Developmental regulation of kidney and liver solute carrier and ATP-binding cassette drug transporters and drug metabolizing enzymes: the role of remote organ communication

Introduction: The ontogeny of drug transport and metabolism is generally studied independently in tissues, yet in the immediate postnatal period the developmental regulation of SLC and ABC transporters and metabolizing enzymes must be coordinated. Using the Remote Sensing and Signaling Hypothesis as a framework, we describe how a systems physiology view helps to make sense of how inter-organ communication via hepatic, renal, and intestinal transporters and drug metabolizing enzymes (DMEs) is regulated from the immediate postnatal period through adulthood.

Areas covered: This review examines patterns of developmental expression and function of transporters and DMEs with a focus on how cross-talk between these proteins in the kidney, liver and other organs (e.g., intestine) may be coordinated postnatally to optimize levels of metabolites and endogenous signaling molecules as well as gut-microbiome products.

Expert opinion/commentary: Developmental expression is considered in terms of the Remote Sensing and Signaling Hypothesis, which addresses how transporters and DMEs participate in inter-organ and inter-organism small molecule communication in health, development, and disease. This hypothesis, for which there is growing support, is particularly relevant to the ‘birth transition’ and post-natal developmental physiology when organs must deal with critical physiological tasks distinct from the fetal period and where remote inter-organ and possibly inter-organismal (e.g. infant-gut microbiome) communication is likely to be critical to maintain homeostasis.     

Adenylyl cyclase type 6 overexpression selectively enhances β-adrenergic and prostacyclin receptor-mediated inhibition of cardiac fibroblast function because of colocalization in lipid rafts

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor beta and inhibited by agents that elevate 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this colocalization was functionally relevant. We found that cardiac fibroblasts produce cAMP in response to agonists for beta-adrenergic (isoproterenol), prostaglandin EP(2) (butaprost), adenosine (adenosine-5'-N-ethylcarboxamide, NECA), and prostacyclin (beraprost) receptors. Overexpression of AC6 increased cAMP production stimulated by isoproterenol and beraprost but not by butaprost or NECA. A key function of fibroblasts is the production of collagen. Isoproterenol- and beraprostmediated inhibition of collagen synthesis was also enhanced by AC6 overexpression, while inhibition by butaprost and NECA were unaltered. Lipid raft fractions from cardiac fibroblasts contain the preponderance of beta-adrenergic receptors and AC6 but exclude EP(2) receptors. While we could not determine the localization of native prostacyclin receptors, we were able to determine that epitope-tagged prostanoid IP receptors (IPR) expressed in COS7 cells did localize, in part, in lipid raft fractions. These findings indicate that IP receptors are expressed in lipid rafts and can activate raft-localized AC isoforms. AC6 is completely compartmentized in lipid raft domains where it is activated solely by coresident G protein-coupled receptors to regulate cardiac fibroblast function.     

IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation

Background  

A recent in vitro study indicates that IGOB131, a novel seed extract of the traditional West African food plant Irvingia gabonensis, favorably impacts adipogenesis through a variety of critical metabolic pathways including PPAR gamma, leptin, adiponectin, and glycerol-3 phosphate dehydrogenase. This study was therefore aimed at evaluating the effects of IGOB131, an extract of Irvingia gabonensis, on body weight and associated metabolic parameters in overweight human volunteers.     

Serum leptin and total dietary energy intake: the INTERLIPID Study

Purpose

It has been hypothesized that leptin-induced appetite suppression is impaired in obese individuals, but little human evidence is available documenting this. We investigated relations between serum leptin and total energy intake using INTERLIPID/INTERMAP data on Japanese–Americans in Hawaii and Japanese in Japan.

Methods

Serum leptin and nutrient intakes were examined by standardized methods in men and women aged 40–59 years from two population samples, one Japanese–American in Hawaii (88 men, 94 women), the other Japanese in central Japan (123 men, 111 women). Multiple linear regression analyses stratified by BMI category (<25 kg/m², 25–29.9 kg/m², and ≥30 kg/m²) with adjustment for possible confounders were used to examine the relation between log-leptin and total dietary energy intake.

Results

In multivariate regression analyses, in those with BMI < 25 kg/m² and in those with BMI between 25 and 29.9 kg/m², log-leptin was not significantly related to total dietary energy intake; in those with BMI ≥ 30 kg/m², it was significantly inversely related to total dietary energy intake (P = 0.029), independent of body weight and physical activity. Physical activity score was significantly positively related to total dietary energy intake only in participants with BMI < 25 kg/m² (P < 0.001).

Conclusion

Leptin was significantly inversely associated with dietary energy intake in obese persons, but not in overweight and normal-weight persons.     

Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations

Vitamin A deficiency (VAD) is an important public health problem worldwide that contributes significantly to the global burden of disease. Vitamin A deficiency disorders include xerophthalmia and increased risk of infectious diseases, both of which increase risk of mortality. Xerophthalmia is also a leading cause of preventable blindness. Areas with highly prevalent VAD often share common dietary and other environmental exposures, including poverty, infectious diseases, limited development and poor availability of vitamin A containing food. Globally, the prevalence of VAD has been declining, which may be due to widespread vitamin A supplementation in conjunction with measles immunisation in at-risk populations. Recent meta-analyses confirm that provision of vitamin A to children aged between 6 months and 5 years confers a significant mortality benefit. Further preventative measures for VAD comprise improving availability of vitamin A containing food, including foods biofortified with vitamin A. Ensuring vitamin A is available in any form in adequate quantities remains problematic, especially in areas affected by environmental catastrophes and conflict, and other areas where access to vitamin A containing foods and healthcare interventions is limited. Hence, it remains essential that maternal and child health workers remain vigilant for VAD in nutritionally vulnerable populations.     

Effect of snake venom procoagulants on snake plasma: implications for the coagulation cascade of snakes.

Several snake venoms contain proteinases that activate zymogens in the coagulation cascade and thus exhibit their procoagulant effects. While most procoagulant proteinases from snake venoms are dissimilar to coagulation factors, Group D (trocarin, notecarin) and C (pseutarin) prothrombin activators are structural and functional homologues of factor Xa and the prothrombinase complex, respectively. We examined the effect of these and other procoagulants from snake venoms as well as mammalian and snake thromboplastins on the coagulation of plasmas of Notechis scutatus, Pseudonaja textilis (both procoagulant venoms), Python reticulatus (non-venomous) and Crotalus atrox (non-procoagulant venom) snakes. The results indicate that the intrinsic pathway seems to be weak or absent only in venomous snakes, while the extrinsic pathway is fully functional in all snakes. Python and Crotalus plasmas have extrinsic pathways similar to that in mammals. In contrast, although Notechis and Pseudonaja plasmas were clotted by a Group C activator, they failed to clot upon the addition of factor Xa and Group D activators. The mechanism of this resistance is still elusive.     

The critical role of transmembrane prolines in human prostacyclin receptor activation

The human prostacyclin receptor (hIP), a G protein-coupled receptor (GPCR), plays important roles in vascular smooth muscle relaxation as well as the prevention of platelet aggregation. It has been postulated that GPCR transmembrane (TM) prolines serve as molecular hinges or swivels and are necessary for proper binding and activation. By individually (as well as collectively) mutating these hIP prolines to alanine, the ability to form key structural and functional configurations was removed. Significant effects on both binding and activation were observed. Two highly conserved prolines across GPCRs, Pro-154, and Pro-254 (TMVI), showed the greatest effect on decreasing both binding and activation when changed to alanine. Along the extracellular boundary of the highly conserved transmembrane III domain, a proline-to-alanine mutation at position 89 (P89A) revealed normal binding affinity in comparison with the 1D4-epitope-tagged hIP (hIP1D4) wild-type control (K(i), iloprost = 3 +/- 2 versus 7 +/- 3 nM, respectively). In contrast, activation was markedly affected, with an EC(50) of 12.0 +/- 2.5 nM compared with that of 1.2 +/- 0.3 nM (10-fold difference) for the hIP1D4. Movement within TMIII has been shown to be necessary for effective GPCR activation. Both the extracellular location (above the putative binding pocket) along with an exclusive effect upon activation suggest that this movement is facilitated by the presence of Pro-89 and independent from the actions of ligand binding. This finding strongly supports a model in which proline residues serve as molecular hinges or swivels, essential for coupling receptor binding to activation.     

Race/ethnicity, income, major risk factors, and cardiovascular disease mortality

OBJECTIVES: We explored differences between Black and White men for cardiovascular disease (CVD) mortality across major risk factor levels. METHODS: Major CVD risk factors were measured among 300,647 White and 20,223 Black men aged 35 to 57 years who were screened for the Multiple Risk Factor Intervention Trial (MRFIT). Hazard ratios for CVD deaths for Black and White men over 25 years of follow-up were calculated for subgroups stratified according to risk factor levels. RESULTS: CVD was responsible for 2518 deaths among Black men and 30,772 deaths among White men. The age-adjusted Black-to-White CVD hazard ratio was 1.35 (95% confidence interval [CI]=1.29, 1.40); the risk- and income-adjusted ratio was 1.05 (95% CI=1.01, 1.10). CVD mortality rates were dramatically lower in cases of favorable risk profiles. However, fully adjusted Black-to-White CVD hazard ratios within groups at low, intermediate, high, and very high levels of overall risk were 1.76, 1.20, 1.10, and 0.94, respectively. Similar gradients were evident for individual risk factors. CONCLUSIONS: Higher CVD mortality rates among Black men were largely mediated by risk factors and income. These data underscore the need for sustained primordial risk factor prevention among Black men.     

Acquisition of responding with a remifentanil-associated conditioned reinforcer in the rat

Rationale

Drug-associated environmental stimuli may serve as conditioned reinforcers to enhance drug self-administration behaviors in humans and laboratory animals. However, it can be difficult to distinguish experimentally the conditioned reinforcing effects of a stimulus from other behavioral processes that can change rates of responding.

Objectives

To characterize the conditioned reinforcing effects of a stimulus paired with the μ-opioid agonist, remifentanil, using a new-response acquisition procedure in the rat.

Methods

First, in Pavlovian conditioning (PAV) sessions, rats received response-independent IV injections of remifentanil and presentations of a light-noise compound stimulus. In paired PAV groups, injections and stimulus presentations always co-occurred. In random PAV control groups, injections and stimulus presentations occurred with no consistent relationship. Second, in instrumental acquisition (ACQ) sessions, all animals could respond in an active nose-poke that produced the stimulus alone or in an inactive nose-poke that had no scheduled consequences.

Results

During ACQ, rats made significantly more active nose-pokes than inactive nose-pokes after paired PAV, but not after random PAV. Between groups, rats also made more active nose-pokes after paired PAV than after random PAV. After paired PAV, increased active responding was obtained under different schedules of reinforcement, persisted across multiple ACQ sessions, and depended on the number of PAV sessions conducted.

Conclusions

The remifentanil-paired stimulus served as a conditioned reinforcer for nose-poking: responding depended on both the contingency between the stimulus and remifentanil and the contingency between the nose-poke and the stimulus. Generally, new-response acquisition procedures may provide valid, flexible models for studying opioid-based conditioned reinforcement.     

A Study of Expectations and the Marital Quality of Participants of a Marital Enrichment Seminar

This longitudinal study investigated the effects of expectations of effort of self and spouse on the marital quality of marital enrichment seminar participants. Self‐report measures of marital quality, expectations regarding effort put into implementing what was learned during the seminar, amount of perceived effort, and satisfaction with effort were administered before and after the seminar, as well as at a 2‐month follow‐up. Participants (147 women, 95 men) attended community‐based marital enrichment seminars in 12 U.S. cities. Multivariate path models indicated that larger discrepancies between expectations of effort postseminar and perceived effort at 2‐month follow‐up were associated with less satisfaction with perceived effort. Furthermore, participants' dissatisfaction in their spouses' effort had a negative effect on marital quality while controlling for initial marital quality, whereas dissatisfaction in their own effort did not. These findings highlight the possible detrimental effect that unmet spousal expectations can have. Implications for marital enrichment programs and couples therapy are discussed.