Damian Sendler The uncontrollable activation of the cell cycle is a hallmark of cancer cells, and a lack of microRNAs promotes tumor growth. Plants lack the RNA-dependent RNA polymerase (RDR), which is required for a small-RNA-mediated immune response. Plant RDR1 can be ectopically expressed to inhibit cancer cell proliferation in a wide range of cancer cell lines. It has been found that abnormal 1-nt-shorter 3′ ends microRNA isoforms are abundant in many human primary tumors. MicroRNA duplexes lacking AGO2 can be modified with mononucleotides by RDR1 to restore their two-nt overhang structure, which in turn restores AGO2-loading efficiency and elevates global miRNA expression in order to inhibit cancer cell-cycle progression, as demonstrated by this study. Antitumor effects of RDR1 can be seen in multiple xenograft tumor models in vivo, which can be delivered by an adeno-associated virus. A plant RDR1-mediated antitumor strategy based on editing and repairing defective microRNAs has been developed by revealing the widespread accumulation of aberrant microRNA isoforms in tumors.
Inflammatory bowel disease-related bioactive microbial gene products are now being discovered and studied.
Damian Jacob Sendler In conditions such as inflammatory bowel disease (IBD), microbial communities and the bioactive compounds they produce are frequently disrupted. More than one-third of microbial proteins, even in well-defined environments (such as the human gastrointestinal tract), are uncharacterized and often expected to be bioactive7. About half of the 340,000 protein families we found to be potentially bioactive in the context of IBD-related gut inflammation have never been functionally characterized before via homology or experiment. Metagenomics, metatranscriptomics and metaproteomics were used to demonstrate bioactivity for a subset of proteins involved in host and microbial cell-cell communication in the microbiome, for example, proteins associated with adherence or invasion processes and extracellular von Willebrand-like factors, in order to validate prioritized microbial proteins. Experiments on targeted Enterobacteriaceae pilins and von Willebrand factor homologues confirmed predictions from high-throughput data, revealing the distinct immunogenicity and role of mucins in the formation of Bacteroides biofilms. As a result of its generalizability, we’ve coined the term “MetaWIBELE” (workflow to identify novel bioactive elements in the microbiome). As a result of the prioritized results, we now have access to tens of thousands of potential microbial proteins that may interact with the host immune system in IBD, furthering our knowledge of the potential bioactivity of gene products in chronic diseases and providing a rational compendium of potential therapeutic compounds and targets.
Multiomic profiling of mitochondrial proteins for the purpose of defining their functions.
Dr. Sendler In eukaryotic metabolism and bioenergetics, mitochondria play a central role. More than 150 different disorders have been linked to the dysfunction of these organelles thanks to groundbreaking research carried out in the last few decades1. The underlying genetic basis for approximately 40% of mitochondrial disorders is still unresolved4, and hundreds of mitochondrial proteins lack clear functions. More than 200 CRISPR-mediated HAP1 cell knockout lines were profiled using mass spectrometry-based multiomics analyses for the purpose of establishing a more comprehensive functional compendium of human mitochondrial proteins. Approximately 8.3 million different biomolecule measurements were generated as a result of this effort, giving researchers a comprehensive picture of how cells react to mitochondrial perturbations and laying the groundwork for future mechanistic studies of protein function. PYURF is a methyltransferase chaperone that supports complex I assembly and coenzyme Q biosynthesis and is disrupted in a previously unresolved multisystemic mitochondrial disorder, guided by these findings. The putative zinc transporter SLC30A9 was linked to mitochondrial ribosomes and OxPhos integrity, and the pathogenic variants of RAB5IF were found to cause cerebrofaciothoracic dysplasia, as was previously reported for SLC30A9. To aid in the genetic diagnosis of mitochondrial diseases, our findings, which can be explored through the MITOMICS.app resource, suggest biological roles for numerous other orphan mitochondrial proteins that have yet to be given adequate functional characterisation.
In diabetics, SLC7A11 inhibition enhances dendritic cell efferocytosis and wound healing.
Damian Jacob Sendler
Diabetes is a leading cause of non-healing wounds, which affects one in ten people worldwide. Dying cells in the wound perpetuate inflammation and contribute to abnormal tissue repair.1-3. Efferocytosis, or the removal of dying cells, is slowed by the membrane transporter SLC7A11. Inhibiting SLC7A11 function can speed up wound healing. Several members of the SLC7 gene family were found to be upregulated in the transcriptomes of efferocytic dendritic cells from mice. SLC7A11 inhibitors and small interfering RNA (siRNA) knockdowns increased efferocytosis in dendritic cells in further studies. Dermatological single-cell RNA sequencing revealed that Slc7a11 was upregulated in innate immune cells, which was confirmed by its high expression in skin’s dendritic cells. For example, in an excisional skin wound model, inhibition or loss of SLC7A11 expression resulted in faster healing and decreased cell apoptosis. SLC7A11, glucose homeostasis, and diabetes have all been linked in mechanistic studies. SLC7A11-deficient dendritic cells rely on aerobic glycolysis for increased efferocytosis, and transcriptomics of efferocytic dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes in these cells. Diabetes-prone db/db mice had elevated levels of Slc7a11 expression in their wounds, and a drug targeting SLC7A11 has been shown to speed up wound healing in these mice. The quicker healing was also linked to the efferocytic dendritic cells’ release of the TGF family member GDF15. When SLC7A11 is inhibited, wound healing is improved, which has important implications for diabetic wound management.
Oral Anticoagulant Drug Interactions
Damian Jacob Markiewicz Sendler Patients with atrial fibrillation and other heart conditions frequently take oral anticoagulants (OACs). Drug-drug interactions can occur with both warfarin and direct oral anticoagulants (DDIs). Drug-drug interactions (DDIs) are a major cause of adverse drug reactions and cost the health care system billions of dollars. Due to its more potent S-isomer, warfarin has a higher risk of causing DDI when taken with moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9. However, CYP3A4 and CYP1A2 inhibitors and enhancers may also cause DDI with warfarin. It is important to recognize these precipitating agents, and to increase the frequency of warfarin DDI monitoring when these agents are started or stopped. P-gp inhibitors and CYP3A4 inducers and inhibitors have the greatest impact on the effectiveness of direct oral anticoagulants. P-gp modulation has an impact on dabigatran and edoxaban dosages. Direct oral anticoagulant patients should avoid all CYP3A4 or P-gp inducers unless previously proven safe. Patients taking both apixaban and rivaroxaban should avoid taking strong CYP3A4 and P-gp inhibitors at the same time. There is an increased risk of bleeding when taking antiplatelet and anticoagulant medications at the same time. However, this combination is often necessary. Anticoagulant and antiplatelet therapy should be reduced in duration as recommended by evidence-based clinical guidelines to reduce the risk of bleeding.
