Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls.

Pharmacogenomics. 2018 Jan;19(2):95-104

Authors: Randesi M, van den Brink W, Levran O, Yuferov V, Blanken P, van Ree JM, Ott J, Kreek MJ

Abstract
AIM: To determine whether specific dopaminergic system gene variants are associated with opioid dependence.
PATIENTS & METHODS: Subjects included 153 healthy controls, 163 opioid exposed, but not dependent and 281 opioid dependent. Genotypes of 90 variants in 13 genes were examined.
RESULTS: The most significant results were obtained for DA β-hydroxylase variants, rs2073837 and rs1611131, which were associated with protection from addiction (q = 0.0172, 0.0415, respectively) and the functional TH variant, rs2070762, was associated with more risk (q = 0.0387). The three variants also showed a combined effect that remained significant after correction for multiple testing (pfinal = 0.0039).
CONCLUSION: These data offer support that dopaminergic gene variants have a role in opioid dependence and warrant further study.

PMID: 29210332 [PubMed - indexed for MEDLINE]

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

Pharmacogenomics. 2018 Jan;19(2):105-112

Authors: Ceppi F, Gagné V, Douyon L, Quintin CJ, Colombini A, Parasole R, Buldini B, Basso G, Conter V, Cazzaniga G, Krajinovic M

Abstract
AIM: We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses.
METHODS: Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome.
RESULTS: The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%).
CONCLUSION: The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

PMID: 29210328 [PubMed - indexed for MEDLINE]

Genetic variation in statin intolerance and a possible protective role for UGT1A1.

Pharmacogenomics. 2018 Jan;19(2):83-94

Authors: V Willrich MA, Kaleta EJ, Bryant SC, Spears GM, Train LJ, Peterson SE, Lennon VA, Kopecky SL, Baudhuin LM

Abstract
The etiology of statin intolerance is hypothesized to be due to genetic variants that impact statin disposition and clearance. We sought to determine whether genetic variants were associated to statin intolerance. The studied cohort consisted of hyperlipidemic participants (n = 90) clinically diagnosed with statin intolerance by a cardiologist and matched controls without statin intolerance. Creatine kinase activity, lipid profiles and genetic analyses were performed on genes involved in statin metabolism and included UGT1A1 and UGT1A3 sequencing and targeted analyses of CYP3A4*22, CYP3A5*3, SLCO1B1*5 and *1b, ABCB1 c.3435C>T, ABCG2 c.421C>A and GATM rs9806699. Although lipids were higher in cases, genetic variant minor allele frequencies were similar between cases and controls, except for UGT1A1*28, which was less prevalent in cases than controls.

PMID: 29210320 [PubMed - indexed for MEDLINE]

NR3C1 gene polymorphisms are associated with steroid resistance in patients with primary nephrotic syndrome.

Pharmacogenomics. 2018 Jan;19(1):45-60

Authors: Liu J, Wan Z, Song Q, Li Z, He Y, Tang Y, Xie W, Xie Y, Zhang J

Abstract
AIM: The aim of this study was to investigate the role of SNPs of genes involved in the glucocorticoid pathway in the development of steroid resistance in patients with primary nephrotic syndrome.
METHODS: Sequenom MassARRAY method was used to sequence 25 SNP genotypes in 154 patients. The frequency distribution of the genotypes was compared between patients with steroid-sensitive nephrotic syndrome and those with steroid-resistant nephrotic syndrome.
RESULTS: NR3C1 rs6196 G allele carriers had a decreased risk of steroid resistance compared with that of the A allele carriers. The presence of rs10052957 and rs258751 A alleles could reduce the incidence of steroid resistance compared with that with G allele. Haplotype analysis showed AAG and GGA haplotypes that contain NR3C1 rs10052957, rs258751 and rs6196 were associated with steroid resistance.
CONCLUSION: NR3C1 gene polymorphisms are significantly associated with the response to glucocorticoids in patients with primary nephrotic syndrome.

PMID: 29207898 [PubMed - indexed for MEDLINE]

Recent trends on the role of epigenomics, metabolomics and noncoding RNAs in rationalizing mood stabilizing treatment.

Pharmacogenomics. 2018 Jan;19(2):129-143

Authors: Pisanu C, Katsila T, Patrinos GP, Squassina A

Abstract
Mood stabilizers are the cornerstone in treatment of mood disorders, but their use is characterized by high interindividual variability. This feature has stimulated intensive research to identify predictive biomarkers of response and disentangle the molecular bases of their clinical efficacy. Nevertheless, findings from studies conducted so far have only explained a small proportion of the observed variability, suggesting that factors other than DNA variants could be involved. A growing body of research has been focusing on the role of epigenetics and metabolomics in response to mood stabilizers, especially lithium salts. Studies from these approaches have provided new insights into the molecular networks and processes involved in the mechanism of action of mood stabilizers, promoting a systems-level multiomics synergy. In this article, we reviewed the literature investigating the involvement of epigenetic mechanisms, noncoding RNAs and metabolomic modifications in bipolar disorder and the mechanism of action and clinical efficacy of mood stabilizers.

PMID: 29199496 [PubMed - indexed for MEDLINE]

A genomic characterization of the influence of silver nanoparticles on bone differentiation in MC3T3-E1 cells.

J Appl Toxicol. 2018 Feb;38(2):172-179

Authors: Qing T, Mahmood M, Zheng Y, Biris AS, Shi L, Casciano DA

Abstract
Silver nanoparticles (AgNPs) have been widely used in a variety of biomedical applications. Previous studies demonstrated that AgNPs significantly enhanced bone cell mineralization and differentiation in MC3T3-1 cells, a model in vitro system, when compared to several other NPs. This increased bone deposition was evaluated by phenotypic measurements and assessment of the expression of miRNAs associated with regulation of bone morphogenic proteins. In the present study, we used RNA-seq technology, a more direct measurement of gene expression, to investigate further the mechanisms of bone differentiation induced by AgNP treatment. Key factors associated with the osteoclast pathway were significantly increased in response to AgNP exposure including Bmp4, Bmp6 and Fosl1. In addition, genes of metabolism and toxicity pathways were significantly regulated as well. Although this study suggests the potential for AgNPs to influence bone morphogenesis in injury or disease applications, further investigation into the efficacy and safety of AgNPs in bone regeneration is warranted.

PMID: 28975650 [PubMed - indexed for MEDLINE]

Structural constraints and importance of caffeic acid moiety for anti-hyperglycemic effects of caffeoylquinic acids from chicory.

Mol Nutr Food Res. 2017 Sep;61(9):

Authors: Jackson KMP, Rathinasabapathy T, Esposito D, Komarnytsky S

Abstract
SCOPE: Chicory (Cichorium intybus L.) is a perennial herb often consumed as a vegetable, whereas the ground and roasted roots are blended as a coffee substitute. Caffeoylquinic or chlorogenic acids (CQA), the abundant intermediates of lignin biosynthesis in chicory, have been reported to improve glucose metabolism in humans, but the functional group in their structure responsible for this effect has not been yet characterized.
METHODS AND RESULTS: Here, we showed that three di-O-caffeoylquinic acids suppressed hepatic glucose production in H4IIE rat hepatoma cells by reducing expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes that regulate hepatic gluconeogenesis. Direct comparisons between CQAs and their metabolites (3-caffeoylquinic, caffeic, and quinic acids) revealed the caffeic acid moiety alone was responsible for the observed effects. Further analysis suggested the activation of PI3K and MAPK pathways as a method of controlling gene expression was shared between caffeoylquinic and caffeic acids. These compounds promoted increased mitochondrial respiration and cellular metabolism, in part by inducing oxidative phosphorylation and proton leak.
CONCLUSION: We concluded that the caffeic acid moiety was important for suppression of hepatic gluconeogenesis and hyperglycemia, ultimately strengthening the link between dietary interventions based on caffeic acid-containing plant foods and healthy glucose metabolism.

PMID: 28371117 [PubMed - indexed for MEDLINE]

Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion.

J Bone Miner Metab. 2018 Jul 21;:

Authors: Yan Z, Zhu S, Tian X, Ye Z, Zhai D, Zhu Z, Wei D, Zhu Q, Lu Z, Cao X

Abstract
Metformin, an anti-hyperglycemic agent used for type 2 diabetes, has recently been found to have more effects apart from glucose regulation. We found that, in ultra-high-molecular-weight polyethylene particle-induced osteolysis mouse models, metformin had bone protect property and reduced the negative regulator of bone formation sclerostin (SOST) and Dickkopf-related protein 1 (DKK1), and increased osteoprotegerin (OPG) secretion and the ratio of OPG/Receptor Activator for Nuclear Factor-κB Ligand (RANKL). In vitro, we established a 3D co-culture system in which metformin affects osteoblasts and osteoclasts through mature osteocytes secretion. Metformin (50 μM) significantly decreased SOST and DKK1 mRNA expression, stimulating alkaline phosphatase activity and proliferation of osteoblast, and increased OPG secretion and the ratio of OPG/RANKL, inhibiting osteoclastogenesis. Moreover, the effect on OPG was reversed by adenosine 5'-monophosphate-activated protein kinase inhibitor, Compound C. Our finding suggests that metformin induces differentiation and mineralization of osteoblasts, while inhibits osteoclastogenesis via mature osteocytes secretion. Therefore, the drug might be beneficial for not only diabetes but also in other bone disorders by acting on mature osteocytes.

PMID: 30032440 [PubMed - as supplied by publisher]

Variation within voltage-gated calcium channel genes and antipsychotic treatment response in a South African first episode schizophrenia cohort.

Pharmacogenomics J. 2018 Jul 22;:

Authors: O'Connell KS, McGregor NW, Malhotra A, Lencz T, Emsley R, Warnich L

Abstract
Voltage-gated calcium channels have been implicated in schizophrenia aetiology; however, little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Twelve regulatory variants within seven genes were shown to be significantly associated with treatment outcome. Most notably, the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.

PMID: 30032160 [PubMed - as supplied by publisher]

Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies.

Eur J Med Chem. 2018 Jul 17;156:631-640

Authors: Szulczyk D, Dobrowolski MA, Roszkowski P, Bielenica A, Stefańska J, Koliński M, Kmiecik S, Jóźwiak M, Wrzosek M, Olejarz W, Struga M

Abstract
A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1-208 μM (0.25-64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 μM).

PMID: 30031974 [PubMed - as supplied by publisher]

PD-1, PD-L1 and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications.

Hum Pathol. 2018 Jul 18;:

Authors: Luchini C, Cros J, Pea A, Pilati C, Veronese N, Rusev B, Capelli P, Mafficini A, Nottegar A, Brosens LAA, Noë M, Offerhaus GJA, Chianchiano P, Riva G, Piccoli P, Parolini C, Malleo G, Lawlor RT, Corbo V, Sperandio N, Barbareschi M, Fassan M, Cheng L, Wood LD, Scarpa A

Abstract
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1 and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extra-pancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas (ACs) were immunostained using antibodies against PD-1, PD-L1 and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17/27 (63%) cases, more often in cases with an associated PDAC (P=.04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than patients with PD-L1-negative UCOGCs (HR: 3.397, 95%CI: 1.023-18.375, P=.034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P=.035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extra-pancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. ACs have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

PMID: 30031096 [PubMed - as supplied by publisher]

Frequency of tumour necrosis factor alpha receptor superfamily 1A multiple sclerosis-associated variants in patients with rheumatoid arthritis with anti-tumour necrosis factor therapy-related demyelinating complications.

Ann Rheum Dis. 2018 Jul 20;:

Authors: Bitoun S, Miceli-Richard C, Verstuyft C, Juge PA, Dieudé P, Berthelot JM, Richez C, Cauquil C, Sordet C, Melac-Ducamp S, Gossec L, Bouvard B, Dernis E, Houvenagel E, Boutry-Bacle MA, Mariette X, Seror R

PMID: 30030263 [PubMed - as supplied by publisher]

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

Pharmacogenomics. 2018 Jul 20;:

Authors: Klein MD, Lee CR, Stouffer GA

Abstract
It is well established that the CYP2C19 nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

PMID: 30028231 [PubMed - as supplied by publisher]

Pharmacogenetics and cognitive symptoms in schizophrenia patients treated with antipsychotics.

Pharmacogenomics. 2018 Jul 20;:

Authors: Musil R, Spellmann I

PMID: 30028229 [PubMed - as supplied by publisher]

HE4 and eIF3a Expression Correlates with Surgical Outcome and Overall Survival in Ovarian Cancer Patients with Secondary Cytoreduction.

J Cancer. 2018;9(14):2472-2479

Authors: Luo CH, Zhao M, Chen XY, Shahabi S, Qiang W, Zeng L, Wang J, Zhou HH

Abstract
For recurrent ovarian cancer (ROC), secondary cytoreductive surgery (SCS) is recommended as one optional treatment. However, little is known about the expression and clinical significance of biomarkers during SCS. Human epididymis protein 4 (HE4) is a clinical biomarker for ovarian cancer. Eukaryotic translation initiation factor 3a (eIF3a) is investigated extensively as a potential biomarker for malignancy. The purpose of this study was to investigate the expressions of HE4 and eIF3a at SCS, as well as their associations with surgical outcome and survival in ROC patients. Immunohistochemistry was performed to determine the expressions of HE4 and eIF3a in ovarian tumors taken from both initial and secondary cytoreductive surgery of 35 ROC patients. eIF3a levels were significantly increased at SCS, compared to those at initial cytoreductive surgery (ICS), while HE4 levels were similar. Both HE4 and eIF3a expressions were associated with surgical outcome, in terms of residual tumor. For ICS, patients with high HE4 expression achieved a higher incidence of optimal cytoreduction than those with low HE4 expression (81.0% vs. 33.3%, P = 0.015). A similar result happened in SCS, indicated by higher incidence of no residual tumor in patients with high HE4 expression (76.4% vs. 44.4%, P = 0.046). And high HE4 expression at SCS was more likely to enhance surgical outcome of SCS (77.8% vs. 29.4%, P = 0.038). Therefore, high HE4 expression at either surgery is a predictor of better overall survival (OS) (P = 0.011 and 0.002). Furthermore, patients with an elevated total score (TS) of HE4 between the two surgeries tended to have prolonged OS, compared to those with a non-elevated TS of HE4 (P = 0.076). For eIF3a, initial eIF3a expression was associated with secondary residual tumor (P = 0.035), and the difference in eIF3a expression between the two surgeries correlated with OS (P = 0.052). The expressions of HE4 and eIF3a in tumor specimens correlated with surgical outcome and predicted OS in ROC patients with SCS, thus meriting further investigation.

PMID: 30026845 [PubMed]

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents.

Child Adolesc Psychiatry Ment Health. 2018;12:37

Authors: Dodsworth T, Kim DD, Procyshyn RM, Ross CJ, Honer WG, Barr AM

Abstract
The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug-drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.

PMID: 30026806 [PubMed]

Bush mint (Hyptis suaveolens) and spreading hogweed (Boerhavia diffusa) medicinal plant extracts differentially affect activities of CYP1A2, CYP2D6 and CYP3A4 enzymes.

J Ethnopharmacol. 2018 Jan 30;211:58-69

Authors: Ekow Thomford N, Dzobo K, Adu F, Chirikure S, Wonkam A, Dandara C

Abstract
ETHNO-PHARMACOLOGICAL RELEVANCE: Hyptis suaveolens (L) Poit and Boerhavia diffusa Linn are medicinal herbal plants commonly found in the tropics and sub-tropics. They are used to treat various conditions among them boils, dyslipidaemia, eczema, malaria, jaundice and gonorrhoea. Thus, the herbal medicinal extracts are now found as part of some commercial herbal formulations. There has not been adequate characterization of these medicinal herbs on their effects on drug metabolising enzymes.
AIM OF THE STUDY: To investigate the effects of extracts of Hyptis suaveolens (HS) and Boerhavia diffusa (BD) on activity of drug metabolising enzymes, CYP1A2, CYP2D6 and CYP3A4, as well predict their potential for herb-drug interaction. A secondary aim was to identify constituent compounds such as polyphenolics, in the crude extract preparations of Hyptis suaveolens and Boerhavia diffusa and measure them for activity.
MATERIALS AND METHODS: CYP450 inhibition assays using recombinant CYP450 (rCYP) and fluorescence screening employing individual isozymes (CYP1A2, CYP2D6 and CYP3A4) were used to determine reversible- and time-dependent inhibition (TDI) profiles of extracts of Hyptis suaveolens and Boerhavia diffusa. Inhibition kinetic parameters, Ki and Kinact were also estimated. UPLC-MS employing a Synapt G2 (ESI negative) coupled to a PDA detector was used to identify polyphenolic compounds in crude extracts of Hyptis suaveolens and Boerhavia diffusa.
RESULTS: The inhibitory potency of Hyptis suaveolens and Boerhavia diffusa extracts varied among the different enzymes, with CYP1A2 (3.68 ± 0.10µg/mL) being the least inhibited by HS compared to CYP2D6 (1.39 ± 0.01µg/mL) and CYP3A4 (2.36 ± 0.57µg/mL). BD was most potent on CYP3A4 (7.36 ± 0.94µg/mL) compared to both CYP2D6 (17.79 ± 1.02µg/mL) and CYP1A2 (9.48 ± 0.78µg/mL). Extracts of Hyptis suaveolens and Boerhavia diffusa exhibited TDIs on all CYPs. The most prominent phenolic candidates identified in both medicinal herbs using UPLC-MS analysis included caffeic acid, rutin, quercetin, citric acid, ferulic acid and gluconic acid. These phenolic compounds are thought to potentially give HS and BD their therapeutic effects and inhibitory characteristics affecting CYP450 activities. In vivo predictions showed the potential for HS and BD extracts to cause significant interactions if co-administered with other medications.
CONCLUSIONS: The study reveals that crude aqueous extracts of HS and BD potentially inhibit drug metabolising isozymes CYP1A2, CYP2D6 and CYP3A4 in a reversible and time-dependent manner. Thus care should be taken when these extracts are co-administered with drugs that are substrates of CYP1A2, CYP2D6 and CYP3A4.

PMID: 28942133 [PubMed - indexed for MEDLINE]

Calcium Signaling in Liver Injury and Regeneration.

Front Med (Lausanne). 2018;5:192

Authors: Oliva-Vilarnau N, Hankeova S, Vorrink SU, Mkrtchian S, Andersson ER, Lauschke VM

Abstract
The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non-iterative insults. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis. Calcium is a versatile secondary messenger that regulates multiple hepatic functions, including lipid and carbohydrate metabolism, as well as bile secretion and choleresis. Accordingly, dysregulation of calcium signaling is a hallmark of both acute and chronic liver diseases. In addition, recent research implicates calcium transients as essential components of liver regeneration. In this review, we provide a comprehensive overview of the role of calcium signaling in liver health and disease and discuss the importance of calcium in the orchestration of the ensuing regenerative response. Furthermore, we highlight similarities and differences in spatiotemporal calcium regulation between liver insults of different etiologies. Finally, we discuss intracellular calcium control as an emerging therapeutic target for liver injury and summarize recent clinical findings of calcium modulation for the treatment of ischemic-reperfusion injury, cholestasis and NAFLD.

PMID: 30023358 [PubMed]

Phenobarbital-induced phosphorylation converts nuclear receptor RORα from a repressor to an activator of the estrogen sulfotransferase gene Sult1e1 in mouse livers.

FEBS Lett. 2018 Jul 19;:

Authors: Fashe M, Hashiguchi T, Yi M, Moore R, Negishi M

Abstract
The estrogen sulfotransferase SULT1E1 sulfates and inactivates estrogen, which is reactivated via desulfation by steroid sulfatase, thus regulating estrogen homeostasis. Phenobarbital (PB), a clinical sedative, activates Sult1e1 gene transcription in mouse livers. Here, the molecular mechanism by which the nuclear receptors CAR, which is targeted by PB, and RORα communicate through phosphorylation to regulate Sult1e1 activation has been studied. RORα, a basal activity repressor of the Sult1e1 promoter, becomes phosphorylated at serine 100 and converts to an activator of the Sult1e1 promoter in response to PB. CAR regulates both the RORα phosphorylation and conversion. Our findings suggest that PB signals CAR to communicate with RORα via serine 100 phosphorylation, converting RORα from transcription repressor to activator of the Sult1e1 gene and inducing SULT1E1 expression in mouse livers. This article is protected by copyright. All rights reserved.

PMID: 30025153 [PubMed - as supplied by publisher]

Association of ABCC2  polymorphism and gender with high-density lipoprotein cholesterol response to simvastatin.

Pharmacogenomics. 2018 Jul 19;:

Authors: Liu N, Yang G, Hu M, Cai Y, Hu Z, Jia C, Zhang M

Abstract
AIM: The clinical benefits of lipid-lowering therapy with statins are widely recognized. However, the lipid-lowering efficacy of statins shows significant differences between individuals. ABCC2 has been demonstrated to contribute to the transmembrane transport of the substrate compounds. The ABCC2 SNPs may be important factors that affect individual differences in clinical drug response. The aim of this study was to evaluate the association of rs717620 of ABCC2 with treatment response to simvastatin in a Chinese Han population.
METHODS: A total of 318 subjects were medicated with simvastatin 20 mg/day for 12 weeks after enrollment. Venous blood was obtained before and after simvastatin treatment for measurement of blood lipid profile. Subjects were classified into high-response and low-response groups depending on whether their lipid profile change was higher or lower than median change values. The ABCC2 SNP rs717620 was genotyped from blood samples with a snapshot assay.
RESULTS: A total of 12 weeks of treatment with simvastatin significantly decreased low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs) and significantly increased high-density lipoprotein cholesterol (HDL-C; p < 0.05). In multivariate analysis, there were no significant genetic effects of SNP rs717620 on the incidence of high- or low-response patients among TC, TG and LDL-C groups. However, rs717620 A-allele and female gender are significantly associated with the risk of low-response of HDL-C elevation after simvastatin treatment.
CONCLUSION: ABCC2 rs717620 and female gender may be related to the low-effect of simvastatin treatment on the HDL-C level in the Chinese Han population. Female Chinese patients with hyperlipidemia carrying rs717620 GA/AA genotypes might have reduced benefit from simvastatin treatment.

PMID: 30024814 [PubMed - as supplied by publisher]