Pharmacogenomics of Human ABC Transporter ABCC11 (MRP8): Potential Risk of Breast Cancer and Chemotherapy Failure

Some genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of certain diseases and patients’ responses to medication. Human ABCC11 functions as an ATP-dependent efflux pump for amphipathic anions. One non-synonymous SNP 538G>A (Gly180Arg) has been found to greatly affect the function and stability of de novo synthesized ABCC11 (Arg180) variant protein. The SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum (ER) and readily undergoes proteasomal degradation. This ER-associated degradation of ABCC11 protein underlies the molecular mechanism of affecting the function of apocrine glands. On the other hand, the wild type (Gly180) of ABCC11 is associated with wettype earwax, axillary osmidrosis, colostrum secretion from the mammary gland, and the potential susceptibility of breast cancer. Furthermore, the wild type of ABCC11 reportedly has ability to efflux cyclic nucleotides and nucleoside-based anticancer drugs. The SNP (538G>A) of the ABCC11 gene is suggested to be a clinical biomarker for prediction of chemotherapeutic efficacy. Major obstacle to the successful chemotherapy of human cancer is development of resistance, and nucleoside-based chemotherapy is often characterized by inter-individual variability. This review provides an overview about the discovery and the genetic polymorphisms in human ABCC11. Furthermore, we focus on the impact of ABCC11 538G>A on the apocrine phenotype, patients’ response to nucleoside-based chemotherapy, and the potential risk of breast cancer

Enhanced synaptic long-term potentiation in the anterior cingulate cortex of adult wild mice as compared with that in laboratory mice

Activation of N-methyl D-aspartate (NMDA) receptor is important for learning, memory and persistent pain. Genetic enhancement of NMDA receptor function by overexpressing NR2B subunit significantly enhances hippocampal long-term potentiation (LTP), behavioral learning as well as persistent pain. Recent studies found that NMDA NR2B subunits can undergo long-term upregulation in the brain under certain conditions including peripheral injury and environmental enrichment. Considering the fact that laboratory grown animals live in an artificial comfort environment, we wondered if NMDA receptor functions and its related LTP would differ in animals living in a natural wild environment. In this report we performed whole-cell patch-clamp recordings from both laboratory wild-type mice and wild mice from a natural environment. We found that LTP was significantly enhanced in the anterior cingulate cortex (ACC) of the wild mice as compared with that of laboratory mice. In parallel, NMDA receptor NR2B/total NMDA receptor mediated EPSC ratio was significantly increased in slices of wild mice. Our findings provide the first evidence that NMDA NR2B receptors play an important role in experience-dependent synaptic potentiation within the ACC in wild mice as previously reported in laboratory mice

Phase-sensitive quantum effects in Andreev conductance of the SNS system of metals with macroscopic phase breaking length

The dissipative component of electron transport through the doubly connected SNS Andreev interferometer indium (S)-aluminium (N)-indium (S) has been studied. Within helium temperature range, the conductance of the individual sections of the interferometer exhibits phase-sensitive oscillations of quantum-interference nature. In the non-domain (normal) state of indium narrowing adjacent to NS interface, the nonresonance oscillations have been observed, with the period inversely proportional to the area of the interferometer orifice. In the domain intermediate state of the narrowing, the magneto-temperature resistive oscillations appeared, with the period determined by the coherence length in the magnetic field equal to the critical one. The oscillating component of resonance form has been observed in the conductance of the macroscopic N-aluminium part of the system. The phase of the oscillations appears to be shifted by $\pi$ compared to that of nonresonance oscillations. We offer an explanation in terms of the contribution into Josephson current from the coherent quasiparticles with energies of order of the Thouless energy. The behavior of dissipative transport with temperature has been studied in a clean normal metal in the vicinity of a single point NS contact.Comment: 9 pages, 7 figures, to be published in Low Temp. Phys., v. 29, No. 12, 200

Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications

The ATP-binding cassette transporter G2 (ABCG2; also known as breast cancer resistance protein, BCRP) has been suggested to be involved in clinical multidrug resistance (MDR) in cancer like other ABC transporters such as ABCB1 (P-glycoprotein). As an efflux pump exhibiting a broad substrate specificity localized on cellular plasma membrane, ABCG2 excretes a variety of endogenous and exogenous substrates including chemotherapeutic agents, such as mitoxantrone and several tyrosine kinase inhibitors. Moreover, in the normal tissues, ABCG2 is expressed on the apical membranes and plays a pivotal role in tissue protection against various xenobiotics. For this reason, ABCG2 is recognized to be an important determinant of the pharmacokinetic characteristics of its substrate drugs. Although the clinical relevance of reversing the ABCG2-mediated MDR has been inconclusive, an appropriate modulation of ABCG2 function during chemotherapy should logically enhance the efficacy of anti-cancer agents by overcoming the MDR phenotype and/or improving their pharmacokinetics. To confirm this possibility, considerable efforts have been devoted to developing ABCG2 inhibitors, although there is no clinically available substance for this purpose. As a clue for addressing this issue, this mini-review provides integrated information covering the technical backgrounds necessary to evaluate the ABCG2 inhibitory effects on the target compounds and a current update on the ABCG2 inhibitors. This essentially includes our recent findings, as we serendipitously identified febuxostat, a well-used agent for hyperuricemia as a strong ABCG2 inhibitor, that possesses some promising potentials. We hope that an overview described here will add value to further studies involving in the multidrug transporters

Total electron emission yield measurement of insulator by a scanning small detector

Due to the injection of primary electrons and the emission of secondary electrons in the surface layer of insulating materials, the target surface will be negatively or positively charged. A method by injecting a single pulse beam and using a small current detector for the total electron emission yield measurement of insulating material is proposed, which can avoid the influence from charged surface. Using the developed system, the total electron emission yield of 25 μm thick polyimide film has been studied, as induced by a single 50 μs pulse of primary electrons with energy up to 2500 eV

Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model

ヒトiPS細胞分化モデルを用いた膵内胚葉分化におけるHHEXの役割の解明. 京都大学プレスリリース. 2023-06-09.Identification of HHEX as a crucial factor in pancreatic endoderm differentiation using a human iPS cell differentiation model. 京都大学プレスリリース. 2023-06-15.For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreatic endoderm differentiation by searching for factors that regulate a crucial pancreatic endoderm marker gene, NKX6.1. Unbiasedly screening an siRNA knockdown library, we identified a candidate transcription factor, HHEX. HHEX knockdown suppressed the expression of another pancreatic endoderm marker gene, PTF1A, as well as NKX6.1, independently of PDX1, a known regulator of NKX6.1 expression. In contrast, the overexpression of HHEX upregulated the expressions of NKX6.1 and PTF1A. RNA-seq analysis showed decreased expressions of several genes related to pancreatic development, such as NKX6.1, PTF1A, ONECUT1 and ONECUT3, in HHEX knockdown pancreatic endoderm. These results suggest that HHEX plays a key role in pancreatic endoderm differentiation

Andreev Conductance of Chaotic and Integrable Quantum Dots

We examine the voltage V and magnetic field B dependent Andreev conductance of a chaotic quantum dot coupled via point contacts to a normal metal and a superconductor. In the case where the contact to the superconductor dominates, we find that the conductance is consistent with the dot itself behaving as a superconductor-- it appears as though Andreev reflections are occurring locally at the interface between the normal lead and the dot. This is contrasted against the behaviour of an integrable dot, where for a similar strong coupling to the superconductor, no such effect is seen. The voltage dependence of the Andreev conductance thus provides an extremely pronounced quantum signature of the nature of the dot's classical dynamics. For the chaotic dot, we also study non-monotonic re-entrance effects which occur in both V and B.Comment: 13 pages, 9 figure