Identification of Core Genes and Pathways in Melanoma Metastasis via Bioinformatics Analysis

Metastasis is the leading cause of melanoma-related mortality. Current therapies are rarely curative for metastatic melanoma, revealing the urgent need to identify more effective preventive and therapeutic targets. This study aimed to screen the core genes and molecular mechanisms related to melanoma metastasis. A gene expression profile, GSE8401, including 31 primary melanoma and 52 metastatic melanoma clinical samples, was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between melanoma metastases and primary melanoma were screened using GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses of DEGs were performed using the Database for Annotation Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape with Molecular Complex Detection (MCODE) plug-in tools were utilized to detect the protein–protein interaction (PPI) network among DEGs. The top 10 genes with the highest degrees of the PPI network were defined as hub genes. In the results, 425 DEGs, including 60 upregulated genes and 365 downregulated genes, were identified. The upregulated genes were enriched in ECM–receptor interactions and the regulation of actin cytoskeleton, while 365 downregulated genes were enriched in amoebiasis, melanogenesis, and ECM–receptor interactions. The defined hub genes included CDK1, COL17A1, EGFR, DSG1, KRT14, FLG, CDH1, DSP, IVL, and KRT5. In addition, the mRNA and protein levels of the hub genes during melanoma metastasis were verified in the TCGA database and paired post- and premetastatic melanoma cells, respectively. Finally, KRT5-specific siRNAs were utilized to reduce the KRT5 expression in melanoma A375 cells. An MTT assay and a colony formation assay showed that KRT5 knockdown significantly promoted the proliferation of A375 cells. A Transwell assay further suggested that KRT5 knockdown significantly increased the cell migration and cell invasion of A375 cells. This bioinformatics study provided a deeper understanding of the molecular mechanisms of melanoma metastasis. The in vitro experiments showed that KRT5 played the inhibitory effects on melanoma metastasis. Therefore, KRT5 may serve important roles in melanoma metastasis.

InterCellar enables interactive analysis and exploration of cell−cell communication in single-cell transcriptomic data

Deciphering cell−cell communication is a key step in understanding the physiology and pathology of multicellular systems. Recent advances in single-cell transcriptomics have contributed to unraveling the cellular composition of tissues and enabled the development of computational algorithms to predict cellular communication mediated by ligand−receptor interactions. Despite the existence of various tools capable of inferring cell−cell interactions from single-cell RNA sequencing data, the analysis and interpretation of the biological signals often require deep computational expertize. Here we present InterCellar, an interactive platform empowering lab-scientists to analyze and explore predicted cell−cell communication without requiring programming skills. InterCellar guides the biological interpretation through customized analysis steps, multiple visualization options, and the possibility to link biological pathways to ligand−receptor interactions. Alongside convenient data exploration features, InterCellar implements data-driven analyses including the possibility to compare cell−cell communication from multiple conditions. By analyzing COVID-19 and melanoma cell−cell interactions, we show that InterCellar resolves data-driven patterns of communication and highlights molecular signals through the integration of biological functions and pathways. We believe our user-friendly, interactive platform will help streamline the analysis of cell−cell communication and facilitate hypothesis generation in diverse biological systems.

Theoretical Study of the Structural Stability, Chemical Reactivity, and Protein Interaction for NMP Compounds as Modulators of the Endocannabinoid System

The cannabinoid receptors (CB1/CB2) and the T-type calcium channels are involved in disorders associated with both physiological pain and depressive behaviors. Valuable pharmacological species carbazole derivatives such as the NMP-4, NMP-7, and NMP-181 (Neuro Molecular Production) regulate both biological entities. In this work, DFT calculations were performed to characterize theoretically their structural and chemical reactivity properties using the BP86/cc-pVTZ level of theory. The molecular orbital contributions and the chemical reactivity analysis reveal that a major participation of the carbazole group is in the donor-acceptor interactions of the NMP compounds. The DFT analysis on the NMP compounds provides insights into the relevant functional groups involved during the ligand-receptor interactions. Molecular docking analysis is used to reveal possible sites of interaction of the NMP compounds with the Cav3.2 calcium channel. The interaction energy values and reported experimental evidence indicate that the site denominated as “Pore-blocking”, which is formed mainly by hydrophobic residues and the T586 residue, is a probable binding site for the NMP compounds.

Transcriptomic Analysis of Breast Cancer Patients Sensitive and Resistant to Chemotherapy: Looking for Overall Survival and Drug Resistance Biomarkers

Worldwide breast cancer ranks first in mortality and incidence rates in women over 20 years old. Rather than one disease, breast cancer is a heterogeneous group of diseases that express distinct molecular profiles. Neoadjuvant chemotherapy is an important therapeutic strategy for breast cancer patients independently of their molecular subtype, with the drawback of resistance development. In addition, chemotherapy has adverse effects that combined with resistance could contribute to lower overall survival. Although great efforts have been made to find diagnostic and prognostic biomarkers for breast cancer and for response to targeted and immune therapy for this pathology, little has been explored regarding biomarkers of response to anthracyclines and taxanes based neoadjuvant chemotherapy. This work aimed to evaluate the molecular profile of patients who received neoadjuvant chemotherapy to identify differentially expressed genes (DEGs) that could be used as biomarkers of chemotherapy response and overall survival. Breast cancer patients who were candidates for neoadjuvant chemotherapy were enrolled in this study. After treatment and according to their pathological response, they were assigned as sensitive or resistant. To evaluate DEGs, Gene Ontology, Kyoto Encyclopedia Gene and Genome (KEGG), and protein–protein interactions, RNA-seq information from all patients was obtained by next-generation sequencing. A total of 1985 DEGs were found, and KEGG analysis indicated a great number of DEGs in metabolic pathways, pathways in cancer, cytokine–cytokine receptor interactions, and neuroactive ligand-receptor interactions. A selection of 73 DEGs was used further for an analysis of overall survival using the METABRIC study and the ductal carcinoma dataset of The Cancer Genome Atlas (TCGA) database. Nine DEGs correlated with overall survival, of which the subexpression of C1QTNF3, CTF1, OLFML3, PLA2R1, PODN, KRT15, HLA-A, and the overexpression of TUBB and TCP1 were found in resistant patients and related to patients with lower overall survival.

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents

Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers—thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines—and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure–activity relationship (SAR) and classify their synthetic pathways. This review explains the main access route to synthesize thienopyrimidines from thiophene derivatives or from pyrimidine analogs. In addition, SAR study and promising anti-infective activity of these scaffolds are summarized in figures and explanatory diagrams. Ligand–receptor interactions were modeled when the biological target was identified and the crystal structure was solved.

A quantitative view of strategies to engineer cell-selective ligand binding

A critical property of many therapies is their selective binding to target populations. Exceptional specificity can arise from high-affinity binding to surface targets expressed exclusively on target cell types. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells. More complex binding strategies have been developed to overcome this limitation, including multi-specific and multivalent molecules, creating a combinatorial explosion of design possibilities. Guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we employ a uniquely general multivalent binding model to dissect multi-ligand and multi-receptor interactions. This model allows us to analyze and explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, valency changes, multi-specific molecules and ligand competition. Each of these strategies can optimize selectivity in distinct cases, leading to enhanced selectivity when employed together. The proposed model, therefore, provides a comprehensive toolkit for the model-driven design of selectively binding therapies.

Boesenbergia pandurata as Anti-breast Cancer: Molecular Docking and ADMET Study

Background: Boesenbergia pandurata or fingerroot is known to have various pharmacological activities, including anticancer. Extracts from these plants are known to inhibit the growth of cancer cells, including breast cancer. Anti-breast cancer activity is significantly influenced by the inhibition of two receptors: ER-α and HER2. However, it is unknown which metabolites of B. pandurata play the most crucial role in their anticancer activity Objective: This study aimed to determine the metabolites of B. pandurata with the best potential as ER-α and HER2 inhibitors. Method: The method used was molecular docking of several B. pandurata metabolites to ER-α and HER2 receptors, followed by an ADMET study of several metabolites with the best docking results. Results: The docking results showed eight metabolites with the best docking results for the two receptors based on the docking score and ligand-receptor interactions. Of these eight compounds, compounds 11 ((2S)-7,8-dihydro-5-hydroxy-2-methyl-2-(4''-methyl-3''-pentenyl)-8-phenyl-2H,6H-benzo(1,2-b-5,4-b')dipyran-6-one) and 34 (geranyl-2,4-dihydroxy-6-phenethylbenzoate) showed the potential to inhibit both receptors. Both ADMET profiles also show mixed results but still allow for further development Conclusion: In conclusion, the metabolites of B. pandurata, especially compounds 11 and 34, can be developed as anti-breast cancer through the inhibition of ER-α and HER2.

Integrated multiple transcriptomes in oviductal tissue across the porcine oestrous cycle reveal functional roles in oocyte maturation and transport

Understanding the changes in the swine female reproductive system is important for solving issues related to reproductive failure and litter size. Elucidating the regulatory mechanisms of the natural oestrous cycle in the oviduct under non-fertilisation conditions can improve our understanding of its role in the reproductive system. Herein, whole transcriptome RNA sequencing of oviduct tissue samples was performed. The differentially expressed genes (DEGs) were identified for each time point relative to Day 0 and classified into three clusters based on their expression patterns. Clusters 1 and 2 included genes involved in the physiological changes through the oestrous cycle. Cluster 1 genes were mainly involved in PI3K-Akt signalling and steroid hormone biosynthesis pathways. Cluster 2 genes were involved in extracellular matrix-receptor interactions and protein digestion pathways. In Cluster 3, the DEGs were downregulated in the luteal phase; they were strongly associated with cell cycle, calcium signalling, and oocyte meiosis. The gene expression in the oviduct during the oestrous cycle influenced oocyte transport and fertilisation. Our findings provide a basis for successfully breeding pigs and elucidating the mechanisms underlying the changes in the pig oviduct during the oestrous cycle.

Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs

Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.