terrestrial, riverine or marine ecosystems. 4. Totake lessons from natural systems to generate novel biomimetic or bioinspired materials,according to soft chemical processes. These research trends organized the action in fourworking groups. The present paper evaluates four and half years of functioning of thenetwork. It reviews some of the major results, in particular those acquired in the frame ofShort-Term Scientific Missions (STSMs), and lists the corresponding scientific papers.

Competing endogenous RNA networks: tying the essential knots for cancer biology and therapeutics.

A recently discovered dimension of post-transcriptional gene regulation involves co-regulatory crosstalk between RNA transcripts, which compete for common pools of microRNA (miRNA) molecules. These competing endogenous RNAs (ceRNAs), or natural miRNA sponges, have an active role in regulating miRNA availability within the cell and form intertwined regulatory networks. Recent reports have implicated diverse RNA species including protein-coding messenger RNAs and non-coding RNAs as ceRNAs in human development and diseases including human cancer. In this review, we discuss the most recent discoveries that implicate natural miRNA decoys in human cancer biology, as well as exciting advances in the study of ceRNA networks and dynamics. The structure and topology of intricate genome-scale ceRNA networks can be predicted computationally, and their dynamic response to fluctuations in ceRNA and miRNA levels can be studied via mathematical modeling. Additionally, the development of new methods to quantitatively determine absolute expression levels of miRNA and ceRNA molecules have expanded the capacity to accurately study the efficiency of ceRNA crosstalk in diverse biological models. These major milestones are of critical importance to identify key components of ceRNA regulatory networks that could aid the development of new approaches to cancer diagnostics and oligonucleotide-based therapeutics.

Quantifying Learning Creativity through Simulation and Modeling of Swarm Intelligence and Neural Networks

This research work presents a systematic investigational study of a challenging phenomenon observed in natural world. Mainly, the study is concerned with conceptual interdisciplinary analysis and evaluation of quantified learning creativity phenomenon. In association, it deals with diverse aspects of measurable behavioral learning performance and is observed by two diverse natural biological system models (i.e. human and non-human creatures). Specifically, the studies of two biological models consider the comparison of quantified learning creativity phenomenon. The first model involves the human interactive tutoring/learning processes with environment while the other modal presents the ecological behavioral learning of swarm intelligence agents (i.e. ants) in performing the foraging process. Furthermore, a comparative study is presented which is inspired by naturally realistic models of Artificial Neural Network (ANN) and Swarm Intelligence. The obtained simulation and modeling results shows that the learning performance curves of both models behave with close similarity to each other. Precisely, the analysis and evaluation of learning performance curves of two diverse biological models revealed that both obey exponentially decayed learning curves; following least mean square (LMS) error algorithm.

Glutamate Uptake Triggers Transporter-Mediated GABA Release from Astrocytes

BackgroundGlutamate (Glu) and γ-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes.Methodology/Principal FindingsHere we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca2+ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process.Conclusions/SignificanceOur results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia.

Action of plant proteinase inhibitors on enzymes of physiopathological importance

Obtained from leguminous seeds, various plant proteins inhibit animal proteinases, including human, and can be considered for the development of compounds with biological activity. Inhibitors from the Bowman-Birk and plant Kunitz-type family have been characterized by proteinase specificity, primary structure and reactive site. Our group mostly studies the genus Bauhinia, mainly the species bauhinioides, rufa, ungulata and variegata. In some species, more than one inhibitor was characterized, exhibiting different properties. Although proteins from this group share high structural similarity, they present differences in proteinase inhibition, explored in studies using diverse biological models.