Emerging Roles of 5-Lipoxygenase Phosphorylation in Inflammation and Cell Death.

Oxid Med Cell Longev. 2019;2019:2749173

Authors: Sun QY, Zhou HH, Mao XY

Abstract
5-Lipoxygenase (ALOX5) is an iron-containing and nonheme dioxygenase that catalyzes the peroxidation of polyunsaturated fatty acids such as arachidonic acid. ALOX5 is the rate-limiting enzyme for the biosynthesis of leukotrienes, a family of proinflammatory lipid mediators derived from arachidonic acid. ALOX5 also make great contributions to mediating lipid peroxidation. In recent years, it has been discovered that ALOX5 plays a central role in cell death including apoptosis, pyroptosis, and ferroptosis, a newly discovered type of cell death. According to the previous studies, ALOX5 can regulate cell death in two ways: one is inflammation and the other is lipid peroxidation. Meanwhile, it has been shown that ALOX5 activity is regulated by several factors including protein phosphorylation, ALOX5-interactng protein, redox state, and metal ions such as iron and calcium. In this review, we aim to summarize the knowledge on the emerging roles of ALOX5 protein phosphorylation in the regulation of cell death and inflammation in order to explore a potential target for human diseases.

PMID: 31871543 [PubMed - in process]

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Non-Genetic Regulators.

Drug Metab Dispos. 2019 Dec 23;:

Authors: Her L, Zhu HJ

Abstract
Carboxylesterase 1 (CES1) is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and non-genetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including single-nucleotide polymorphisms (SNPs) and copy number variants, and non-genetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENT: Carboxylesterase 1 (CES1) is a major phase I drug-metabolizing enzyme responsible for 80-95% of total hydrolytic activity in human livers. CES1 plays a crucial role in metabolizing a wide range of drugs, pesticides, environmental pollutants, and endogenous compounds. The clinical relevance of CES1 has been well demonstrated in various clinical trials with methylphenidate, oseltamivir, and clopidogrel. Here, we discuss genetic polymorphisms and non-genetic contributors that influence CES1 functionality and the PK and PD of drugs metabolized by CES1.

PMID: 31871135 [PubMed - as supplied by publisher]

Differential impact of nevirapine on artemether-lumefantrine pharmacokinetics in individuals stratified by CYP2B6 c.516G>T genotypes.

Antimicrob Agents Chemother. 2019 Dec 23;:

Authors: Abdullahi ST, Soyinka JO, Olagunju A, Bolarinwa RA, Olarewaju OJ, Bakare-Odunola MT, Winterberg M, Tarning J, Owen A, Khoo S

Abstract
There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes were administered a complete treatment dose of 3-days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted and plasma concentrations of artemether/dihydroartemisinin and, lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared with those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39% and 34% respectively. These reductions were significantly greater in GG versus TT subjects for artemether [ratio of geometric mean (90% confidence interval): 0.42 (0.29 - 0.61) versus 0.81 (0.51 - 1.28)] and for desbutyl-lumefantrine [0.56 (0.43 - 0.74) versus 0.75 (0.56 - 1.00)]. On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47% and 30% respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin [1.67 (1.20 - 2.34) versus 1.25 (0.88 - 1.78)] and for lumefantrine [1.51 (1.20 - 1.90) versus 1.08 (0.82 - 1.42)]. This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition.

PMID: 31871092 [PubMed - as supplied by publisher]

Association of ABCC2 with levels and toxicity of methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL).

Pediatr Hematol Oncol. 2019 Dec 23;:1-13

Authors: Razali RH, Noorizhab MNF, Jamari H, James RJ, Teh KH, Ibrahim HM, Teh LK, Salleh MZ

Abstract
Studies had shown that genetic polymorphism plays a significant role in the pharmacokinetics and pharmacodynamics variation of high dose methotrexate (MTX), 5000 mg/m2 regimen. The objective of this study was to investigate the genetic variations associated with the serum level and toxicity of MTX in Malaysian children with acute lymphoblastic leukemia (ALL). Thirty-eight patients were genotyped for rs717620 (ABCC2), rs4948496 (ARID5B), rs1801133 (MTHFR) and rs4149056 (SLCO1B1). Serum levels of MTX at 48 h post 24 h of intravenous infusion were analyzed by high-performance liquid chromatography-mass spectrometry. The ABCC2 genotype was significantly associated with the serum levels of MTX at 48 h after treatment (p = 0.017). Patients with CT and TT of rs717620 (ABCC2) and TC and CC of rs4948496 (ARID5B) were significantly associated with leukopenia grade I-IV (Fisher Exact Test; p = 0.03 and 0.02, respectively). The three most common MTX related toxicities were leukopenia (60.5%), increased alanine aminotransferase enzyme (47.4%), and thrombocytopenia (47.4%). Our results demonstrate that by prescreening of patients for ABCC2 and ARID5B associated with the serum levels and adverse effects of MTX would identify patients at risk and therefore help a pediatric oncologist to personalize chemotherapy drugs for precision health.

PMID: 31870219 [PubMed - as supplied by publisher]

Genetic factors influencing warfarin dose in Black-African patients: a systematic review and meta-analysis.

Clin Pharmacol Ther. 2019 Dec 23;:

Authors: Asiimwe IG, Zhang EJ, Osanlou R, Krause A, Dillon C, Suarez-Kurtz G, Zhang H, Perini JA, Renta JY, Duconge J, Cavallari LH, Marcatto LR, Beasly MT, Perera MA, Limdi NA, Santos PCJL, Kimmel SE, Lubitz SA, Scott SA, Kawai VK, Jorgensen AL, Pirmohamed M

Abstract
Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high inter-individual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in Black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively while rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in Black Africans to evaluate genetic factors determining warfarin response.

PMID: 31869433 [PubMed - as supplied by publisher]

QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity.

EMBO Rep. 2019 Dec 23;:e47929

Authors: Lu H, Ye Z, Zhai Y, Wang L, Liu Y, Wang J, Zhang W, Luo W, Lu Z, Chen J

Abstract
Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depletion of QKI in mice enhances cold-induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP-cAMP response element-binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

PMID: 31868295 [PubMed - as supplied by publisher]

A new liver eQTL map from 1,183 individuals provides evidence for novel eQTLs of drug response, metabolic and sex-biased phenotypes.

Clin Pharmacol Ther. 2019 Dec 23;:

Authors: Etheridge AS, Gallins PJ, Jima D, Broadaway KA, Ratain MJ, Schuetz E, Schadt E, Schroder A, Molony C, Zhou Y, Mohlke KL, Wright FA, Innocenti F

Abstract
Expression quantitative trait locus (eQTL) studies in human liver are crucial for elucidating how genetic variation influences variability in disease risk and therapeutic outcomes and may help guide strategies to obtain maximal efficacy and safety of clinical interventions. Associations between expression microarray and genome-wide genotype data from four human liver eQTL studies (n=1,183) were analyzed. More than 2.3 million cis-eQTLs for 15,668 genes were identified. When eQTLs were filtered against a list of 1,496 drug response genes, 187,829 cis-eQTLs for 1,191 genes were identified. Additionally, 1,683 sex-biased cis-eQTLs were identified, as well as 49 and 73 cis-eQTLs that colocalized with GWAS signals for blood metabolite or lipid levels, respectively. Translational relevance of these results is evidenced by linking DPYD eQTLs to differences in safety of chemotherapy, linking the sex-biased regulation of PCSK9 expression to anti-lipid therapy, and identifying the G-protein coupled receptor GPR180 as a novel drug target for hypertriglyceridemia.

PMID: 31868224 [PubMed - as supplied by publisher]

Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.

Circulation. 2019 03 12;139(11):1407-1421

Authors: Bartolomaeus H, Balogh A, Yakoub M, Homann S, Markó L, Höges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kräker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, Eckardt KU, Dechend R, Rump LC, Forslund SK, Müller DN, Stegbauer J, Wilck N

Abstract
BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage.
METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate.
RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent.
CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

PMID: 30586752 [PubMed - indexed for MEDLINE]

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components.

J Clin Med. 2019 Dec 20;9(1):

Authors: Turner RM, Pirmohamed M

Abstract
Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

PMID: 31861911 [PubMed]

Chronic Kidney Disease Has a Graded Association with Death and Cardiovascular Outcomes in Stable Coronary Artery Disease: An Analysis of 21,911 Patients from the CLARIFY Registry.

J Clin Med. 2019 Dec 18;9(1):

Authors: Vidal-Petiot E, Greenlaw N, Kalra PR, Garcia-Moll X, Tardif JC, Ford I, Zamorano J, Ferrari R, Tendera M, Fox KM, Steg PG, On Behalf Of The Clarify Investigators

Abstract
: Chronic kidney disease (CKD) is associated with an increased cardiovascular risk in a broad spectrum of populations. However, the risk associated with a reduced estimated glomerular filtration rate (eGFR) in patients with stable coronary artery disease receiving standard care in the modern era, independently of baseline cardiovascular disease, risk factors, and comorbidities, remains unclear. We analyzed data from 21,911 patients with stable coronary artery disease, enrolled in 45 countries between November 2009 and July 2010 in the CLARIFY registry. Patients with abnormal renal function were older, with more comorbidities, and received slightly lower-although overall high-rates of evidence-based secondary prevention therapies than patients with normal renal function. The event rate of patients with CKD stage 3b or more (eGFR <45 mL/min/1.73 m2) was much higher than that associated with any comorbid condition. In a multivariable adjusted Cox proportional hazards model, lower eGFR was independently associated with a graded increased risk of cardiovascular mortality, with adjusted HRs (95% CI) of 0.98 (0.81-1.18), 1.31 (1.05-1.63), 1.77 (1.38-2.27), and 3.12 (2.25-4.33) for eGFR 60-89, 45-59, 30-44, and <30 mL/min/1.73 m2, compared with eGFR ≥90 mL/min/1.73 m2. A strong graded independent relationship exists between the degree of CKD and cardiovascular mortality in this large cohort of patients with chronic coronary artery disease, despite high rates of secondary prevention therapies. Among clinical risk factors and comorbid conditions, CKD stage 3b or more is associated with the highest cardiovascular mortality.

PMID: 31861379 [PubMed]

A single-center, retrospective analysis of genotype-phenotype correlations in children with Dravet syndrome.

Seizure. 2019 Dec 13;75:1-6

Authors: Gertler TS, Calhoun J, Laux L

Abstract
PURPOSE: Dravet syndrome is an early-onset epileptic encephalopathy caused most often by loss-of-function SCN1A variants. Following recognition of its genetic basis and unique clinical features, Dravet syndrome has become one of the most well-studied genetic epilepsies. We sought to evaluate the genetic diversity and correlative seizure phenotype, comorbidities, and response to antiepileptic therapies of patients with clinically-diagnosed Dravet syndrome seen in a tertiary care center. The goal of this study was to examine genotype-phenotype correlations and to ascertain if specific antiepileptic therapies may be more effective on the basis of genetic test result alone.
METHOD: Retrospective chart review of demographics, comorbidities, seizure types, and responses to antiepileptic therapies of all patients (n = 137) with a clinical diagnosis of Dravet syndrome seen at Lurie Children's Hospital of Chicago from 2008 to 2016.
RESULTS: Of the 96% of Dravet syndrome patients with pathogenic SCN1A variants subdivided by missense or truncating variant, there was no difference in clinical presentation. Response to antiepileptic therapies did not differ by genotype with regard to medication class.
CONCLUSIONS: This is the largest cohort of Dravet patients from within the US to report medication response with respect to genotype. Missense variants in SCN1A were most common in the voltage-sensor and pore domains. All patients were most likely to respond to the recommended medication triad compared to other antiepileptic therapies.

PMID: 31864146 [PubMed - as supplied by publisher]

Translational Knowledge Discovery between Drug Interactions and Pharmacogenetics.

Clin Pharmacol Ther. 2019 Dec 21;:

Authors: Wu HY, Shendre A, Zhang S, Zhang P, Wang L, Zeruesenay D, Rocha LM, Shatkay H, Quinney SK, Ning X, Li L

Abstract
Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidences make it difficult to consolidate and link them to clinical consequences. Consequently, we developed information retrieval (IR) models to retrieve DDI and drug-gene interaction (DGI) evidences from 25 million PubMed abstracts, and distinguish DDI evidences into in-vitro pharmacokinetics (PK), and clinical PK and pharmacodynamics (PD) studies for FDA-approved and withdrawn drugs. Additionally, information extraction models were developed to extract DDI- and DGI-pairs from the IR-retrieved abstracts. An overlapping analysis identified 986 DDI-pairs between all three types of evidences. Another 2,157 and 13,012 DDI-pairs, and 3,173 DGI-pairs were identified from known clinical PK-PD DDI, clinical PD DDI, and DGI evidences, respectively. By integrating DDI and DGI evidences, we discovered 119 and 18 new pharmacogenetic hypotheses associated with CYP3A and CYP2D6, respectively. Some of these DGI evidences can also aid us in understanding DDI mechanisms.

PMID: 31863452 [PubMed - as supplied by publisher]

Single-nucleotide polymorphism of rs7944135 (macrophage-expressed gene 1) is associated with hepatitis B surface antigen seroclearance in chronic hepatitis B infection: A cohort study.

Medicine (Baltimore). 2019 Dec;98(51):e17936

Authors: Irham LM, Wong HS, Perwitasari DA, Chou WH, Yang HI, Chang WC

Abstract
Clearance of the hepatitis B surface antigen (HBsAg) is the ultimate aim of treatment for patients with chronic hepatitis B (CHB) infection. Genetic, factor age, and gender were reported to be involved in the clearance of HBsAg. However, the rate of HBsAg seroclearance in CHB patients is still low globally and few of the single-nucleotide polymorphism (SNP) had been identified to associated with HBsAg seroclearance in CHB patients.Recently, 3 associated SNPs (rs7944135, rs171941, and rs6462008) were reported in the clearance of HBsAg in the Korean population. However, these SNPs have not been investigated in the CHB Taiwanese population. In present study, these 3 SNPs were genotyped in 2565 Taiwanese CHB patients including 493 CHB patients with HBsAg seroclearance and 2072 without HBsAg seroclearance.We observed that SNP rs7944135 was solely associated with HBsAg seroclearance. Subjects with the AA genotype at rs7944135 of macrophage-expressed gene 1 had a higher susceptibility to HBsAg clearance, compared to those with the AG or GG genotype under the genotypic model (odds ratio [OR] = 1.76. 95% confidence interval [CI] = 1.14-2.72, P = .045). Furthermore, we found a 1.74-fold increased risk of acquiring HBsAg seroclearance associated with the AA genotype compared to AG + GG of rs7944135 under the recessive model (OR = 1.74. 95% CI = 1.13-2.66, P = .014). According to the cumulative fraction curve with the log-rank test revealed that patients with the AA genotype of rs7944135 showed higher susceptibility to occur HBsAg seroclearance (P = .039) and HBV DNA undetectable (P = .0074) compared to those with the AG or GG genotype.This study examined the associations of 3 SNPs (rs7944135, rs171941, and rs6462008) with HBsAg seroclearance, and we identified that rs7944135 is solely associated with HBsAg seroclearance in Taiwanese CHB patients.

PMID: 31860948 [PubMed - in process]

Application of pharmacogenomics and bioinformatics to exemplify the utility of human ex vivo organoculture models in the field of precision medicine.

PLoS One. 2019;14(12):e0226564

Authors: Cowan K, Macluskie G, Finch M, Palmer CNA, Hair J, Bylesjo M, Lynagh S, Brankin P, McNeil M, Low C, Mallinson D, Gourlay EM, Child H, Cheyne L, Bunton DC

Abstract
Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response.

PMID: 31860681 [PubMed - in process]

The biotransformation of Bupleuri Radix by human gut microbiota.

Xenobiotica. 2019 Dec 20;:1-30

Authors: Tang C, Fu Q, Chen X, Hu Y, Renaud H, Ma C, Rao T, Chen Y, Tan Z, Klaassen CD, Shi S, Guo Y

Abstract
1. Bupleuri Radix (BR) is a herbal medicine traditionally used orally in oriental countries, which inevitably comes into contact with the intestinal microbiota. However, whether gut microbiota contribute to the biotransformation of BR, and/or the formation of pharmacologically active compounds remains unknown.2. In this study the main saikosaponins (SAPs) of Bupleurum (including saikosaponin a, b1, b2, c, d, f, h) and BR extract (BRE) were individually incubated with human fecal suspensions (HFS), and metabolic time courses of SAPs and their metabolites by human gut bacteria were systematically characterized.3. Deglycosylation and dehydration were the main metabolic pathways identified for SAPs including newly investigated saikosaponin f (SSf) and saikosaponin h (SSh); dehydration had not been reported previously. A total of 19 dehydrated and deglycosylated metabolites of SAPs were detected and characterized, and 10 of them were newly identified. Moreover, SAPs of BRE were found to be deglycosylated to prosaikogenins. In addition, Thirteen metabolic pathways related to human gut microbiota were identified for phytochemicals of BRE except for SAPs. Gut microbiota may play a significant role in the biotransformation of BR in humans.

PMID: 31858877 [PubMed - as supplied by publisher]

Maternal Weight, Weight Gain, and Metabolism are Associated with Changes in Fetal Heart Rate and Variability.

Obesity (Silver Spring). 2020 Jan;28(1):114-121

Authors: Mat Husin H, Schleger F, Bauer I, Fehlert E, Kiefer-Schmidt I, Weiss M, Kagan KO, Brucker S, Pauluschke-Fröhlich J, Eswaran H, Häring HU, Fritsche A, Preissl H

Abstract
OBJECTIVE: Prepregnancy obesity and extensive weight gain can lead to diseases in the offspring later in life. The aim of this study was to evaluate the effect of anthropometric and metabolic factors on the fetal autonomic nervous system (ANS) in uncomplicated pregnancies.
METHODS: A total of 184 pregnant women in the second or third trimester were included, and for 104 women, maternal insulin sensitivity (ISI) was determined. Fetal heart rate (HR) and heart rate variability (HRV) were determined by magnetic recording. Associations of maternal prepregnancy BMI, weight gain, and ISI with fetal HR and HRV were evaluated by ANCOVA, partial correlation, and mediation analysis.
RESULTS: HR was increased and HRV decreased in fetuses of mothers with overweight or obesity in comparison to normal-weight mothers. Fetal HR was negatively correlated with maternal weight gain. Maternal prepregnancy BMI was positively correlated with fetal high frequency and was negatively correlated with low frequency and low/high frequency ratio. Maternal ISI showed a negative correlation with fetal HR.
CONCLUSIONS: The results show that the fetal ANS is sensitive to alterations of prepregnancy BMI, weight changes, and glucose metabolism. These findings highlight the importance of the intrauterine environment on the developing ANS and the possible programming of obesity.

PMID: 31858736 [PubMed - in process]

Defining screening panel of functional variants of CYP1A1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 genes in Serbian population.

Int J Legal Med. 2019 Dec 20;:

Authors: Skadrić I, Stojković O

Abstract
Plethora of drugs and toxic substances is metabolized by cytochrome P450 enzymes (CYP450). These enzymes are coded by highly variable genes abundant with single nucleotide variants (SNVs) and small insertions/deletions (indels) that affect the functionality of the enzymes, increasing or decreasing their activity. CYP genes genotyping, followed by haplotype inference, provides substrate specific metabolic phenotype prediction. This is crucial in pharmacogenetics and applicable in molecular autopsy. However, high number of alleles in CYP450 superfamily and interethnic variability in frequency distribution require precise gene panel customization. To estimate informativeness of SNVs and alleles in CYP gene families 1, 2, and 3, associated with metabolic alterations, 500 unrelated individuals from 5 regions of Serbia were genotyped using TaqMan assays to determine frequencies of CYP2C9 *2 and *3, CYP2C19 *2 and *17 alleles, four variants in CYP2D6 (rs3892097, rs1065852, rs28371725, rs28371706) gene, and CYP3A4*1B allele. In addition, CYP1A1 rs4646903 and rs1048943 (m1 and m2) variants were genotyped by RFLP. Our results showed that frequencies of tested variants in Serbian population corresponded to general European population and somewhat differed from neighboring populations. SNV rs1065852, the main contributor to non-functional CYP2D6 *4, significantly departed from Hardy-Weinberg equilibrium. With the exception of rs28371706 in CYP2D6 and rs2740574 in CYP3A4, which were very rare in our sample, all other tested variants in CYP2 family are informative and appropriate for pharmacogenetic testing, molecular autopsy, and medico-legal genetic analyses.

PMID: 31858263 [PubMed - as supplied by publisher]

PPARs as Nuclear Receptors for Nutrient and Energy Metabolism.

Molecules. 2019 Jul 12;24(14):

Authors: Hong F, Pan S, Guo Y, Xu P, Zhai Y

Abstract
It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.

PMID: 31336903 [PubMed - indexed for MEDLINE]

Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors.

Int J Mol Sci. 2019 Jul 10;20(14):

Authors: Garutti M, Pelizzari G, Bartoletti M, Malfatti MC, Gerratana L, Tell G, Puglisi F

Abstract
Breast cancer (BC) is the most frequent oncologic cause of death among women and the improvement of its treatments is compelling. Platinum salts (e.g., carboplatin, cisplatin, and oxaliplatin) are old drugs still used to treat BC, especially the triple-negative subgroup. However, only a subset of patients see a concrete benefit from these drugs, raising the question of how to select them properly. Therefore, predictive biomarkers for platinum salts in BC still represent an unmet clinical need. Here, we review clinical and preclinical works in order to summarize the current evidence about predictive or putative platinum salt biomarkers in BC. The association between BRCA1/2 gene mutations and platinum sensitivity has been largely described. However, beyond the mutations of these two genes, several other proteins belonging to the homologous recombination pathways have been linked to platinum response, defining the concept of BRCAness. Several works, here reviewed, have tried to capture BRCAness through different strategies, such as homologous recombination deficiency (HRD) score and genetic signatures. Moreover, p53 and its family members (p63 and p73) might also be used as predictors of platinum response. Finally, we describe the mounting preclinical evidence regarding base excision repair deficiency as a possible new platinum biomarker.

PMID: 31295913 [PubMed - indexed for MEDLINE]

Impact of CYP2C9, VKORC1, ApoE and ABCB1 polymorphisms on stable warfarin dose requirements in elderly Chinese patients.

Pharmacogenomics. 2019 Dec 19;:

Authors: Li W, Zhao P, Chen L, Lai X, Shi G, Li L, Dong J

Abstract
Aim: To analyze the impact of nongenetic factors and gene polymorphisms on warfarin dose requirements in elderly Shanghai Han Chinese patients. Materials & methods: Genotypes of CYP2C9 (rs1799853 and rs1057910), FPGS (rs7856096), ApoE (rs7412 and rs429358), GGCX (rs699664 and rs12714145), EPHX1 (rs4653436, rs1877724, rs1051740 and rs1131873), NQO1 (rs1800566 and rs10517), ABCB1 (rs1045642), VKORC1 (rs9923231) and CYP4F2 (rs2108622) in 214 patients with stable warfarin dose were determined and their demographic characteristics were recorded. Results: Multiple linear regression analysis revealed that VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone could explain 37.0% of the individual variations of daily stable warfarin dose. Conclusion: VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone play an important role in stable dose variation of warfarin in elderly Shanghai Han Chinese patients, whereas ABCB1 rs1045642 is not a significant genetic factor.

PMID: 31854268 [PubMed - as supplied by publisher]