Pharmaco-epigenomics: On the Road of Translation Medicine.

Adv Exp Med Biol. 2019;1168:31-42

Authors: López-Camarillo C, Gallardo-Rincón D, Álvarez-Sánchez ME, Marchat LA

Abstract
Epigenomics refers to the study of genome-wide changes in epigenetic mechanisms including DNA methylation, histone modifications and non-coding RNAs expression. The alterations in normal DNA methylation and histone acetylation/deacetylation patterns lead to deregulated transcription and chromatin organization resulting in altered gene expression profiles that facilitates tumor development and progression. In consequence, novel therapeutic strategies aimed at reversing aberrant epigenetic marks in cancer cells have been developed and used in recent molecular studies and clinical trials. Pharmaco-epigenomics is a research area, which refers to the study of epigenome changes in cancer development and how chemotherapeutic agents can reverse these aberrant epigenetic marks by targeting the epigenetic machinery. Besides, the effects of genome-wide polymorphisms in populations leading to variations in drug response are also study subject of pharmaco-epigenomics and are being studied extensively in cancer. Recent findings showed that drug response could be largely influenced by the presence of aberrant epigenetic marks of the whole genome. This implies that biological pathways and cellular processes are under the impact of epigenome status. However, data about the relationship between drug response and the epigenomic variations is still scarce mainly because the epigenome is highly variable between individuals. The present chapter reviewed the advances on the epigenetics changes mainly DNA methylation and histones modifications on cervical and breast human cancers. A special emphasis in how they could be used as targets for the development and use of novel drugs in cancer therapy is delineated.

PMID: 31713163 [PubMed - indexed for MEDLINE]

Recipient ABCB1, donor and recipient CYP3A5 genotypes influence tacrolimus pharmacokinetics in liver transplant cases.

Pharmacol Rep. 2019 Jun;71(3):385-392

Authors: Naushad SM, Pavani A, Rupasree Y, Hussain T, Alrokayan SA, Kutala VK

Abstract
BACKGROUND: Effective immunosuppression through optimization of trough levels tacrolimus reduces post-transplant mortality rate in liver transplant cases.
METHODS: Meta-analysis was carried out to evaluate how donor/recipient CYP3A5 (n = 678) and recipient ABCB1 (n = 318) genotypes influence tacrolimus pharmacokinetics till one-month of transplantation.
RESULTS: The donor CYP3A5*3/*3 genotype exhibited higher concentration/dose (C/D) ratio of tacrolimus in week 1 (mean difference: 65.04, 95% CI: 15.30-114.79 ng/ml/mg/kg), week 2 (mean difference: 21.7, 95% CI: 12.6-30.9 ng/ml/mg/kg) and week 4 (mean difference: 43.28, 95% CI: 17.09 - 69.49 ng/ml/mg/kg) compared to *1/*1 and *1/*3 genotypes. The recipient CYP3A5 *3/*3 genotype did not showed significant difference in tacrolimus C/D ratio in week 1 compared to other two genotypes. However, week 2 (mean difference: 44.16, 95% CI: 3.68-84.65 ng/ml/mg/kg) and week 4 (mean difference: 43.74, 95% CI: 12.50-75.00 ng/ml/mg/kg) availability was higher in *3/*3 mutant recipients. However, the recipient ABCB1 3435 C > T polymorphism has no significant influence on tacrolimus pharmacokinetics till one month of transplant.
CONCLUSIONS: The donor and recipient CYP3A5*3 polymorphism influences tacrolimus pharmacokinetics in the first month post-transplantation, whereas the association with recipient ABCB1 3435 C > T is inconclusive.

PMID: 31003147 [PubMed - indexed for MEDLINE]

Sensory cortical control of movement.

Nat Neurosci. 2019 Nov 18;:

Authors: Karadimas SK, Satkunendrarajah K, Laliberte AM, Ringuette D, Weisspapir I, Li L, Gosgnach S, Fehlings MG

Abstract
Walking in our complex environment requires continual higher order integrated spatiotemporal information. This information is processed in the somatosensory cortex, and it has long been presumed that it influences movement via descending tracts originating from the motor cortex. Here we show that neuronal activity in the primary somatosensory cortex tightly correlates with the onset and speed of locomotion in freely moving mice. Using optogenetics and pharmacogenetics in combination with in vivo and in vitro electrophysiology, we provide evidence for a direct corticospinal pathway from the primary somatosensory cortex that synapses with cervical excitatory neurons and modulates the lumbar locomotor network independently of the motor cortex and other supraspinal locomotor centers. Stimulation of this pathway enhances speed of locomotion, while inhibition decreases locomotor speed and ultimately terminates stepping. Our findings reveal a novel pathway for neural control of movement whereby the somatosensory cortex directly influences motor behavior, possibly in response to environmental cues.

PMID: 31740813 [PubMed - as supplied by publisher]

Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response.

Transl Psychiatry. 2019 Nov 18;9(1):308

Authors: da Silva BS, Leffa DT, Beys-da-Silva WO, Torres ILS, Rovaris DL, Victor MM, Rohde LA, Mota NR, Oliveira C, Berger M, Yates JR, Sabnis R, Peña RD, Campos AR, Grevet EH, Santi L, Bau CHD, Contini V

Abstract
Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.

PMID: 31740662 [PubMed - in process]

Inflammatory bowel disease in children and adolescents.

CMAJ. 2019 02 11;191(6):E164

Authors: Chanchlani N, Russell RK

PMID: 30745401 [PubMed - indexed for MEDLINE]

PP2Cm overexpression alleviates MI/R injury mediated by a BCAA catabolism defect and oxidative stress in diabetic mice.

Eur J Pharmacol. 2019 Nov 15;:172796

Authors: Lian K, Guo X, Wang Q, Liu Y, Wang RT, Gao C, Li CY, Li CX, Tao L

Abstract
Diabetic patients are sensitive to myocardial ischemia-reperfusion (MI/R) injury. During diabetes, branched-chain amino acid (BCAA) catabolism is defective and mitochondrial phosphatase 2C (PP2Cm) expression is reduced. This study aims to elucidate the relationship between PP2Cm downregulation and BCAA catabolism defect in diabetic mice against MI/R injury. PP2Cm was significantly downregulated in hearts of diabetic mice. The cardiac function was improved and the myocardial infarct size and apoptosis were decreased in diabetic mice overexpressing PP2Cm after MI/R. In diabetic mice, the cardiac BCAA and its metabolites branched-chain keto-acids (BCKA) levels, and p-BCKDE1α (E1 subunit of BCKA dehydrogenase)/BCKDE1α ratio were increased while the BCKD activity was decreased. Treatment of diabetic mice subjected to MI/R injury with BT2, a BCKD kinase (BDK) inhibitor, alleviated the BCAA catabolism defect, and improved the cardiac function alongside reduced apoptosis. PP2Cm overexpression alleviated the BCAA catabolism defect and MI/R injury. Similarly, MnTBAP ameliorated the oxidative stress and MI/R injury. BCKA treatment of H9C2 cells under simulated ischemia/reperfusion (SI/R) injury significantly decreased cell viability and increased LDH release and apoptosis. These effects were alleviated by BT2 and MnTBAP treatments. These results suggested that PP2Cm directly mediates the BCAA catabolism defect and oxidative stress observed after MI/R in diabetes. Overexpression of PP2Cm alleviates MI/R injury by reducing the catabolism of BCAA and oxidative stress.

PMID: 31738932 [PubMed - as supplied by publisher]

Targeted Metabolomic Analysis of Serum Fatty Acids for the Prediction of Autoimmune Diseases.

Front Mol Biosci. 2019;6:120

Authors: Tsoukalas D, Fragoulakis V, Sarandi E, Docea AO, Papakonstaninou E, Tsilimidos G, Anamaterou C, Fragkiadaki P, Aschner M, Tsatsakis A, Drakoulis N, Calina D

Abstract
Autoimmune diseases (ADs) are rapidly increasing worldwide and accumulating data support a key role of disrupted metabolism in ADs. This study aimed to identify an improved combination of Total Fatty Acids (TFAs) biomarkers as a predictive factor for the presence of autoimmune diseases. A retrospective nested case-control study was conducted in 403 individuals. In the case group, 240 patients diagnosed with rheumatoid arthritis, thyroid disease, multiple sclerosis, vitiligo, psoriasis, inflammatory bowel disease, and other AD were included and compared to 163 healthy individuals. Targeted metabolomic analysis of serum TFAs was performed using GC-MS, and 28 variables were used as input for the predictive models. The primary analysis identified 12 variables that were statistically significantly different between the two groups, and metabolite-metabolite correlation analysis revealed 653 significant correlation coefficients with 90% level of significance (p < 0.05). Three predictive models were developed, namely (a) a logistic regression based on Principal Component Analysis (PCA), (b) a straightforward logistic regression model and (c) an Artificial Neural Network (ANN) model. PCA and straightforward logistic regression analysis, indicated reasonably well adequacy (74.7 and 78.9%, respectively). For the ANN, a model using two hidden layers and 11 variables was developed, resulting in 76.2% total predictive accuracy. The models identified important biomarkers: lauric acid (C12:0), myristic acid (C14:0), stearic acid (C18:0), lignoceric acid (C24:0), palmitic acid (C16:0) and heptadecanoic acid (C17:0) among saturated fatty acids, Cis-10-pentadecanoic acid (C15:1), Cis-11-eicosenoic acid (C20:1n9), and erucic acid (C22:1n9) among monounsaturated fatty acids and the Gamma-linolenic acid (C18:3n6) polyunsaturated fatty acid. The metabolic pathways of the candidate biomarkers are discussed in relation to ADs. The findings indicate that the metabolic profile of serum TFAs is associated with the presence of ADs and can be an adjunct tool for the early diagnosis of ADs.

PMID: 31737644 [PubMed]

Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A.

Front Pharmacol. 2019;10:1297

Authors: Rafehi M, Faltraco F, Matthaei J, Prukop T, Jensen O, Grytzmann A, Blome FG, Berger RG, Krings U, Vormfelde SV, Tzvetkov MV, Brockmöller J

Abstract
Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity.

PMID: 31736764 [PubMed]

Identification and in Silico Characterization of a Novel CASK c.2546T>C (p.V849A) Mutation in a Male Infant with Pontocerebellar Hypoplasia.

Ann Indian Acad Neurol. 2019 Oct-Dec;22(4):523-524

Authors: Rama Devi AR, Lingappa L, Naushad SM

PMID: 31736593 [PubMed]

Incidence of T790M in Patients With NSCLC Progressed to Gefitinib, Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA.

Clin Lung Cancer. 2019 Oct 13;:

Authors: Del Re M, Petrini I, Mazzoni F, Valleggi S, Gianfilippo G, Pozzessere D, Chella A, Crucitta S, Rofi E, Restante G, Miccoli M, Garassino MC, Danesi R

Abstract
BACKGROUND: Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib.
PATIENTS AND METHODS: The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay.
RESULTS: A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001).
CONCLUSIONS: Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.

PMID: 31735523 [PubMed - as supplied by publisher]

Cetyltrimethyl ammonium mediated enhancement of the red emission of carbon dots and an advanced method for fluorometric determination of iron(III).

Mikrochim Acta. 2019 Nov 16;186(12):791

Authors: Li T, Xie L, Long R, Tong C, Guo Y, Tong X, Shi S, Lin Q

Abstract
Red-emissive carbon dots (CDs) were synthesized by one-step hydrothermal technique using citric acid (CA), and urea in N,N-dimethylformamide (DMF) solution. The CDs has an average diameter of 2.3 nm, excitation/emission maxima at 553/606 nm, and a low photoluminescence quantum yield (4%). Fluorescence is weakly quenched by the ions Fe3+, Hg2+, Cu2+, Co2+, Zn2+, Ca2+, Ni2+, and Pb2+. After addition of cetyltrimethyl ammonium ion (CTAB), electrostatic interaction between negatively charged CDs and CTAB causes the CDs to self-aggregate. The formation of CD/CTAB increases the average particle diameter to around 13 nm and enhances the quantum yield to 24%. The hydrophobic segments of CTAB twined into a network structure can selectively trap Fe3+ and then interact with surface groups of the CDs to cause quenching. The CD/CTAB nanoprobe enables fluorometric determination of Fe3+ with a linear response in the 0.10-10 μM concentration range and a 0.03 μM limit of detection. The probe was utilized for determination of Fe3+ in human serum samples, and satisfactory results were obtained. Graphical abstractSchematic representation of fluorometric analysis of Fe(III) ion by cetyltrimethyl ammonium ion (CTAB) mediated red emission carbon dots (CDs). The hydrophobic segments of CTAB twined into a network structure can selectively trap Fe(III) and then interact with surface groups of the CDs to cause quenching.

PMID: 31734753 [PubMed - in process]

Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis.

Toxicol Appl Pharmacol. 2019 Nov 14;:114829

Authors: Zhou L, Chen L, Zeng X, Liao J, Ouyang D

Abstract
Sodium valproate (SVP) is a first-line treatment for various forms of epilepsy; however, it can cause severe liver injury. Ginsenoside compound K (G-CK) is the main active ingredient of the traditional herbal medicine ginseng. According to our previous research, SVP-induced elevation of ALT and AST levels, as well as pathological changes of liver tissue, was believed to be significantly reversed by G-CK in LiCl-pilocarpine induced epileptic rats. Thus, we aimed to evaluate the protective effect of G-CK on hepatotoxicity caused by SVP. The rats treated with SVP showed liver injury with evident increases in hepatic index, transaminases activity, alkaline phosphatase level, and lipid peroxidation; a significant decreases in serum albumin level and antioxidant capacity; and obvious changes in histopathological and subcellular structures. All of these changes could be mitigated by co-administration with G-CK. Proteomic analysis indicated that hepcidin, soluble epoxide hydrolase (sEH, UniProt ID P80299), and the peroxisome pathway were involved in the hepatoprotective effect of G-CK. Changes in protein expression of hepcidin and sEH were verified by ELISA and Western blot analysis, respectively. In addition, we observed that the hepatic iron rose in SVP group and decreased in the combination group. In summary, our findings demonstrate the clear hepatoprotective effect of G-CK against SVP-induced hepatotoxicity through the antioxidant effect, regulation of peroxisome pathway relying on sEH (P80299) downregulation, as well as regulation of iron homeostasis dependent on hepcidin upregulation.

PMID: 31734319 [PubMed - as supplied by publisher]

Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure.

Cardiovasc Drugs Ther. 2019 Nov 14;:

Authors: Luzum JA, Ting C, Peterson EL, Gui H, Shugg T, Williams LK, Li L, Sadee W, Wang D, Lanfear DE

Abstract
PURPOSE: Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown.
METHODS: Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models.
RESULTS: The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all).
CONCLUSIONS: A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.

PMID: 31728800 [PubMed - as supplied by publisher]

Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells.

Leukemia. 2019 Nov 14;:

Authors: Scheffold A, Baig AH, Chen Z, von Löhneysen SE, Becker F, Morita Y, Avila AI, Groth M, Lechel A, Schmid F, Kraus JM, Kestler HA, Stilgenbauer S, Philipp M, Burkhalter MD

Abstract
Accumulation of DNA damage and myeloid-skewed differentiation characterize aging of the hematopoietic system, yet underlying mechanisms remain incompletely understood. Here, we show that aging hematopoietic progenitor cells particularly of the myeloid branch exhibit enhanced resistance to bulky DNA lesions-a relevant type of DNA damage induced by toxins such as cancer drugs or endogenous aldehydes. We identified aging-associated activation of the Hedgehog (Hh) pathway to be connected to this phenotype. Inhibition of Hh signaling reverts DNA damage tolerance and DNA damage-resistant proliferation in aged hematopoietic progenitors. Vice versa, elevating Hh activity in young hematopoietic progenitors is sufficient to impair DNA damage responses. Altogether, these findings provide experimental evidence for aging-associated increases in Hh activity driving DNA damage tolerance in myeloid progenitors and myeloid-skewed differentiation. Modulation of Hh activity could thus be explored as a therapeutic strategy to prevent DNA damage tolerance, myeloid skewing, and disease development in the aging hematopoietic system.

PMID: 31728056 [PubMed - as supplied by publisher]

Glucuronidation of Abiraterone and its Pharmacologically Active Metabolites by UGT1A4, Influence of Polymorphic Variants and their Potential as Inhibitors of Steroid Glucuronidation.

Drug Metab Dispos. 2019 Nov 14;:

Authors: Vaillancourt J, Turcotte V, Caron P, Villeneuve L, Lacombe L, Pouliot F, Levesque E, Guillemette C

Abstract
Abiraterone acetate (AA) is a prodrug of abiraterone (Abi), a CYP17A1 inhibitor used to treat patients with advanced prostate cancer (PCa). Abi is a selective steroidal inhibitor that blocks the biosynthesis of androgens. It undergoes extensive biotransformation by steroid pathways leading to the formation of pharmacologically active Δ4-abiraterone (D4A) and 5α-abiraterone (5α-Abi). This study aimed to characterize the glucuronidation pathway of Abi and its two active metabolites. We show that Abi, its metabolites and another steroidal inhibitor galeterone (Gal), undergo secondary metabolism to form glucuronides (G) in human liver microsomes with minor formation by intestine and kidney microsomal preparations. The potential clinical relevance of this pathway is supported by the detection by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of Abi-G, D4A-G and 5α-Abi-G in patients under AA therapy. A screening of UGT enzymes reveals that UGT1A4 is the main enzyme involved. This is supported by inhibition experiments using a selective UGT1A4 inhibitor hecogenin. A number of common and rare nonsynonymous variants significantly abrogate the UGT1A4-mediated formation of Abi-G, D4A-G and 5α-Abi-G in vitro. We also identify Gal, Abi and its metabolites as highly potent inhibitors of steroid inactivation by the UGT pathway with submicromolar Ki values. They reduce the glucuronidation of both the adrenal precursors and potent androgens in human liver, prostate cancer cells and by recombinant UGTs involved in their inactivation. In conclusion, tested CYP17A1 inhibitors are metabolized through UGT1A4 and germline variations affecting this metabolic pathway may also influence drug metabolism. SIGNIFICANCE STATEMENT: The antiandrogen abiraterone (Abi) is a selective steroidal inhibitor of the cytochrome P450 17α-hydroxy/17,20-lyase (CYP17A1), an enzyme involved in the biosynthesis of androgens. Abi is metabolized to pharmacologically active metabolites by steroidogenic enzymes. We demonstrate that Abi and its metabolites are glucuronidated in the liver and that their glucuronide derivatives are detected in circulation of treated prostate cancer patients at variable levels. UGT1A4 is the primary enzyme involved and nonsynonymous germline variations affect this metabolic pathway in vitro, suggesting a potential influence of drug metabolism and action in patients. Their inhibitory effect on drug and steroid glucuronidation raises the possibility that these pharmacological compounds might affect the UGT-associated drug-metabolizing system and pre-receptor control of androgen metabolism in patients.

PMID: 31727674 [PubMed - as supplied by publisher]

Increased risk of aspirin-induced gastric mucosal erosion in elderly Chinese men harboring SLCO1B1*1b/*1b while using aspirin and an ACEI or ARB concomitantly.

BMC Med Genet. 2019 Nov 14;20(1):183

Authors: Duan L, Bai Y, Li M, Li H, Li Y, Liu H

Abstract
BACKGROUND: It is well established that long-term use of aspirin can cause gastric mucosal injury. ACEIs and ARBs are inversely related to gastric ulcer development. This study aimed to evaluate the relationship between SLCO1B1 polymorphisms, which can affect ACEI and ARB transport, and gastric mucosal erosion in elderly male Chinese patients with cardiovascular disease who use aspirin.
METHODS: Patients taking aspirin and an ACEI or ARB concomitantly who had undergone endoscopic screening for gastric erosion were analyzed for SLCO1B1 polymorphisms by a TaqMan assay.
RESULTS: The frequency of the SLCO1B1*1b/*1b diplotype (42% vs. 24%; p = 0.002) was significantly higher in the gastric mucosal erosion group than in the control group. After adjustment for significant factors, SLCO1B1*1b/*1b (OR, 2.64; 95% CI, 1.59-4.17; p < 0.05) was found to be associated with gastric mucosal erosion in aspirin users.
CONCLUSIONS: The presence of the SLCO1B1*1b/*1b diplotype may be a risk factor for aspirin-induced gastric mucosal erosion in elderly Chinese men taking aspirin and an ACEI or ARB concomitantly.

PMID: 31727004 [PubMed - in process]

Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins.

Clin Genet. 2018 08;94(2):191-199

Authors: Shadrina A, Tsepilov Y, Smetanina M, Voronina E, Seliverstov E, Ilyukhin E, Kirienko A, Zolotukhin I, Filipenko M

Abstract
Heredity plays an important role in the etiology of varicose veins (VVs). However, the genetic basis underlying this condition remains poorly understood. Our aim was to replicate top association signals from genome-wide association studies (GWASs) for VVs of lower extremities using 2 independent datasets-our sample of ethnic Russian individuals (709 cases and 278 controls) and a large cohort of British residents from UK Biobank (10 861 cases and 397 594 controls). Associations of polymorphisms rs11121615, rs6712038, rs507666, rs966562, rs7111987, rs6062618, and rs6905288 were validated in the UK Biobank individuals at a Bonferroni-corrected significance level. In Russian cohort, only rs11121615 reached a nominal significance level of P < .05. Results of original GWAS and replication studies were combined by a meta-analysis, and polymorphisms listed above as well as rs111434909 and rs4463578 passed a genome-wide significant threshold. Notably, the majority of these polymorphisms were located within or near genes involved in vascular development and remodeling, and regulation of inflammatory response. Our results confirm the role of these polymorphisms in genetic susceptibility to VVs and indicate the revealed genomic regions as good candidates for further fine-mapping studies and functional analysis. Moreover, our findings implicate inflammation and abnormal vascular architecture in VVs pathogenesis.

PMID: 29660117 [PubMed - indexed for MEDLINE]

Off-label use of tacrolimus in children with glomerular disease: Effectiveness, Safety and Pharmacokinetics.

Br J Clin Pharmacol. 2019 Nov 14;:

Authors: Hao GX, Song LL, Zhang DF, Su LQ, Jacqz-Aigrain E, Zhao W

Abstract
Glomerular diseases are leading causes of end-stage renal disease in children. Tacrolimus is frequently used off-label in the recent treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children were reviewed in this paper to provide evidence to support for its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6-97.6%. In 4 clinical trials on children with lupus nephritis, the overall remission rate was 81.8-89.5%. In a pilot study with paediatric Henoch-Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin-C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow-up are needed to definitely demonstrate the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.

PMID: 31725919 [PubMed - as supplied by publisher]

Author Correction: c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies.

Nat Immunol. 2019 Nov 13;:

Authors: Bernink JH, Ohne Y, Teunissen MBM, Wang J, Wu J, Krabbendam L, Guntermann C, Volckmann R, Koster J, van Tol S, Ramirez I, Shrestha Y, de Rie MA, Spits H, Ros XR, Humbles AA

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31723260 [PubMed - as supplied by publisher]

HIV-1 Tat Interacts with a Kaposi's Sarcoma-Associated Herpesvirus Reactivation-Upregulated Antiangiogenic Long Noncoding RNA, LINC00313, and Antagonizes Its Function.

J Virol. 2019 Nov 13;:

Authors: Yang WS, Lin TY, Chang L, Yeh WW, Huang SC, Chen TY, Hsieh YT, Chen ST, Li WC, Pan CC, Campbell M, Yen CH, Chen YA, Chang PC

Abstract
Kaposi's sarcoma associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an acquired immunodeficiency syndrome (AIDS)-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency viruses (HIV)-infected AIDS patients has been ascribed to HIV-1 and KSHV interaction, focusing on secretory proteins. HIV-1 secreted protein HIV-Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV-Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long non-coding RNA (lncRNA) that interacts with HIV-Tat. We found that LINC00313 overexpression inhibits cell migration, invasion and tube formation, and this suppressive effect was relieve by HIV-Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components and this interaction was disrupted by HIV-Tat suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and HIV-Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV-Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV-Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313 that is up-regulated during KSHV reactivation interacts with HIV-Tat to promote endothelial cell motility. These results demonstrate that a lncRNA serves as a novel connector in HIV-KSHV interactions.IMPORTANCE KS is a prevalent tumor associated with two distinct viral infections, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the viral-viral interaction associated with KS formation has focused on secretory factors. HIV-Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA up-regulated during KSHV lytic reactivation, as a novel HIV-Tat interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially through interacting with chromatin remodeling complex PRC2 and down-regulation of cell migration regulating genes. Interaction between HIV-Tat and LINC00313 contributed to dissociation of PRC2 from LINC00313 and disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV co-infection.

PMID: 31723026 [PubMed - as supplied by publisher]