Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health.

This review explores the likely clinical impact of Pregnane X Receptor (PXR) activation by vitamin K on human health. PXR, initially recognized as a master regulator of xenobiotic metabolism in liver, emerges as a key regulator influencing intestinal homeostasis, inflammation, oxidative stress, and autophagy. The activation of PXR by vitamin K highlights its role as a potent endogenous and local agonist with diverse clinical implications.

Theranostics with photodynamic therapy for personalized medicine: to see and to treat.

Photodynamic Therapy (PDT) is an approved treatment modality, which is presently receiving great attention due to its limited invasiveness, high selectivity and limited susceptibility to drug resistance. Another related research area currently expanding rapidly is the development of novel theranostic agents based on the combination of PDT with different imaging technologies, which allows for both therapy and diagnosis. This combination can help to address issues of suboptimal biodistribution and selectivity through regional imaging, while therapeutic agents enable an effective and personalized therapy.

The Interface between Cell Signaling Pathways and Pregnane X Receptor.

Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies.

Sterilization and sanitizing of 3D-printed personal protective equipment using polypropylene and a Single Wall design.

Background: The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic during the fall of 2019 and into the spring of 2020 has led to an increased demand of disposable N95 respirators and other types of personal protective equipment (PPE) as a way to prevent virus spread and help ensure the safety of healthcare workers. The sudden demand led to rapid modification, development, and dissemination of 3D printed PPE. The goal of this study was to determine the inherent sterility and re-sterilizing ability of 3D printed PPE in order to provide sterile equipment to the healthcare field and the general public.

Associations between Pregnane X Receptor and Breast Cancer Growth and Progression.

Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism.

Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor.

The pregnane X receptor (PXR), or nuclear receptor (NR) 1I2, is a ligand-activated NR superfamily member that is enriched in liver and intestine in mammals. Activation of PXR regulates the expression of genes encoding key proteins involved in drug metabolism, drug efflux, and drug transport. Recent mechanistic investigations reveal that post-translational modifications (PTMs), such as phosphorylation, play a critical role in modulating the bimodal function of PXR-mediated transrepression and transactivation of target gene transcription.

Allopregnanolone is required for prepulse inhibition deficits induced by D dopamine receptor activation.

Introduction: The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown.

Clinical applications of small molecule inhibitors of Pregnane X receptor.

The canonical effect of Pregnane X Receptor (PXR, NR1I2) agonism includes enhanced hepatic uptake and a concomitant increase in the first-pass metabolism and efflux of drugs in mammalian liver and intestine. In patients undergoing combination therapy, PXR-mediated gene regulation represents the molecular basis of numerous food-drug, herb-drug, and drug-drug interactions. Moreover, PXR activation promotes chemotherapeutic resistance in certain malignancies.

The Molecular Interface Between the SUMO and Ubiquitin Systems.

The SUMO conjugation system regulates key cellular processes including cell growth, division, mitochondrial dynamics, and the maintenance of genome stability in eukaryotic cells. The ubiquitin conjugation system regulates the stability of a myriad of vital cellular proteins in a signal-dependent manner by targeting them for destruction via the proteasome-mediated degradation pathway. Recent research efforts have unveiled an evolutionarily conserved and fundamental molecular interface between the SUMO and ubiquitin systems.

A SUMO-acetyl switch in PXR biology.

Post-translational modification (PTM) of nuclear receptor superfamily members regulates various aspects of their biology to include sub-cellular localization, the repertoire of protein-binding partners, as well as their stability and mode of degradation. The nuclear receptor pregnane X receptor (PXR, NR1I2) is a master-regulator of the drug-inducible gene expression in liver and intestine. The PXR-mediated gene activation program is primarily recognized to increase drug metabolism, drug transport, and drug efflux pathways in these tissues.

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes.

Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin-signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression.

Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes.

Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs).

Protein targets of thioacetamide metabolites in rat hepatocytes.

Thioacetamide (TA) has long been known as a hepatotoxicant whose bioactivation requires S-oxidation to thioacetamide S-oxide (TASO) and then to the very reactive S,S-dioxide (TASO2). The latter can tautomerize to form acylating species capable of covalently modifying cellular nucleophiles including phosphatidylethanolamine (PE) lipids and protein lysine side chains. Isolated hepatocytes efficiently oxidize TA to TASO but experience little covalent binding or cytotoxicity because TA is a very potent inhibitor of the oxidation of TASO to TASO2.

Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver.

Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid-transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid-activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver.

Liver protein targets of hepatotoxic 4-bromophenol metabolites.

The hepatotoxicity of bromobenzene (BB) is directly related to the covalent binding of both initially formed epoxide and secondary quinone metabolites to at least 45 different liver proteins. 4-Bromophenol (4BP) is a significant BB metabolite and a precursor to reactive quinone metabolites; yet, when administered exogenously, it has negligible hepatotoxicity as compared to BB. The protein adducts of 4BP were thus labeled as nontoxic [Monks, T.

Covalent modification of lipids and proteins in rat hepatocytes and in vitro by thioacetamide metabolites.

Thioacetamide (TA) is a well-known hepatotoxin in rats. Acute doses cause centrilobular necrosis and hyperbilirubinemia while chronic administration leads to biliary hyperplasia and cholangiocarcinoma. Its acute toxicity requires its oxidation to a stable S-oxide (TASO) that is oxidized further to a highly reactive S,S-dioxide (TASO(2)).

Post-translational modification of pregnane x receptor.

Pregnane x receptor (PXR, NR1I2) was originally characterized as a broad spectrum entero-hepatic xenobiotic 'sensor' and master-regulator of drug inducible gene expression. A compelling description of ligand-mediated gene activation has been unveiled in the last decade that firmly establishes this receptor's central role in the metabolism and transport of xenobiotics in mammals. Interestingly, pharmacotherapy with potent PXR ligands produces several profound side effects including decreased capacities for gluconeogenesis, lipid metabolism, and inflammation; likely due to PXR-mediated repression of gene expression programs underlying these pivotal physiological functions.

Pregnane X receptor is SUMOylated to repress the inflammatory response.

Long-term treatment of patients with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. We show here that activation of the inflammatory response in hepatocytes strongly modulates SUMOylation of ligand-bound PXR. We provide evidence that the SUMOylated PXR contains SUMO3 chains, and feedback represses the immune response in hepatocytes.

Nuclear receptor-mediated regulation of carboxylesterase expression and activity.

Importance Of The Field: Emerging evidence demonstrates that several nuclear receptor (NR) family members regulate drug-inducible expression and activity of several important carboxylesterase (CES) enzymes in mammalian liver and intestine. Numerous clinically prescribed anticancer prodrugs, carbamate and pyrethroid insecticides, environmental toxicants and procarcinogens are substrates for CES enzymes. Moreover, a key strategy used in rational drug design frequently utilizes an ester linkage methodology to selectively target a prodrug, or to improve the water solubility of a novel compound.

A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein.

The pregnane X receptor (PXR, NR1I2) regulates the expression of genes that encode drug-metabolizing enzymes and drug transporter proteins in liver and intestine. Understanding the molecular mechanisms that modulate PXR activity is therefore critical for the development of effective therapeutic strategies. Several recent studies have implicated the activation of kinase signaling pathways in the regulation of PXR biological activity, although direct evidence and molecular mechanisms are currently lacking.

Regulation of tissue-specific carboxylesterase expression by pregnane x receptor and constitutive androstane receptor.

The liver- and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress.

Cyclic AMP-dependent protein kinase signaling modulates pregnane x receptor activity in a species-specific manner.

Pregnane x receptor is a ligand-activated transcription factor that regulates drug-inducible expression of several key cytochrome P450 enzymes and drug transporter proteins in liver and intestine in a species-specific manner. Activation of this receptor modulates several key biochemical pathways, including gluconeogenesis, beta-oxidation of fatty acids, fatty acid uptake, cholesterol homeostasis, and lipogenesis. It is of current interest to determine whether the interaction between pregnane x receptor and these key biochemical pathways is evolutionarily conserved.