The Interaction of Myeloperoxidase with the Industrial Contaminant 6-PPD: A Potential Pathway for Reactive Metabolites.

6-PPD (-[1,3-dimethylbutyl]-'-phenyl--phenylenediamine) is an industrial antioxidant reported to be an environmental contaminant. It was found to be highly toxic to coho salmon and potentially other aquatic organisms. The toxicity of 6-PPD in humans, however, remains unknown.

Application of electron paramagnetic resonance spectroscopy for determining the relative nanoenvironment fluidity of polymeric micelles.

Polymeric micelles are nanocarriers for drug, protein and gene delivery due to their unique core/shell structure, which encapsulates and protects therapeutic cargos with diverse physicochemical properties. However, information regarding the micellar nanoenvironment's fluidity can provide unique insight into their makeup. In this study, we used electron paramagnetic resonance (EPR) spectroscopy to study free radical spin probe (5-doxylstearate methyl ester, 5-MDS, and 16-doxylstearic acid, 16-DS) behaviour in methoxy-poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-PBCL) and methoxy-poly(ethylene oxide)-poly(ε-caprolactone) (PEO-PCL) polymeric micelles.

Comparing the oxidative functions of neutrophil myeloperoxidase and cytochrome P450 enzymes in drug metabolism.

Drug metabolism is an essential process that chemically alters xenobiotic substrates to activate or terminate drug activity. Myeloperoxidase (MPO) is a neutrophil-derived haem-containing enzyme that is involved in killing invading pathogens, although consequentially, this same oxidative activity can produce metabolites that damage host tissue and play a role in various human pathologies. Cytochrome P450s (CYPs) are a superfamily of haem-containing enzymes that are significantly involved in the metabolism of drugs by functioning as monooxygenases and can be induced or inhibited, resulting in significant drug-drug interactions that lead to unanticipated adverse drug reactions.

Proof of concept: Pull down assay using bovine serum albumin and an immunomodulator small molecule.

In the past decade, there has been increasing interest in use of small molecules for immunomodulation. The affinity-based pull-down purification is an essential tool for target identification of small molecules and drug discovery. This study presents our recent efforts to investigate the cellular target(s) of Compound A, a small molecule with demonstrated immunomodulatory properties in human peripheral blood mononuclear cells (PBMCs).

Target identification of small molecules: an overview of the current applications in drug discovery.

Target identification is an essential part of the drug discovery and development process, and its efficacy plays a crucial role in the success of any given therapy. Although protein target identification research can be challenging, two main approaches can help researchers make significant discoveries: affinity-based pull-down and label-free methods. Affinity-based pull-down methods use small molecules conjugated with tags to selectively isolate target proteins, while label-free methods utilize small molecules in their natural state to identify targets.

Effect of Plasma-Activated Water Bubbles on , Deoxynivalenol, and Germination of Naturally Infected Barley during Steeping.

Contamination of barley by deoxynivalenol (DON), a mycotoxin produced by , causes considerable financial loss to the grain and malting industries. In this study, two atmospheric cold plasma (ACP) reactors were used to produce plasma-activated water (PAW) bubbles. The potential of PAW bubbles for the steeping of naturally infected barley (NIB) during the malting process was investigated.

Heating of consumer cannabis oils can lead to free radical initiated degradation, causing CBD and THC depletion.

Commercial cannabis oil products are widely available in Canada even though there is a significant gap in scientific information regarding them. Oils, such as vegetable oils, are known to undergo oxidative changes through free radical mechanisms when they are heated or aged, but the cannabis oils used in this study did not have expiry dates or best-before usage dates. This led to the question of how these products would be affected with time.

β-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models.

Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer.

The many roles of myeloperoxidase: From inflammation and immunity to biomarkers, drug metabolism and drug discovery.

This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical background, from peroxidase activity to the discovery of MPO, to its role in disease and drug development. MPO is discussed in terms of its necessity, as specific individuals lack MPO expression.

Interactions of the antioxidant enzymes NAD(P)H: Quinone oxidoreductase 1 (NQO1) and NRH: Quinone oxidoreductase 2 (NQO2) with pharmacological agents, endogenous biochemicals and environmental contaminants.

Quinone Oxidoreductase 1 (NQO1) is an antioxidant enzyme that catalyzes the two-electron reduction of several different classes of quinone-like compounds (quinones, quinone imines, nitroaromatics, and azo dyes). One-electron reduction of quinone or quinone-like metabolites is considered to generate semiquinones to initiate redox cycling that is responsible for the generation of reactive oxygen species and oxidative stress and may contribute to the initiation of adverse drug reactions and adverse health effects. On the other hand, the two-electron reduction of quinoid compounds appears important for drug activation (bioreductive activation) via chemical rearrangement or autoxidation.

Reversing T-cell exhaustion in immunotherapy: a review on current approaches and limitations.

:T cell functions are altered during chronic viral infections and tumor development. This is mainly manifested by significant changes in T cells' epigenetic and metabolic landscapes, pushing them into an 'exhausted' state. Reversing this T cell exhaustion has been emerging as a 'game-changing' therapeutic approach against cancer and chronic viral infection.

Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis.

The burden of breast cancer is imposing a huge global problem. Drug discovery research and novel approaches to treat breast cancer have been carried out extensively over the last decades. Although immune checkpoint inhibitors are showing promising preclinical and clinical results in treating breast cancer, they are facing multiple limitations.

Treatment of a mixture of pharmaceuticals, herbicides and perfluorinated compounds by powdered activated carbon and ozone: Synergy, catalysis and insights into non-free OH contingent mechanisms.

Powdered activated carbon (PAC) is a strong adsorbent also capable of catalyzing ozonation processes. Ozone (O) and PAC were simultaneously applied to treat a mixture of 17 micropollutants (MPs) at low concentrations, including 13 compounds that were studied for the first time by simultaneous addition of O and PAC system. Synergy and catalysis improved the removals and specific degradation rates of MPs in the first minute of the treatment.

Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action.

The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase-peroxidase enzyme KatG in Mycobacterium tuberculosis (Mtb). This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent Mtb lacking a typical cell wall, and (c) why isoniazid treatment time is remarkably long in contrast to most other antibiotics. To address these questions, a novel comprehensive mode of action of isoniazid has been proposed here.

Comprehensive in vitro characterization of PD-L1 small molecule inhibitors.

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed.

Myeloperoxidase-mediated oxidation of edaravone produces an apparent non-toxic free radical metabolite and modulates hydrogen peroxide-mediated cytotoxicity in HL-60 cells.

Edaravone is considered to be a potent antioxidant drug known to scavenge free radical species and prevent free radical-induced lipid peroxidation. In this study, we investigated the effect of edaravone on the myeloperoxidase (MPO) activity, an enzyme responsible for the production of an array of neutrophil-derived oxidants that can cause cellular damage. The addition of edaravone to the reaction of MPO and hydrogen peroxide (HO) significantly enhanced the reduction of MPO Compound II back to native MPO.

Caution for the routine use of phenol red - It is more than just a pH indicator.

Phenol red (PR) is the standard pH indicator in various cell and tissue culture media, as it provides a quick check for the health of the culture. PR has also been used in multiple protocols to detect cellular hydrogen peroxide as well as peroxidase activity from human peroxidase enzymes. The majority of promyelocytic leukemia cell lines (e.

Eosinophil peroxidase oxidizes isoniazid to form the active metabolite against M. tuberculosis, isoniazid-NAD.

The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD) by the mycobacterial catalase-peroxidase enzyme, KatG, was known to be the major component of the mode of action of isoniazid (INH), an anti-tuberculosis drug. However, there are other enzymes that may catalyze this reaction. We have previously reported that neutrophil myeloperoxidase (MPO) is capable of metabolizing INH through the formation of INH-NAD adduct, which could be attributed to being a possible mode of action of INH.

Isoniazid induces a monocytic-like phenotype in HL-60 cells.

Isoniazid (INH) is one of the oldest drugs for the treatment of tuberculosis (TB) and is of continual clinical and research interest. The aim of the current study is to investigate the ability of INH to induce monocyte differentiation and the underlying signaling pathway involved in this phenomenon using HL-60 cells. In this study, HL-60 cells were treated with different non-cytotoxic concentrations of INH or vitamin D (a well-known inducer of monocytic differentiation) to determine key functional changes in the phenotype of these cells using several biochemical and cytobiological experiments.

Reactive Oxygen Species Mediate Therapeutic Ultrasound-Induced, Mitogen-Activated Protein Kinase Activation in C28/I2 Chondrocytes.

Low-intensity pulsed ultrasound (LIPUS) has been used for the treatment of non-healing fractures because of its therapeutic properties of stimulating enhancing endochondral bone formation. However, its mechanism of action remains unclear. In this study, we hypothesized that LIPUS activates mitogen-activated protein kinases through generation of reactive oxygen species.

2-Methoxyestradiol protects against pressure overload-induced left ventricular hypertrophy.

Numerous experimental studies have supported the evidence that 2-methoxyestradiol (2 ME) is a biologically active metabolite that mediates multiple effects on the cardiovascular system, largely independent of the estrogen receptor. 2 ME is a major cytochrome P450 1B1 (CYP1B1) metabolite and has been reported to have vasoprotective and anti-inflammatory actions. However, whether 2 ME would prevent cardiac hypertrophy induced by abdominal aortic constriction (AAC) has not been investigated yet.

Characterization of Mechanisms of Glutathione Conjugation with Halobenzoquinones in Solution and HepG2 Cells.

Halobenzoquinones (HBQs) are a class of emerging disinfection byproducts. Chronic exposure to chlorinated drinking water is potentially associated with an increased risk of human bladder cancer. HBQ-induced cytotoxicity involves depletion of cellular glutathione (GSH), but the underlying mechanism remains unclear.

Differential eNOS-signalling by platelet subpopulations regulates adhesion and aggregation.

Aims: In addition to maintaining haemostasis, circulating blood platelets are the cellular culprits that form occlusive thrombi in arteries and veins. Compared to blood leucocytes, which exist as functionally distinct subtypes, platelets are considered to be relatively simple cell fragments that form vascular system plugs without a differentially regulated cellular response. Hence, investigation into platelet subpopulations with distinct functional roles in haemostasis/thrombosis has been limited.