In mammalian systems, pregnane X receptor (PXR) and constitutive androstane (CAR) have been recognized as xenobiotic-sensors which can up-regulate the functional expression of drug transporters, such P-glycoprotein (P-gp). brain, an increase in P-gp further limit permeability across blood-brain barrier (BBB) potentially reduce CNS pharmacotherapy efficacy. At present, involvement human PXR (hPXR) CAR (hCAR) regulation at BBB is unknown. this study, we investigate role hPXR hCAR using a...

The testes are a potential viral sanctuary site for HIV-1 infection. Our study aims to provide insight into the expression and localization of key drug transporters metabolic enzymes relevant ART in this tissue compartment. We characterized gene protein 12 representative two testicular samples obtained from uninfected (n = 8) virally suppressed HIV-1-infected subjects on 5) quantified antiretroviral concentrations plasma tissues using LC/MS/MS subjects. data demonstrate that ABC...

Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate systems, i.e., reduced carrier (RFC), proton-coupled transporter (PCFT), receptor alpha (FRα), known to be regulated ligand-activated nuclear receptors, such as vitamin D (VDR). uptake at the choroid plexus, which requires actions of both FRα PCFT, critical cerebral delivery. Inactivating or PCFT mutations cause severe deficiency resulting early childhood...

Significance Folates are critical for brain development and function. Abnormalities in folate transport have been implicated a number of childhood neurodevelopmental disorders, including cerebral deficiency syndrome, hereditary malabsorption, autism spectrum disorders. These disorders devastating effects young children, current therapeutic approaches not sufficiently effective. In this study, we demonstrate that functional expression the transporter, reduced carrier, at blood–brain barrier...

Folates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) reduced folate-carrier (RFC; SLC19A1/Slc19a1) (3) proton-coupled transporter (PCFT; SLC46A1/Slc46a1). into out CNS occurs at blood-cerebrospinal fluid barrier (BCSFB), FRα PCFT. Impairment BCSFB...

Abstract Dolutegravir (DTG)‐based antiretroviral therapy is the contemporary first‐line to treat HIV infection. Despite its efficacy, mounting evidence has suggested a higher risk of neuropsychiatric adverse effect (NPAE) associated with DTG use, limited understanding underlying mechanisms. Our laboratory previously reported toxic but not bictegravir (BTG) in disrupting blood–brain barrier (BBB) integrity. The current study aimed investigate mechanism toxicity. Primary cultures mouse brain...

Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) membrane-associated drug efflux transporter, is known to localize at the blood-brain barrier (BBB) and can significantly restrict xenobiotic permeability in brain. The objective of this study investigate regulation BCRP functional expression by peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated transcription factor primarily involved lipid metabolism, cerebral microvascular endothelial cell...

ABSTRACT This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on expression intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), breast cancer resistance protein (BCRP), metabolic enzymes, such as cytochrome P450s (CYPs), in human upper tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV + ) subjects, HIV subjects receiving ART (10...

Poor antiretroviral drug (ARV) penetration in the testes could be due, part, to presence of ATP-binding cassette (ABC) membrane–associated efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance–associated proteins (MRPs) expressed at blood-testis barrier (BTB). The functional expression these is known regulated by ligand-activated nuclear receptors pregnane X receptor (PXR) constitutive androstane (CAR) various tissues. This study...

Sister chromatids duplicated in S phase are connected with each other during G2 and M until the onset of anaphase. This chromatid cohesion is essential for correct segregation genetic material to daughter cells. Recently, understanding molecular mechanisms governing yeast has been greatly advanced, whereas these processes mammalian cells remain unclear. We report here biochemical cytological analyses human Rad21, a homologue cohesin subunit, Scc1p/Mcd1p. hRad21 nuclear phosphorylated...

ABSTRACT The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, permeability evaluated in vitro (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated 1 (MRP1), or MRP4-overexpressing MDA-MDR1 HEK-ABCG2, HeLa-MRP1, HEK-MRP4 cells, respectively; (ii) cell culture systems human blood-brain...

Neuroinflammation is a common immune response associated with brain human immunodeficiency virus-1 (HIV-1) infection. Identifying therapeutic compounds that exhibit better permeability and can target signaling pathways involved in inflammation may benefit treatment of HIV-associated neurological complications. The objective this study was to implement an vivo model by intracerebroventricular administration the HIV-1 viral coat protein gp120 rats examine anti-inflammatory properties HIV...

Despite the use of combination antiretroviral therapy for treatment HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets in are macrophages, microglia, a certain extent astrocytes which response infection release inflammatory markers, proteins [i.e., glycoprotein 120 (gp120)] exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) members nuclear receptor...

Abstract Breast cancer resistance protein (Bcrp/Abcg2) localized at the blood–brain barrier ( BBB ) limits permeability into brain of many xenobiotics, including pharmacological agents. Peroxisome proliferator‐activated receptor α (Pparα), a ligand‐activated transcription factor, primarily involved in lipid metabolism, has been shown to regulate functional expression Bcrp human cerebral microvascular endothelial cells hCMEC /D3). The aim this study was investigate ex vivo and , regulation by...

Due to the critical role of folates in neurodevelopment, it is important understand potential interactions between anti-HIV drugs used during pregnancy, and folate delivery pathways placenta. This study investigates effect dolutegravir (DTG) exposure on functional expression reduced carrier (RFC), proton-coupled transporter (PCFT), receptor-α (FRα) placenta.Human placental cell lines, human explants, a pregnant mouse model treated with clinically relevant concentrations DTG were used. Gene...

Abstract Integrase strand transfer inhibitors (INSTIs) based antiretroviral therapy (ART) is currently used as first‐line regimen to treat HIV infection. Despite its high efficacy and barrier resistance, ART‐associated neuropsychiatric adverse effects remain a major concern. Recent studies have identified potential interaction between the INSTI, dolutegravir (DTG), folate transport pathways at placental barrier. We hypothesized that such interactions could also occur two blood–brain...

Scc1/Mcd1 is a component of the cohesin complex that plays an essential role in sister chromatid cohesion eukaryote cells. Knockout experiments this gene have been described budding yeast, fission and chicken cells, but no study has reported on human Scc1 thus far. In study, we found N-terminally truncated shows dominant-negative effect, examined phenotypes cells defective function. defects led to failure both interphase mitotic Interestingly, four chromatids derived from two homologues...

Abstract Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the ATP-binding cassette superfamily membrane transport proteins and confers to nucleoside nucleotide analogues as well camptothecin derivatives. MRP4 also mediates transmembrane several eicosanoids, conjugated estrogens, cyclic AMP. The subcellular localization depends on cell type in which it expressed, but molecular determinants responsible for trafficking plasma are unknown. Here, we describe interaction Na+/H+...

Abstract The use of antiretroviral therapy (ART) as pre‐exposure prophylaxis (PrEP) has gained global attention a promising HIV prevention strategy in men who have sex with men. Permeability these agents the rectal mucosa may be partially regulated by interactions drug efflux transporters, P‐glycoprotein (P‐gp), multidrug resistance‐associated proteins (MRPs) and/or breast cancer resistance protein (BCRP). objective this work was to investigate expression transporters recto‐sigmoid colon...

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit clinical efficacy safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate expression 25 clinically relevant DMETs Vero E6 cells postmortem lung tissues from patients. Also, assessed role 2 inflammatory 4 regulatory proteins modulating dysregulation human tissues. We...