The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing ...enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
•CAR, PXR, and AhR coordinate xenobiotic biotransformation and detoxification.•All three xenobiotic receptors also regulate energy homeostasis and cell proliferation.•These receptors are activated through both ligand binding (direct) and indirect mechanisms.•A particular focus is given to ligand-independent (indirect) activation of these receptors.
Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been ...extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.
Drug-metabolizing enzymes (DMEs) and transporters play pivotal roles in the disposition and detoxification of numerous foreign and endogenous chemicals. To accommodate chemical challenges, the ...expression of many DMEs and transporters is up-regulated by a group of ligand-activated transcription factors namely nuclear receptors (NRs). The importance of NRs in xenobiotic metabolism and clearance is best exemplified by the most promiscuous xenobiotic receptors: pregnane X receptor (PXR, NR1I2) and constitutive androstane/activated receptor (CAR, NR1I3). Together, these two receptors govern the inductive expression of a largely overlapping array of target genes encoding phase I and II DMEs, and drug transporters. Moreover, PXR and CAR also represent two distinctive mechanisms of NR activation, whereby CAR demonstrates both constitutive and ligand-independent activation. In this review, recent advances in our understanding of PXR and CAR as xenosensors are discussed with emphasis placed on the differences rather than similarities of these two xenobiotic receptors in ligand recognition and target gene regulation.
A series of behavioral tests measuring social dominance, social motivation, and non-social motivation are examined in adult male C57BL6 mice. By using the well-known tube dominance test to determine ...social dominance and rank, we find that, in the absence of competition for resource and mating, group-housed mouse cage-mates display stable and mostly linear and transitive social hierarchies. Mice with top and bottom social ranks are subjected to a three-chamber social interaction test to measure social motivation. The top ranked mice spend more time interacting with a stranger mouse than the bottom ranked mice, suggesting that social dominance may positively influence social motivation. When subjected to a novel environment, mice with different social ranks show similar locomotion and exploring activity in the open field test, suggesting no detectable difference in certain aspects of non-social motivation. These results demonstrate a behavioral correlation between social dominance and social motivation.
Nonalcoholic fatty liver disease (NAFLD) is strongly linked to the global epidemic of obesity and type 2 diabetes mellitus (T2DM). Notably, NAFLD can progress from the mildest form of simple ...steatosis to nonalcoholic steatohepatitis (NASH) that increases the risk for hepatocellular carcinoma (HCC), which is a malignancy with a dismal prognosis and rising incidence in the United States and other developed counties, possibly due to the epidemic of NAFLD. Metformin, the first-line drug for T2DM, has been suggested to reduce risks for several types of cancers including HCC and protect against NASH-related HCC, as revealed by epidemical studies on humans and preclinical studies on animal models. This review focuses on the pathogenesis of NASH-related HCC and the mechanisms by which metformin inhibits the initiation and progression of NASH-related HCC. Since the functional role of immune cells in liver homeostasis and pathogenesis is increasingly appreciated in developing anti-cancer therapies on liver malignancies, we discuss both the traditional targets of metformin in hepatocytes and the recently defined effects of metformin on immune cells.
Two-dimensional (2D) MXene Ti3C2 nanosheets are prepared by liquid phase exfoliation of layered Ti3AlC2 in aqueous solution of HF, followed by alkalization and calcination. The electrical properties ...of the as-prepared Ti3C2 nanosheets are investigated as a function of calcining temperatures to find the optimum process condition. The microstructures and structural changes of the MXene Ti3C2 nanosheets are studied by X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). It is found that the post-treatment processes could effectively remove the functional groups on the surface of 2D nanosheets to enhance the electrical properties of MXene Ti3C2. As a result, the MXene Ti3C2 nanosheets after calcination at 600°C exhibit a high conductivity of 2140S/cm, nearly three times as high as that of the un-treated Ti3C2 samples.
•The conductivity of 2D Ti3C2 nanosheets was greatly improved by post-treatments.•Calcination removed effectively surface OH functional groups of MXene nanosheets.•The flake nanostructure of Ti3C2 collapsed to form TiO2 after 800°C calcination.
The type 1 and 8 adenylyl cyclase (ADCY1 and ADCY8) exclusively account for Ca
2+
-stimulated cyclic AMP (cAMP) production and regulate activity-dependent synaptic modification. In this study, we ...examined distinct forms of synaptic plasticity in the hippocampus of
Adcy1
−/−
and
Adcy8
−/−
mice. We found that, at the Schaffer collateral-CA1 synapses, while the
Adcy8
−/−
mice displayed normal long-term potentiation (LTP) following various induction protocols with high-frequency stimulation (HFS), the
Adcy1
−/−
mice showed protocol-dependent deficits in LTP. We also found that long-term depression (LTD) requires ADCY1 but not ADCY8. Interestingly, both
Adcy1
−/−
and
Adcy8
−/−
mice showed defective synaptic depotentiation (i.e., activity-dependent reversal of LTP); the deficits in
Adcy8
−/−
mice were dependent on the induction protocol. Examination of spatial memory found that ADCY1 is required for the formation of both initial and reversal memory. ADCY8 is only required for reversal memory formation. These data demonstrate that ADCY1 and ADCY8 play distinct roles in regulating synaptic and cognitive flexibility that involves bidirectional modification of synaptic function.
•We examined multiple behavioral phenotypes in Fmr1 KO mice on the C57BL/6 background.•Both male and female Fmr1 KO mice displayed significant audiogenic seizures and hyperactivity in the open field ...and light–dark test.•Both male and female Fmr1 KO mice showed impaired contextual and passive avoidance memory and altered PPI.
Fragile X syndrome (FXS) is a monogenic disease caused by mutations in the FMR1 gene. The Fmr1 knockout (KO) mice show many aspects of FXS-related phenotypes, and have been used as a major pre-clinical model for FXS. Although FXS occurs in both male and female patients, most studies on the mouse model use male animals. Few studies test whether gender affects the face validity of the mouse model. Here, we examined multiple behavioral phenotypes with male hemizygous and female homozygous Fmr1 KO mice on C57BL/6 background. For each behavioral paradigm, we examined multiple cohorts from different litters. We found that both male and female Fmr1 KO mice displayed significant audiogenic seizures, hyperactivity in the open field test, deficits in passive avoidance and contextual fear memory, and significant enhancement of PPI at low stimulus intensity. Male and female Fmr1 KO mice also showed more transitional movement between the lit and dark chambers in the light–dark tests. The lack of gender effects suggests that the Fmr1 KO mouse is a reasonable tool to test the efficacy of potential FXS therapies.
Recently, extensive studies unveiled that lncRNAs exert critical function in the development and progression of cervical cancer (CC). EGFR-AS1 is a novel lncRNA which has not been well-explored in ...CC.
Our study aimed to research the function and molecular mechanism of EGFR-AS1 in CC cells. qRT-PCR analysis was performed to detect gene expression. Colony formation, EdU, flow cytometry, TUNEL, western blot and transwell assays were performed to assess the effect of EGFR-AS1 on CC cell growth. The regulatory mechanism of EGFR-AS1 was dug out through mechanism experiments.
EGFR-AS1 was notably overexpressed in CC cell lines. Loss-of-functional experiments revealed that EGFR-AS1 promoted CC cell proliferation, migration and invasion, and suppressed cell apoptosis. Mechanistically, up-regulation of EGFR-AS1 was attributed to the activation of H3K27 acetylation (H3K27ac). Further, EGFR-AS1 was revealed to function as miR-2355-5p sponge. Additionally, miR-2355-5p was down-regulated in CC cells and ACTN4 was identified as a target gene of miR-2355-5p. Ultimately, overexpressed ACTN4 could reserve the suppressive role of EGFR-AS1 silencing in CC cell growth. Last but not least, EGFR-AS1 facilitated CC cell growth via ACTN4-mediated WNT pathway.
H3K27ac-activated EGFR-AS1 sponged miR-2355-5p and promoted CC cell growth through ACTN4-mediated WNT pathway.
Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed.The discovery of multiple important substrates of CYP2B6 as well as ...polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme.The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor(CAR) and pregnane X receptor(PXR) in the liver.In addition to CYP2B6,these receptors also mediate the inductive expression of CYP3A4,and a number of important phase II enzymes and drug transporters.CYP2B6 has been demonstrated to play a role in the metabolism of 2%–10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide,anesthetics propofol and ketamine,synthetic opioids pethidine and methadone,and the antiretrovirals nevirapine and efavirenz,among others.Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs.These variances arise from a number of sources including genetic polymorphism,and xenobiotic intervention.In this review,we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug–drug interactions.
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