Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.

Protein arginine -methyltransferases (PRMT) are a family of -adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers.

Extracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity.

Attenuation of adipose hormone sensitive lipase (HSL) may impair lipolysis and exacerbate obesity. We investigate the role of cytokine, macrophage migration inhibitory factor (MIF) in regulating adipose HSL and adipocyte hypertrophy. Extracellular MIF downregulates HSL in an autocrine fashion, by activating the AMPK/JNK signaling pathway upon binding to its membrane receptor, CD74.

Protein arginine N-methyltransferase 2 plays a noncatalytic role in the histone methylation activity of PRMT1.

Protein arginine N-methyltransferases are a family of epigenetic enzymes responsible for monomethylation or dimethylation of arginine residues on histones. Dysregulation of protein arginine N-methyltransferase activity can lead to aberrant gene expression and cancer. Recent studies have shown that PRMT2 expression and histone H3 methylation at arginine 8 are correlated with disease severity in glioblastoma multiforme, hepatocellular carcinoma, and renal cell carcinoma.

Bioinformatics driven discovery of small molecule compounds that modulate the FOXM1 and PPARA pathway activities in breast cancer.

Our previous studies demonstrated that the FOXM1 pathway is upregulated and the PPARA pathway downregulated in breast cancer (BC), and especially in the triple negative breast cancer (TNBC) subtype. Targeting the two pathways may offer potential therapeutic strategies to treat BC, especially TNBC which has the fewest effective therapies available among all BC subtypes. In this study we identified small molecule compounds that could modulate the PPARA and FOXM1 pathways in BC using two methods.

Bioinformatic Analyses of Broad H3K79me2 Domains in Different Leukemia Cell Line Data Sets.

A subset of expressed genes is associated with a broad H3K4me3 (histone H3 trimethylated at lysine 4) domain that extends throughout the gene body. Genes marked in this way in normal cells are involved in cell-identity and tumor-suppressor activities, whereas in cancer cells, genes driving the cancer phenotype (oncogenes) have this feature. Other histone modifications associated with expressed genes that display a broad domain have been less studied.

Predicting breast cancer drug response using a multiple-layer cell line drug response network model.

Background: Predicting patient drug response based on a patient's molecular profile is one of the key goals of precision medicine in breast cancer (BC). Multiple drug response prediction models have been developed to address this problem. However, most of them were developed to make sensitivity predictions for multiple single drugs within cell lines from various cancer types instead of a single cancer type, do not take into account drug properties, and have not been validated in cancer patient-derived data.

The treatment of SARS-CoV2 with antivirals and mitigation of the cytokine storm syndrome: the role of gene expression.

In the absence of a vaccine, the treatment of SARS-CoV2 has focused on eliminating the virus with antivirals or mitigating the cytokine storm syndrome (CSS) that leads to the most common cause of death: respiratory failure. Herein we discuss the mechanisms of antiviral treatments for SARS-CoV2 and treatment strategies for the CSS. Antivirals that have shown in vitro activity against SARS-CoV2, or the closely related SARS-CoV1 and MERS-CoV, are compared on the enzymatic level and by potency in cells.

SARS-CoV-2 multifaceted interaction with the human host. Part II: Innate immunity response, immunopathology, and epigenetics.

The SARS-CoV-2 makes its way into the cell via the ACE2 receptor and the proteolytic action of TMPRSS2. In response to the SARS-CoV-2 infection, the innate immune response is the first line of defense, triggering multiple signaling pathways to produce interferons, pro-inflammatory cytokines and chemokines, and initiating the adaptive immune response against the virus. Unsurprisingly, the virus has developed strategies to evade detection, which can result in delayed, excessive activation of the innate immune system.

SARS-CoV-2 multifaceted interaction with human host. Part I: What we have learnt and done so far, and the still unknown realities.

SARS-CoV-2, the causing agent of the ongoing COVID-19 pandemic, is a beta-coronavirus which has 80% genetic homology with SARS-CoV, but displays increased virulence and transmissibility. Initially, SARS-CoV-2 was considered a respiratory virus generally causing a mild disease, only severe and fatal in the elderly and individuals with underlying conditions. Severe illnesses and fatalities were attributed to a cytokine storm, an excessive response from the host immune system.

Deep graph embedding for prioritizing synergistic anticancer drug combinations.

Drug combinations are frequently used for the treatment of cancer patients in order to increase efficacy, decrease adverse side effects, or overcome drug resistance. Given the enormous number of drug combinations, it is cost- and time-consuming to screen all possible drug pairs experimentally. Currently, it has not been fully explored to integrate multiple networks to predict synergistic drug combinations using recently developed deep learning technologies.

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors.

The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model.

Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer.

Different breast cancer (BC) subtypes have unique gene expression patterns, but their regulatory mechanisms have yet to be fully elucidated. We hypothesized that the top upregulated (Yin) and downregulated (Yang) genes determine the fate of cancer cells. To reveal the regulatory determinants of these Yin and Yang genes in different BC subtypes, we developed a lasso regression model integrating DNA methylation (DM), copy number variation (CNV) and microRNA (miRNA) expression of 391 BC patients, coupled with miRNA-target interactions and transcription factor (TF) binding sites.

The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant.

Purpose: Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3±1.

Antimicrobial Prophylaxis for Patients Undergoing Cardiac Surgery: Intraoperative Cefazolin Concentrations and Sternal Wound Infections.

This study characterizes the pharmacodynamics of antimicrobial prophylaxis and sternal wound infections following cardiac surgery. Duration of surgery and cefazolin plasma concentration during wound closure were independently associated with surgical site infection at 30 days. Furthermore, a duration of surgery of >346 min and a total cefazolin closure concentration of <104 mg/liter were significant thresholds for an increased risk of infection.

Selective DOT1L, LSD1, and HDAC Class I Inhibitors Reduce HOXA9 Expression in MLL-AF9 Rearranged Leukemia Cells, But Dysregulate the Expression of Many Histone-Modifying Enzymes.

Mixed lineage leukemia results from chromosomal rearrangements of the gene mixed lineage leukemia (MLL). MLL-AF9 is one such rearrangement that recruits the lysine methyltransferase, human disruptor of telomere silencing 1-like (DOT1L) and lysine specific demethylase 1 (LSD1), resulting in elevated expression of the Homeobox protein A9 (HOXA9), and leukemia. Inhibitors of LSD1 or DOT1L reduce HOXA9 expression, kill MLL-rearranged cells, and may treat leukemia.

Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth.

Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile.

Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass.

Objectives: Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L.

Methods: Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied.

Increased Post-Translational Lysine Acetylation of Myelin Basic Protein Is Associated with Peak Neurological Disability in a Mouse Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

Citrullination of arginine residues is a post-translational modification (PTM) found on myelin basic protein (MBP), which neutralizes MBPs positive charge, and is implicated in myelin damage and multiple sclerosis (MS). Here we identify lysine acetylation as another neutralizing PTM to MBP that may be involved in myelin damage. We quantify changes in lysine and arginine PTMs on MBP derived from mice induced with an experimental autoimmune encephalomyelitis (EAE) model of MS using liquid chromatography tandem mass spectrometry.

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids.

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration.

Pharmacokinetic Analysis of an Oral Multicomponent Joint Dietary Supplement (Phycox) in Dogs.

Despite the lack of safety, efficacy and pharmacokinetic (PK) studies, multicomponent dietary supplements (nutraceuticals) have become increasingly popular as primary or adjunct therapies for clinical osteoarthritis in veterinary medicine. Phycox is a line of multicomponent joint support supplements marketed for joint health in dogs and horses. Many of the active constituents are recognized anti-inflammatory and antioxidant agents.

Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage.

Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1.

Simultaneous quantification of reparixin and paclitaxel in plasma and urine using ultra performance liquid chromatography-tandem mass spectroscopy (UHPLC-MS/MS): Application to a preclinical pharmacokinetic study in rats.

A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay was developed and validated to simultaneously quantify anticancer drugs reparixin and paclitaxel in this study. The compounds were extracted from plasma and urine samples by protein precipitation with acetone (supplemented with 0.1% formic acid).

PRMT2 interacts with splicing factors and regulates the alternative splicing of BCL-X.

Protein arginine N-methyltransferase 2 (PRMT2) functions in JAK-STAT and Wnt/β-catenin signalling pathways, serves as a nuclear receptor-dependent transcriptional co-activator, and represses NF-κB and E2F1 transcription factor activities to promote apoptosis. We have previously demonstrated that PRMT2 interacts with PRMT1 and increases its activity. Here, we reveal associations using proteomics between the PRMT2 SH3 domain and splicing factors including Src-associated in mitosis 68 kDa protein (SAM68), a PRMT1 substrate and trans-acting factor that mediates BCL-X alternative splicing.

Quantification of cefazolin in serum and adipose tissue by ultra high performance liquid chromatography-Tandem mass spectrometry (UHPLC-MS/MS): application to a pilot study of obese women undergoing cesarean delivery.

Higher doses of cefazolin are required in obese patients for preoperative antibiotic prophylaxis, owing to its low lipophilicity. An ultra high performance liquid chromatography-tandem mass spectrometry method was developed to quantify cefazolin in serum and adipose tissue from 6 obese patients undergoing cesarean delivery, and using stable-isotope labeled cefazolin as an internal standard. The method has a 2μg/g lower limit of quantitation.