ABCB subfamily in GtoPdb v.2023.1

The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [8, 1]

ABCA subfamily in GtoPdb v.2023.1

To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [1, 2]

ABCC subfamily in GtoPdb v.2023.1

Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [7, 2]

ABCA subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [1]

ABCC subfamily in GtoPdb v.2021.3

Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [7, 2]

Physical Therapist Faculty Transition To Academic Leadership

The Commission on Accreditation in Physical Therapy Education (CAPTE) has elevated the accreditation standards for physical therapy (PT) faculty and program directors. These increased standards along with the proliferation of new physical therapy education programs and retirements of current program directors has created a nationwide program director shortage. The purpose of this quantitative descriptive study identified factors that influence PT faculty in pursuing the position of program director as well as their perceptions of the responsibilities of program director. Qualified PT faculty (n=51) from accredited physical therapy education programs in the Middle Atlantic and New England regions of the United States completed an on-line survey. The survey consisted of Likert scale questions asking the likelihood respondents would apply for a program director position based on job responsibilities identified by CAPTE. The respondents were also asked to rank the program director responsibilities from most to least essential. Frequencies, t-test and Fisher’s exact test were completed to analyze the data. Respondents rated ‘facilitate change’, ‘represent the department at college/university-level meetings’ and ‘oversee the curriculum content, design and evaluation’ as factors that would influence their likelihood to apply for a program director position. Respondents’ ranking of program director responsibilities identified ‘maintain accreditation’ as the most essential responsibility followed by ‘faculty advocate to higher administration’ and ‘develop strategic plans’. In contrast, respondents rated ‘maintain accreditation’ as a factor to unlikely apply for a program director position. Results indicated females (p=0.01) were more likely to consider applying for a program director position than males and there was an association between gender and ‘maintain program accreditation’ (p=0.04) and ‘develop strategic plans’ (p=0.02). Findings from this study may be beneficial for current program directors and higher education administrators when recruiting for physical therapy program directors as well as determining succession of current program directors. The implementation of professional development plans could include informal and formal support of program director responsibilities that influenced PT faculty to pursue a program director position as well as addressing barriers to applying for the position

Hepatic bile formation: Canalicular osmolarity and paracellular and transcellular water flow

The purpose of this minireview is to show that a new paradigm is developing regarding hepatic bile flow. The focus thus far has been on carrier-mediated transport of bile acids and other solutes, such as glutathione, which create an osmotic gradient for the transcellular and paracellular flow of water into canaliculi. In addition to the physicochemical properties of bile acids, which govern the osmotic gradient, data now exist showing that the tight junctions governing paracellular water flow and Aquaporin-8 water channels governing transcellular water flow are regulated independently. Thus, the rate of water flow into the canaliculus in response to bile acid transport is variable and determines canalicular bile acid concentration, which affects the production and solubilization of cholesterol-lecithin vesicles. These new considerations modify thinking regarding the occurrence of cholestasis and its progression and reorient the design of experimental studies that can distinguish the different determinants of bile flow. SIGNIFICANCE STATEMENT The paradigm that water flow into the canaliculus is determined only by the rate of carrier-mediated transport has been challenged recently by the changes that occur in hepatic bile composition in the Claudin-2 knockout mouse and with the cholestatic effect of estradiol 17b-D-glucuronide. Thus, a respective reduction in paracellular or transcellular canalicular water flow, probably via Aquaporin 8, has no significant effect on bile acid excretion.Fil: Marinelli, Raul Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Vore, Mary. University of Kentucky; Estados UnidosFil: Javitt, Norman B.. University of New York. School of Medicine; Estados Unido

Prolactin Increases N&/Taurocholate Cotransport in Isolated Hepatocytes fromPostpartum RatsandOvariectomized Rats―2

ABSTRACT The role of prolactin (PAL) in regulating the transport of the bile acid taurocholate (TC) was assessed using isolated rat hepato cytes. Na4-depandent TC cotransportwas determinedin hepa tocytes from female nonpregnant, pregnant (19-20 days preg nant), postpartum (48 hr postpartum) and postpartum rats treated with bromocnptine to block PAL secretion. In separate experiments ovariectomized rats were infused i.v. with solvent alone (OVX) or with ovine PAL (100, 300 and 600 ,@g/day) for 7 days (OVX + oPAL). The least squares estimates of Km(AM) and Vrna@x (nmol/min/mg protein) for Na4-dependent TC uptake were, respectively: 15 and I in nonpregnant, 9 and 0.4 in pregnant, 9 and 1.1 in postpartum and 15 and 1 in bromocriptine-treated postpartum rats, and were 15 and 1 in OVX, 15 and 1 in OVX + oPRL (100 pg/day), 30 and 2 in OVX + oPAL (300 ,@g/day)and 18 and 2 in OVX + oPRL (600 ag/day) rats, respectively. Calculationof the 95% joint confidencelimits for Km9fld Vmsx showed that Na-dependent TC uptake was slgnfficantly de creased in pregnant rats, and significantly increased in postpar turn rats relative to nonpregnant controls. Bromocriptine-treated postpartum rats were not different from COntrOlS. Infusion of 300 and 600 ag/day oPAL significantly increased Na4-dependentTC transport relative to OVX rats. Na@-K'-ATPaseactMty did not differ among the groups. These data indicate that PRL is re sponsible for the increased Na-dependent transport of TC in the maternal liver postpartum, and that administration of oPRL to ovariectomized rats Increases this transport In a dose-de pendantmanner. Bile formation is a complex process involving concentrative and vectorial transport of osmotically active solutes, primarily bile acids, from the plasma into the bile canalicuii leading to a passive movement of water and counterions (Blitzer and Boyer, 1982; Nathanson and Boyer, 1991). TC is the major bile acid in the rat and its hepatic transport is well characterized (Meier, 1989). TC is taken up by the basolateral domain of the plasma membrane via a carrier-mediated process driven by the in wardily directed Na4 gradient that is maintained by the baso lateral Na@-K4-ATPase (secondary active symport) ABBREVIATIONSTC taurocholatePRL prolactinOVX ovarlectomizedSRm seO@tOfy rate maximumoPRL ovinePAL. 8

Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes

BACKGROUND: Lactation increases energy demands four- to five-fold, leading to a two- to three-fold increase in food consumption, requiring a proportional adjustment in the ability of the lactating dam to absorb nutrients and to synthesize critical biomolecules, such as cholesterol, to meet the dietary needs of both the offspring and the dam. The size and hydrophobicity of the bile acid pool increases during lactation, implying an increased absorption and disposition of lipids, sterols, nutrients, and xenobiotics. In order to investigate changes at the transcriptomics level, we utilized an exon array and calculated expression levels to investigate changes in gene expression in the liver, duodenum, jejunum, and ileum of lactating dams when compared against age-matched virgin controls. RESULTS: A two-way mixed models ANOVA was applied to detect differentially expressed genes. Significance calls were defined as a p \u3c 0.05 for the overall physiologic state effect (lactation vs. control), and a within tissue pairwise comparison of p \u3c 0.01. The proportion of false positives, an estimate of the ratio of false positives in the list of differentially expressed genes, was calculated for each tissue. The number of differentially expressed genes was 420 in the liver, 337 in the duodenum, 402 in the jejunum, and 523 in the ileum. The list of differentially expressed genes was in turn analyzed by Ingenuity Pathways Analysis (IPA) to detect biological pathways that were overrepresented. In all tissues, sterol regulatory element binding protein (Srebp)-regulated genes involved in cholesterol synthesis showed increased mRNA expression, with the fewest changes detected in the jejunum. We detected increased Scap mRNA in the liver only, suggesting an explanation for the difference in response to lactation between the liver and small intestine. Expression of Cyp7a1, which catalyzes the rate limiting step in the bile acid biosynthetic pathway, was also significantly increased in liver. In addition, decreased levels of mRNA associated with T-cell signaling were found in the jejunum and ileum. Several members of the Solute Carrier (SLC) and Adenosine Triphosphate Binding Cassette (ABC) superfamilies of membrane transporters were found to be differentially expressed; these genes may play a role in differences in nutrient and xenobiotic absorption and disposition. mRNA expression of SLC39a4_predicted, a zinc transporter, was increased in all tissues, suggesting that it is involved in increased zinc uptake during lactation. Microarray data are available through GEO under GSE19175. CONCLUSIONS: We detected differential expression of mRNA from several pathways in lactating dams, including upregulation of the cholesterol biosynthetic pathway in liver and intestine, consistent with Srebp activation. Differential T-Cell signaling in the two most distal regions of the small intestine (ileum and jejunum) was also noted, as well as differential expression of transporters that likely play a key role in nutrient uptake

Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor

Multidrug resistance–associated protein 3 (Mrp3; Abcc3) expression and activity are up-regulated in rat liver after in vivo repeated administration of ethynylestradiol (EE), a cholestatic synthetic estrogen, whereas multidrug resistance-associated protein 2 (Mrp2) is down-regulated. This study was undertaken to determine whether Mrp3 induction results from a direct effect of EE, independent of accumulation of any endogenous common Mrp2/Mrp3 substrates resulting from cholestasis and the potential mediation of estrogen receptor (ER). In in vivo studies, male rats were given a single, noncholestatic dose of EE (5 mg/kg s.c.), and basal bile flow and the biliary excretion rate of bile salts and glutathione were measured 5 hours later. This treatment increased Mrp3 mRNA by 4-fold, detected by real-time polymerase chain reaction, despite the absence of cholestasis. Primary culture of rat hepatocytes incubated with EE (1–10 µM) for 5 hours exhibited a 3-fold increase in Mrp3 mRNA (10 µM), consistent with in vivo findings. The increase in Mrp3 mRNA by EE was prevented by actinomycin D, indicating transcriptional regulation. When hepatocytes were incubated with an ER antagonist [7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI182/780), 1 µM], in addition to EE, induction of Mrp3 mRNA was abolished, implicating ER as a key mediator. EE induced an increase in ER-α phosphorylation at 30 minutes and expression of c-Jun, a well-known ER target gene, at 60 minutes, as detected by Western blotting of nuclear extracts. These increases were prevented by ICI182/780. In summary, EE increased the expression of hepatic Mrp3 transcriptionally and independently of any cholestatic manifestation and required participation of an ER, most likely ER-α, through its phosphorylation.Fil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Rigalli, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Arias, Agostina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Banchio, Claudia Elena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Vore, Mary. University Of Kentucky; Estados UnidosFil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); ArgentinaFil: Catania, Viviana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentin