Clin Pharmacol Ther. 2022 May 10. doi: 10.1002/cpt.2637. Online ahead of print.

ABSTRACT

Therapy of molybdenum co-factor (Moco) deficiency has received FDA approval in 2021. While urothione, the urinary excreted catabolite of Moco, is used as diagnostic biomarker for Moco-deficiency, its catabolic pathway remains unknown. Here, we identified the urothione-synthesizing methyltransferase using mouse liver tissue by anion exchange/size exclusion chromatography and peptide mass fingerprinting. We show that the catabolic Moco S-methylating enzyme corresponds to thiopurine S-methyltransferase (TPMT), a highly polymorphic drug-metabolizing enzyme associated with drug-related haematotoxicity but unknown physiological role. Urothione synthesis was investigated in vitro using recombinantly expressed human TPMT protein, liver lysates from Tpmt wild-type and knock-out (Tpmt-/-) mice as well as human liver cytosol. Urothione levels were quantified by LC-MS/MS in kidney and urine of mice. TPMT-genotype/phenotype and excretion levels of urothione were investigated in human samples and validated in an independent population-based study. As Moco provides a physiological substrate (thiopterin) of TPMT, thiopterin-methylating activity was associated with TPMT activity determined with its drug substrate (6-thioguanin) in mice and humans. Urothione concentration was extremely low in kidney and urine of Tpmt-/- mice. Urinary urothione concentration in TPMT-deficient patients depends on common TPMT polymorphisms, with extremely low levels in homozygous variant carriers (TPMT*3A/*3A) but normal levels in compound heterozygous carriers (TPMT*3A/*3C) as validated in the population-based study. Our work newly identified an endogenous substrate for TPMT and shows an unprecedented link between Moco-catabolism and drug-metabolism. Moreover, the TPMT example indicates that phenotypic consequences of genetic polymorphisms may differ between drug- and endogenous substrates.

PMID:35538648 | DOI:10.1002/cpt.2637

Br J Clin Pharmacol. 2022 May 10. doi: 10.1111/bcp.15393. Online ahead of print.

ABSTRACT

AIMS: Methadone metabolism and clearance are determined principally by polymorphic cytochrome P4502B6 (CYP2B6). Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo.

METHODS: CYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome b5 . Metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances determined. Adolescents receiving methadone for surgery were genotyped for CYP2B6, CYP2C19 and POR, and methadone clearance and metabolite formation clearance determined.

RESULTS: In vitro, CYP2B6.4 was more active than wild type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5, and P228L had lower rates of methadone metabolism than wild-type reductase. In vivo, methadone clinical clearance decreased linearly with the number of CYP2B6 slow metabolizer alleles, but were not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the POR*28 allele.

CONCLUSIONS: Several CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in CYP2B6, but not CYP2C19 or P450 reductase, affected methadone clearance in vivo. CYP2B6 polymorphisms 516G>T and 983T>C code for canonical loss of function variants, and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients.

PMID:35538637 | DOI:10.1111/bcp.15393

Annu Rev Genomics Hum Genet. 2022 May 10. doi: 10.1146/annurev-genom-111621-102737. Online ahead of print.

ABSTRACT

Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately 90-95% of individuals have an actionable genotype for at least one pharmacogene. For pharmacogenomic testing to have the greatest impact on medication safety and clinical care, genetic information should be made available at the time of prescribing (preemptive testing). However, the use of preemptive pharmacogenomic testing is associated with some logistical concerns, such as consistent reimbursement, processes for reporting preemptive results over an individual's lifetime, and result portability. Lessons can be learned from institutions that have implemented preemptive pharmacogenomic testing. In this review, we discuss the rationale and best practices for implementing pharmacogenomics preemptively. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:35537468 | DOI:10.1146/annurev-genom-111621-102737

Cancer Res. 2022 May 10:canres.2395.2021. doi: 10.1158/0008-5472.CAN-21-2395. Online ahead of print.

ABSTRACT

Identifying biomarkers predictive of cancer cell response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have opened new avenues of research to develop predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common pitfall to these methods is the lack of interpretability as to how they make predictions, hindering the clinical translation of these models. To alleviate this issue, we used the recent logic modeling approach to develop a new machine learning pipeline that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. The performance of this approach was showcased in a compendium of the three largest in vitro pharmacogenomic data sets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rates in independent datasets. These results along with in vivo and clinical validation, support a better translation of gene expression biomarkers between model systems using bimodal gene expression.

PMID:35536872 | DOI:10.1158/0008-5472.CAN-21-2395

J Hum Genet. 2022 May 9. doi: 10.1038/s10038-022-01040-1. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is a research area aimed at identifying genetic factors that are associated with drug responses, including drug efficacy, adverse drug reactions, and the appropriate drug dosage on a case-to-case basis. To promote the clinical implementation of PGx testing, which is currently of limited use in clinical practice, recent research has focused on providing reliable evidence for its clinical utility. In neurology, psychiatry, and neurosurgery, several human leukocyte antigen (HLA) alleles have been reportedly associated with cutaneous adverse drug reactions (cADRs) induced by antiepileptic drugs, which significantly carry the risk of developing cADRs. Prior to using antiepileptic drugs such as carbamazepine and lamotrigine, which are prone to cause severe cADRs, preemptive HLA genetic testing and therapeutic interventions such as drug selection and dosage adjustment based on the results of the tests can reduce the incidence of cADRs in the population before the initiation of treatment.

PMID:35534674 | DOI:10.1038/s10038-022-01040-1

Cell Death Dis. 2022 May 9;13(5):445. doi: 10.1038/s41419-022-04905-7.

NO ABSTRACT

PMID:35534470 | DOI:10.1038/s41419-022-04905-7

Res Pharm Sci. 2022 Apr 18;17(3):231-241. doi: 10.4103/1735-5362.343077. eCollection 2022 Jun.

ABSTRACT

BACKGROUND AND PURPOSE: The study was aimed at validating a simple, rapid, and low-cost LC-MS/MS method for carvedilol and 4/-hydroxyphenyl carvedilol assay in human plasma. The validated method was applied to investigate the pharmacokinetics after a low dose of 6.25 mg. carvedilol.

EXPERIMENTAL APPROACH: In this study, the plasma was extracted by liquid-liquid extraction and evaporated the organic layer to dryness, then both analytes in the residue were reconstituted and detected by LC- MS/MS. The method was validated following the guideline on bioanalytical method validation. Thirty-one healthy volunteers participated in the pharmacokinetic study. After 10 h of fasting, each volunteer received one tablet of 6.25 mg carvedilol orally. Blood samples were collected at 16 prescheduled time points. The plasma samples were analyzed for pharmacokinetics.

FINDINGS/RESULTS: The method was linear over a range of 0.050-50.049 ng/mL for carvedilol and 0.050- 10.017 ng/mL for 4/-hydroxyphenyl carvedilol. Crucial validated results reached the requirements of selectivity, accuracy, precision, and stability. Pharmacokinetics of carvedilol and 4/-hydroxyphenyl carvedilol were evaluated which showed Cmax at 21.26 ± 9.23 and 2.42 ± 2.07 ng/mL; AUC0-t 66.95 ± 29.45 and 5.93 ± 3.51 ng.h/mL; AUC0-inf 68.54 ± 30.11 and 6.78 ± 3.49 ng.h/mL; and T1/2 6.30 ± 1.95 and 6.31 ± 6.45 h, respectively.

CONCLUSION AND IMPLICATIONS: The validated method was able to detect and quantify both analytes in plasma samples and can be applied to the pharmacokinetic study of carvedilol and 4/-hydroxyphenyl carvedilol after receiving carvedilol at 6.25 mg orally.

PMID:35531138 | PMC:PMC9075024 | DOI:10.4103/1735-5362.343077

Cell Genom. 2022 Jan 12;2(1):100084. doi: 10.1016/j.xgen.2021.100084. Epub 2022 Jan 13.

ABSTRACT

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10-9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

PMID:35530816 | PMC:PMC9075703 | DOI:10.1016/j.xgen.2021.100084

Cancer Diagn Progn. 2022 May 3;2(3):405-410. doi: 10.21873/cdp.10123. eCollection 2022 May-Jun.

ABSTRACT

BACKGROUND: Colorectal cancer is a common cancer worldwide, with 5-10% of cases being hereditary. Familial adenomatous polyposis syndrome (FAP) is caused by germline mutations in the APC gene or rarely in the MUTYH gene.

PATIENTS AND METHODS: This work did not identify germline mutations in the MUTYH, NTHL1, POLD1 and POLE genes in 15 individuals belonging to five families with classic FAP, who had the mutation in the APC gene confirmed in a previous study. Our results support mutations in the APC gene as the main genetic contribution of classical FAP with severe phenotype. In the family that had the most aggressive form of the disease, we performed an array-based Comparative Genomic Hybridization analysis and identified the germinal loss of an allele of the NOTCH2 and BMPR2 genes in the mother (proband) and daughter. In order to validate the involvement of these genes in the other four families of this study, we analyzed the DNA copy number variation in the peripheral blood of the 15 participants.

RESULTS: FAP is a syndrome with considerable genetic and phenotypic heterogeneity and this phenomenon may explain the presence of secondary genetic alterations, such as the allelic loss of NOTCH2 and BMPR2 genes, found only in one family in this study. The CNV analysis confirmed that only the two members of the FAP2 family (patient 02H and 02F) had a deletion of these two genes, as the aCGH methodology had found. The other study participants did not show allelic loss for these two genes.

CONCLUSION: Validation in a larger number of families could confirm the presence of these new genetic alterations in classic FAP and improve understanding of the different types of aggressiveness of the disease.

PMID:35530639 | PMC:PMC9066544 | DOI:10.21873/cdp.10123

Acta Pharm Sin B. 2022 Mar;12(3):1514-1522. doi: 10.1016/j.apsb.2021.10.007. Epub 2021 Oct 16.

ABSTRACT

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

PMID:35530157 | PMC:PMC9069400 | DOI:10.1016/j.apsb.2021.10.007

Acta Pharm Sin B. 2022 Mar;12(3):1148-1162. doi: 10.1016/j.apsb.2021.09.024. Epub 2021 Sep 30.

ABSTRACT

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. However, most reported polymeric systems have sizes above 100 nm, which limits effective extravasation into tumors that are poorly vascularized and have dense stroma. This will, in turn, limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting. In this study, we combined the passive targeting via ultra-small-sized gemcitabine (GEM)-based nanoparticles (NPs) with the active targeting provided by folic acid (FA) conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages (TAMs). We developed an FA-modified prodrug carrier based on GEM (PGEM) to load doxorubicin (DOX), for co-delivery of GEM and DOX to tumors. The co-delivery system showed small particle size of ∼10 nm in diameter. The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile. The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor (FR), but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR. Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model. Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2, which was selectively expressed on TAMs. Thus, targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

PMID:35530140 | PMC:PMC9072252 | DOI:10.1016/j.apsb.2021.09.024

BJPsych Adv. 2021 May;27(3):153-157. doi: 10.1192/bja.2021.21. Epub 2021 Apr 23.

ABSTRACT

Stress is the most important proximal precipitant of depression, yet most large genome-wide association studies (GWAS) do not include stress as a variable. Here, we review how gene × environment (G × E) interaction might impede the discovery of genetic factors, discuss two examples of G × E interaction in depression and addiction, studies incorporating high-stress environments, as well as upcoming waves of genome-wide environment interaction studies (GWEIS). We discuss recent studies which have shown that genetic distributions can be affected by social factors such as migrations and socioeconomic background. These distinctions are not just academic but have practical consequences. Owing to interaction with the environment, genetic predispositions to depression should not be viewed as unmodifiable destiny. Patients may genetically differ not just in their response to drugs, as in the now well-recognised field of pharmacogenetics, but also in how they react to stressful environments and how they are affected by behavioural therapies.

PMID:35529524 | PMC:PMC9075164 | DOI:10.1192/bja.2021.21

Pharmacogenomics. 2022 May 9. doi: 10.2217/pgs-2022-0039. Online ahead of print.

ABSTRACT

Since its founding in 2013, Coriell Life Sciences (CLS) has built technologies leveraging genetic testing to empower physicians and has invested in research that advances the field of personalized medicine. The company focuses on development, implementation and research with expertise in medication safety, pharmacogenomics, infectious diseases and healthcare analytics. CLS works with healthcare institutions, laboratories, pharmacy benefit management companies, self-insured employers and public sector entities and actively contributes to scientific and clinical consortia. This overview summarizes the CLS service architecture and delivery capabilities for medication safety and risk reporting for pharmacogenomics, comprehensive medication management and infectious diseases. It includes the development and ongoing curation of genetic and non-genetic knowledge repositories, technology infrastructure and end points and research endeavors and it reviews economic, clinical and humanistic outcomes of CLS' pharmacogenomics-enriched comprehensive management program.

PMID:35527701 | DOI:10.2217/pgs-2022-0039

J Pharm Sci. 2022 May 5:S0022-3549(22)00190-3. doi: 10.1016/j.xphs.2022.04.019. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The pharmacokinetics (PK) of methylphenidate (MPH) differ significantly among individuals. Carboxylesterase 1 (CES1) is the primary enzyme metabolizing MPH, and its function is affected by genetic variants, drug-drug interaction (DDI), and sex. The object of this study is to evaluate CES1 pharmacogenetics as related to MPH metabolism using human liver samples and develop a physiologically-based pharmacokinetic (PBPK) modeling approach to investigate the influence of CES1 genotypes and other factors on MPH PK.

METHODS: The effect of the CES1 variant G143E (rs71647871) on MPH metabolism was studied utilizing 102 individual human liver S9 (HLS9) fraction samples. PBPK models were developed using the population-based PBPK software PK-Sim® by incorporating the HLS9 incubation data. The established models were applied to simulate MPH PK profiles under various clinical scenarios, including different genotypes, drug-alcohol interactions, and the difference between males and females.

RESULTSL: The HLS9 incubation study showed that subjects heterozygous for the CES1 variant G143E metabolized MPH at a rate of approximately 50% of that in non-carriers. The developed PBPK models successfully predicted the exposure alteration of MPH from the G143E genetic variant, ethanol-MPH DDI, and sex. Importantly, the study suggests that male G143E carriers who are alcohol consumers are at a higher risk of MPH overexposure.

CONCLUSION: PBPK modeling provides a means for better understanding the mechanisms underlying interindividual variability in MPH PK and PD and could be utilized to develop a safer and more effective MPH pharmacotherapy regimen.

PMID:35526575 | DOI:10.1016/j.xphs.2022.04.019

BMC Cancer. 2022 May 7;22(1):512. doi: 10.1186/s12885-022-09580-7.

ABSTRACT

BACKGROUND: Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel.

METHODS: We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database.

RESULTS: Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E.

CONCLUSION: These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.

PMID:35525914 | DOI:10.1186/s12885-022-09580-7

Endocrinology. 2022 May 7:bqac061. doi: 10.1210/endocr/bqac061. Online ahead of print.

ABSTRACT

Diabetes and related metabolic syndrome are common metabolic disorders. Gestational diabetes mellitus (GDM) is rather prevalent in the clinic. Although most of GDM resolves after therapeutic intervention and/or after delivery, the long-term health effect of GDM remains to be better understood. The constitutive androstane receptor (CAR), initially characterized as a xenobiotic receptor, was more recently proposed to be a therapeutic target for obesity and type 2 diabetes mellitus (T2DM). In this study, high-fat diet (HFD) feeding was used to induce GDM. Upon delivery, GDM mice were returned to chow diet until the metabolic parameters were normalized. Parous non-GDM control females or metabolically normalized GDM females were then subjected to HFD feeding to induce non-gestational obesity and T2DM. Our results showed that GDM sensitized mice to metabolic abnormalities induced by a second hit of HFD. Treatment with the CAR agonist 1,4-bis [2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) efficiently attenuated GDM-sensitized and HFD-induced obesity and T2DM, including decreased body weight, improved insulin sensitivity, inhibition of hyperglycemia and hepatic steatosis, increased oxygen consumption, and decreased adipocyte hypertrophy. In conclusion, our results have established GDM as a key risk factor for the future development of metabolic disease. We also propose that CAR is a therapeutic target for the management of metabolic disease sensitized by GDM.

PMID:35524740 | DOI:10.1210/endocr/bqac061

Transl Psychiatry. 2022 May 6;12(1):187. doi: 10.1038/s41398-022-01934-w.

ABSTRACT

Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.

PMID:35523779 | DOI:10.1038/s41398-022-01934-w

Talanta. 2022 Apr 30;246:123517. doi: 10.1016/j.talanta.2022.123517. Online ahead of print.

ABSTRACT

Fabrication of facile, sensitive, and accurate pesticide detection strategies plays crucial roles in food safety, environmental protection, and human health. Here, a novel esterase activatable aggregation-induced emission (AIE) plus excited-state intramolecular proton transfer (ESIPT) probe, kaempferol tetraacetate, was designed and synthesized from purified natural kaempferol for ratiometric sensing of carbaryl. Acetate groups are introduced as the esterase reactive sites and AIE plus ESIPT initiator. Kaempferol tetraacetate is an aggregation-caused quenching compound that shows fluorescent (FL) emission at 415 nm. Esterase specifically hydrolyzes kaempferol tetraacetate to kaempferol with AIE plus ESIPT characteristics (distinct FL emission, 530 nm; a large Stokes shift, 165 nm within a short time (8 min). Molecular docking and kinetics performance indicate the high affinity and specific hydrolysis of esterase and kaempferol tetraacetate. Carbaryl inhibits the activity of esterase to efficiently suppress the production of kaempferol. Thus, a facile ratiometric assay strategy is constructed for carbaryl detection. By measuring the FL intensity ratio, the proposed strategy presents high selectivity and reliability with a wide linear range from 0.02 to 2.00 μg L-1 and a very low limit of detection at 0.007 μg L-1. Furthermore, appropriate recovery from 93.75% to 108.67% with a relative standard deviation less than 5.66% for real sample analysis indicates good accuracy and precision. All results indicate that the fabricated strategy offers a new way for facile, sensitive, and accurate detection of carbaryl in real complex samples.

PMID:35523022 | DOI:10.1016/j.talanta.2022.123517

Front Pharmacol. 2022 Apr 20;13:832048. doi: 10.3389/fphar.2022.832048. eCollection 2022.

ABSTRACT

SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different populations, and the successful implementation of pharmacogenomics in Thailand for the prevention of SCARs.

PMID:35517811 | PMC:PMC9065683 | DOI:10.3389/fphar.2022.832048

Front Aging Neurosci. 2022 Apr 19;14:853277. doi: 10.3389/fnagi.2022.853277. eCollection 2022.

ABSTRACT

Vitamin D is a lipid-soluble molecule and an important transcriptional regulator in many tissues and organs, including the brain. Its role has been demonstrated also in Parkinson's disease (PD) pathogenesis. Vitamin D receptor (VDR) is responsible for the initiation of vitamin D signaling cascade. The aim of this study was to assess the associations of VDR genetic variability with PD risk and different PD-related phenotypes. We genotyped 231 well characterized PD patients and 161 healthy blood donors for six VDR single nucleotide polymorphisms, namely rs739837, rs4516035, rs11568820, rs731236, rs2228570, and rs1544410. We observed that VDR rs2228570 is associated with PD risk (p < 0.001). Additionally, we observed associations of specific VDR genotypes with adverse events of dopaminergic treatment. VDR rs1544410 (GG vs. GA + AA: p = 0.005; GG vs. GA: p = 0.009) was associated with the occurrence of visual hallucinations and VDR rs739837 (TT vs. GG: p = 0.036), rs731236 (TT vs. TC + CC: p = 0.011; TT vs. TC: p = 0.028; TT vs. CC: p = 0.035), and rs1544410 (GG vs. GA: p = 0.014) with the occurrence of orthostatic hypotension. We believe that the reported study may support personalized approach to PD treatment, especially in terms of monitoring vitamin D level and vitamin D supplementation in patients with high risk VDR genotypes.

PMID:35517045 | PMC:PMC9063754 | DOI:10.3389/fnagi.2022.853277