Understanding the Impact of BCRP and PGP Efflux Transporters on the Disposition of Their Endogenous, Xenobiotic and Dietary Substrates

Breast Cancer Resistant Protein (BCRP) and P-glycoprotein (PGP) are membrane-bound efflux transporters that transport multiple chemical classes of compounds and act as barriers to tissue permeability, thereby regulating tissue exposure of their substrates. The role of these transporters in therapeutic resistance of their xenobiotic substrates due to their expression and efflux function at target organs/tissues, especially in brain and intestine, is well established, which has fueled investigation toward identification of their inhibitors. Multiple clinically used drugs and dietary chemicals have been reported to inhibit these transporters and potentially increase the exposure of concomitantly administered BCRP and/or PGP substrates, which might be desirable (to increase efficacy of the substrate drug) as well as undesirable (as it can affect the disposition of the substrate in tissues where it might cause toxicity). Therefore, drug-drug and food-drug interactions with BCRP and PGP are a major concern in drug development, as recognized by US Food and Drug Administration (FDA), European Medicines Agency (EMA) and International Transporter Consortium (ITC). BCRP and PGP transporters are also known to transport endogenous substrates and have been associated with important physiological functions. This includes an inflammatory bowel disease-like phenotype associated with a non-functional PGP polymorphism (Ala893), while a loss of function mutation in BCRP (Q141K) is known to be positively associated with gout and negatively associated with Parkinson’s syndrome. Although a few endogenous substrates of BCRP and PGP have been identified, a systemic understanding of their physiological function and effect on the endogenous metabolome is still lacking. In the current studies, utilizing untargeted metabolomics, coupled with transcriptomic analysis, we sought to understand the endogenous function of Bcrp and/Pgp transporters in rats, by comparing the plasma and cerebrospinal fluid metabolome of wild-type and Bcrp-Pgp double knockout rats. Our findings revealed several putative novel endogenous/dietary substrates of Bcrp and Pgp transporters and established a novel understanding of the physiological function of these transporters. We also identified the anesthetic/analgesic ketamine as a putative substrate of Bcrp and Pgp, and found that ketamine pharmacokinetics (PK), as well as pharmacodynamics (PD), are affected by these efflux transporters. Importantly, the Bcrp-Pgp inhibitor, elacridar, was found to alter the PD of ketamine, indicating that ketamine might be prone toward drug-drug interactions (DDIs) associated with Bcrp-Pgp inhibitors. Finally, utilizing a Bcrp dietary substrate, Pheophorbide A (PhA), we developed an in vivo assay for the assessment of DDI due to inhibition of Bcrp at enterocytes. Our results demonstrated that PhA can be potentially used to create a reliable, high-throughput and less expensive in vivo assay for determining Bcrp-mediated DDIs

An Unnatural Partnership? The Future of U.S.-India Strategic Cooperation

As global competition with an increasingly assertive Chinese Government expands, the strategic relationship between India and the United States is assuming ever-greater importance. From a superficial perspective, a strategic partnership seems to make a great deal of sense for both countries. Yet, enormous political, cultural, and structural obstacles remain between them, which continue to slow the progress in security cooperation to a crawl, relative to China’s economic and military advances. The authors explore these impediments frankly and suggest practical ways to build trust and establish confidence.https://press.armywarcollege.edu/monographs/1923/thumbnail.jp

2019: A Changing International Order? Implications for the Security Environment

KCIS2019 examined the implications of the changing international order for international security. It studied the hypercompetitive, multipolar environment in which we find ourselves, marked by a persistent struggle for influence and position within a “grey zone” of competition. This edited collection features contributions from academic and military experts who have examined the future of the liberal international order and what is at stake. These evidence-based examinations discuss the challenges to the order, and why it has been so difficult to articulate a compelling narrative to support the continuation of American leadership.https://press.armywarcollege.edu/monographs/1922/thumbnail.jp

Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent Manner

Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2-/-) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy

Non-affine extensions of the Raychaudhuri equation in the K-essence framework

We present a new avenue of the Raychaudhuri Equation (RE) by introducing a non-affine parametrization within the k-essence framework. This modification accounts for non-geodesic flow curves, leading to emergent repulsive effects in cosmic evolution. Using a DBI-type k-essence Lagrangian, we derive a modified RE and demonstrate its ability to address the Hubble tension while predicting a natural emergence of a dynamical dark energy equation of state. Our Bayesian analysis, constrained by cosmological data, supports the theoretical scaling relation of the k-essence field (ϕ˙) and the cosmic scale factor (a). Furthermore, we reinterpret the modified RE as an anti-damped harmonic oscillator, we found a caustic avoidance signature, it may reveal classical or quantum-like effects in cosmic expansion. These results suggest a deep connection between scalar field dynamics and modified gravity, offering new perspectives on the nature of the expansion history of the universe