Identification of a Novel Indolizine RORγT Inverse Agonist Using the AI-Driven Drug Design Platform.

Automated multiparameter optimization (MPO) at the point of initial drug design is a powerful emerging approach to improve and expedite drug development. We employed the AI-driven drug design (AIDD) platform to design novel RORγT ligands optimized using QSAR activity models, machine learning ADMET properties, 3D pharmacophore similarity, and synthetic difficulty predictions. We calculated several measures of novelty postdesign and then employed multicriteria decision analysis (MCDA) to select compounds for synthesis for this important drug target.

IL-17B Inhibits Hepatocellular Carcinoma Cell Proliferation.

IL-17RB is a cytokine receptor that binds interleukin (IL)-17B and IL-17E. While analyzing IL-17RB expression in various cancer cell lines, we found that this receptor is highly expressed at both the mRNA and protein levels in hepatocellular carcinoma (HCC) cells. This finding prompted us to investigate the effects of its ligand, IL-17B, on the proliferation of these cells.

Staphylococcus aureus α-hemolysin induces DNA methylation changes in human Th1 cells.

α-Hemolysin is one of the most dangerous virulence factors produced by Staphylococcus aureus. Among the immune cells that respond to this pathogenic bacterium, Th1 lymphocytes play a critical role. In our study, we investigated the impact of α-hemolysin on the methylation of the Th1 cell genome.

The cyclin-dependent kinase inhibitor AT7519 is a human RORγt agonist.

AT7519, which inhibits multiple cyclin-dependent kinases, has been extensively investigated in various types of cancer cells. Previous studies have demonstrated the ability of this molecule to suppress the expression of the nuclear receptor retinoic acid-related orphan receptor gamma (RORγ) and several genes involved in hepatocellular carcinoma progression. In this study, we identified a distinct agonistic effect of AT7519 on RORγt, an isoform expressed by various immune cells, including T helper 17 lymphocytes.

QSPRmodeler - An open source application for molecular predictive analytics.

The drug design process can be successfully supported using a variety of methods. Some of these are oriented toward molecular property prediction, which is a key step in the early drug discovery stage. Before experimental validation, drug candidates are usually compared with known experimental data.

Epigenetic regulation of the human gene.

Mutations in the ganglioside-induced differentiation-associated protein 1 () gene are linked to Charcot-Marie-Tooth (CMT) disease, a hereditary neurodegenerative condition. The protein encoded by this gene is involved in mitochondrial fission and calcium homeostasis. Recently, GDAP1 has also been implicated in the survival of patients with certain cancers.

α-Hemolysin from Staphylococcus aureus Changes the Epigenetic Landscape of Th17 Cells.

The human body harbors a substantial population of bacteria, which may outnumber host cells. Thus, there are multiple interactions between both cell types. Given the common presence of Staphylococcus aureus in the human body and the role of Th17 cells in controlling this pathogen on mucous membranes, we sought to investigate the effect of α-hemolysin, which is produced by this bacterium, on differentiating Th17 cells.

Evaluation of the activity of cardiac glycosides on RORγ and RORγT nuclear receptors.

Cardiac glycosides, derived from plants and animals, have been recognized since ancient times. These substances hinder the function of the sodium-potassium pump within eukaryotic cells. Many reports have shown that these compounds influence the activity of nuclear receptors.

RORγT agonists as immune modulators in anticancer therapy.

RORγT is a transcription factor that directs the development of Th17 lymphocytes and other IL-17-expressing cells (e.g., Tc17 and ILC3 cells).

Anti-hepatocellular carcinoma activity of the cyclin-dependent kinase inhibitor AT7519.

Hepatocellular carcinoma (HCC) is one of the most common cancerous tumors and one of the leading causes of death among cancer-related disorders. Chemotherapy is ineffective in HCC patients, and the number of drugs that are in use is limited. Thus, new molecules are needed that could increase the effectiveness of anti-HCC regimens.

Targeting EGFR in melanoma - The sea of possibilities to overcome drug resistance.

Melanoma is considered one of the most aggressive skin cancers. It spreads and metastasizes quickly and is intrinsically resistant to most conventional chemotherapeutics, thereby presenting a challenge to researchers and clinicians searching for effective therapeutic strategies to treat patients with melanoma. The use of inhibitors of mutated serine/threonine-protein kinase B-RAF (BRAF), e.

Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human RORγT Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity.

RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the expression of numerous Th17-specific cytokines, such as IL-17. Because Th17 cells are implicated in the pathology of autoimmune diseases (e.

Cyanobacterial cell-wall components as emerging environmental toxicants - detection and holistic monitoring by cellular signaling biosensors.

Cyanobacterial blooms constitute a recognized danger to aquatic environment and public health not only due to presence of main group of cyanotoxins, such as microcystins, cylindrospermopsin or anatoxin-a, but also other emerging bioactivities. An innovative approach identifying such bioactivities is the application of cellular biosensors based on reporter genes which detect the impact of cyanobacterial cells and components on actual human cells in a physiological-like setting. In the present study biosensor cell lines detecting four different types of bioactivities (ARE - oxidative stress, NFKBRE - immunomodulatory pathogen-associated molecular patterns, AHRE - persistent organic pollutants, GRE - endocrine disruptors) were exposed to concentrated cyanobacterial cells from 21 environmental bloom samples and from eight cultures (Microcystis aeruginosa, Aphanizomenon flos-aquae, Planktothrix agardhii and Raphidiopsis raciborskii).

Phenolics-Rich Extracts of Dietary Plants as Regulators of Fructose Uptake in Caco-2 Cells via GLUT5 Involvement.

The latest data link the chronic consumption of large amounts of fructose present in food with the generation of hypertension and disturbances in carbohydrate and lipid metabolism, which promote the development of obesity, non-alcoholic fatty liver disease, insulin resistance, and type 2 diabetes. This effect is possible after fructose is absorbed by the small intestine cells and, to a lesser extent, by hepatocytes. Fructose transport is dependent on proteins from the family of glucose transporters (GLUTs), among which GLUT5 selectively absorbs fructose from the intestine.

Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism.

Melanoma cells are resistant to most anticancer chemotherapeutics. Despite poor response rates and short-term efficacy, chemotherapy remains the main approach to treating this cancer. The underlying mechanisms of the intrinsic chemoresistance of melanoma remain unclear, but elucidating these mechanisms is important to improve the efficacy of chemotherapy regimens.

Recombinant immunotoxin targeting GPC3 is cytotoxic to H446 small cell lung cancer cells.

Glypican-3 (GPC3) is a cell membrane glycoprotein that regulates cell growth and proliferation. Aberrant expression or distribution of GPC3 underlies developmental abnormalities and the development of solid tumours. The strongest evidence for the participation of GPC3 in carcinogenesis stems from studies on hepatocellular carcinoma and lung squamous cell carcinoma.

Nucleocapsid and Spike Proteins of the Coronavirus SARS-CoV-2 Induce in Monocytes and Macrophages-Potential Implications for Cytokine Storm Syndrome.

The pandemic of the new coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to the deaths of more than 1.5 million people worldwide. SARS-CoV-2 causes COVID-19, which exhibits wide variation in the course of disease in different people, ranging from asymptomatic and mild courses to very severe courses that can result in respiratory failure and death.

SARS-CoV-2 Proteins Induce in Th1 Lymphocytes Generated from CD4+ Cells from Healthy, Unexposed Polish Donors.

The outbreak of the SARS-CoV-2 virus in December 2019 has caused the deaths of several hundred thousand people worldwide. Currently, the pathogenesis of COVID-19 is poorly understood. During the course of COVID-19 infection, many patients experience deterioration, which might be associated with systemic inflammation and cytokine storm syndrome; however, other patients have mild symptoms or are asymptomatic.

Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells.

The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311.

Identification of Novel Molecular Markers of Human Th17 Cells.

Th17 cells are important players in host defense against pathogens such as , , and . Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of certain autoimmune disorders, e.g.