ATP-binding Cassette Subfamily Research Articles

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.

Activation of the Keap1/Nrf2 Pathway as an Adaptive Response to an Electrophilic Metabolite of Morphine.

Morphinone (MO) is an electrophilic metabolite of morphine that covalently binds to protein thiols via its α,β-unsaturated carbonyl group, resulting in toxicity in vitro and in vivo. Our previous studies identified a variety of redox signaling pathways that are activated during electrophilic stress. Here, we examined in vitro activation of a signaling pathway involving Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in response to MO. Exposure of HepG2 cells to MO caused covalent modification of Keap1 thiols (evaluated using biotin-PEAC5-maleimide labeling) and nuclear translocation of Nrf2, thereby up-regulating downstream genes encoding ATP binding cassette subfamily C member 2, solute carrier family 7 member 11, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione S-transferase alpha 1, and heme oxygenase 1. However, dihydromorphinone, a metabolite of morphine lacking the reactive C7-C8 double bond, had little effect on Nrf2 activation. These results suggest that covalent modification is crucial in the Keap1/Nrf2 pathway activation and that this pathway is a redox signaling-associated adaptive response to MO metabolism.

Exploring genetic influences on adverse outcome pathways using heuristic simulation and graph data science

Adverse outcome pathways provide a powerful tool for understanding the biological signaling cascades that lead to disease outcomes following toxicity. The framework outlines downstream responses known as key events, culminating in a clinically significant adverse outcome as a final result of the toxic exposure. Here we use the AOP framework combined with artificial intelligence methods to gain novel insights into genetic mechanisms that underlie toxicity-mediated adverse health outcomes. Specifically, we focus on liver cancer as a case study with diverse underlying mechanisms that are clinically significant. Our approach uses two complementary AI techniques: Generative modeling via automated machine learning and genetic algorithms, and graph machine learning. We used data from the US Environmental Protection Agency’s Adverse Outcome Pathway Database (AOP-DB; aopdb.epa.gov) and the UK Biobank’s genetic data repository. We use the AOP-DB to extract disease-specific AOPs and build graph neural networks used in our final analyses. We use the UK Biobank to retrieve real-world genotype and phenotype data, where genotypes are based on single nucleotide polymorphism data extracted from the AOP-DB, and phenotypes are case/control cohorts for the disease of interest (liver cancer) corresponding to those adverse outcome pathways. We also use propensity score matching to appropriately sample based on important covariates (demographics, comorbidities, and social deprivation indices) and to balance the case and control populations in our machine language training/testing datasets. Finally, we describe a novel putative risk factor for LC that depends on genetic variation in both the aryl-hydrocarbon receptor (AHR) and ATP binding cassette subfamily B member 11 (ABCB11) genes.

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer.

Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann-Whitney U-test. Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ng/ml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p=0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

The Interaction between Four Polymorphisms and Haplotype of ABCB1, the Risk of Non-Small Cell Lung Cancer, and the Disease Phenotype.

P-glycoprotein, product of the ABCB1 (ATP binding cassette subfamily B member 1) gene, has been reported to play an important role in multiple drug resistance during cancer therapy. However, its influence on non-small cell lung cancer (NSCLC) risk has not been clearly defined. The aim of the present study was to examine the association between clinicopathological factors and SNPs T-129C, C1236T, G2677T/A, and C3435T, as well as its haplotype, and to investigate the role of ABCB1 polymorphisms in NSCLC development. The study included 80 patients who suffered from NSCLC and underwent surgery to remove the tumour and 96 healthy controls. The tissues were genotyped by PCR-RFLP and sequencing methods, and the haplotype frequencies in both groups were estimated. The SNP C3435T was identified as a NSCLC risk factor. The presence of mutated allelic variant T (p=0.0103) or homozygote TT (p=0.0099) was observed significantly more often in cancer patients than in healthy controls. The two groups also demonstrated a highly significant difference in common haplotype frequency (p=0.01). The T-129-T1236-T2677-T3435 haplotype was found to be most closely associated with NSCLC risk. Although the investigated polymorphisms were not related to demographic features, clinicopathological lung tumour characteristics, or blood morphology indices, marginally significant correlations were found with some variables: C1236T with age of disease onset (p=0.0410); C3435T with smoking status (p=0.0561). As the findings indicate, lung cancer and control groups demonstrate significantly different patterns of -129/1236/2677/3435 haplotype distribution; T-T-T-T haplotype contributes to NSCLC susceptibility, and this effect is probably mainly dependent on C3435T. So far, similar studies were published in other populations.

ABCA9, an ER cholesterol transporter, inhibits breast cancer cell proliferation via SREBP-2 signaling.

The association between cholesterol metabolism and cancer development and progression has been recently highlighted. However, the role and function of many cholesterol transporters remain largely unknown. Here, we focused on the ATP-binding cassette subfamily A member 9 (ABCA9) transporter given that its expression is significantly downregulated in both canine mammary tumors and human breast cancers, which in breast cancer patients correlates with poor prognosis. We found that ABCA9 is mainly present in the endoplasmic reticulum (ER) and is responsible for promoting cholesterol accumulation in this structure. Accordingly, ABCA9 inhibited sterol-regulatory element binding protein-2 (SREBP-2) translocation from the ER to the nucleus, a crucial step for cholesterol synthesis, resulting in the downregulation of cholesterol synthesis gene expression. ABCA9 expression in breast cancer cells attenuated cell proliferation and reduced their colony-forming abilities. We identified ABCA9 expression to be regulated by Forkhead box O1 (FOXO1). Inhibition of PI3K induced enhanced ABCA9 expression through the activation of the PI3K-Akt-FOXO1 pathway in breast cancer cells. Altogether, our study suggests that ABCA9 functions as an ER cholesterol transporter that suppresses cholesterol synthesis via the inhibition of SREBP-2 signaling and that its restoration halts breast cancer cell proliferation. Our findings provide novel insight into the vital role of ABCA9 in breast cancer progression.

Efficacy and safety of switching from febuxostat to dotinurad, a novel selective urate reabsorption inhibitor, in hyperuricemic patients with type 2 diabetic kidney disease: Protocol for a single-arm, open-label, prospective, exploratory study.

Dotinurad is a novel uricosuric drug in Japan with selective and potent urate transporter 1 (URAT1) inhibitory activity. This study aims to evaluate the efficacy and safety of dotinurad in hyperuricemic patients with type 2 diabetic kidney disease by comparing serum levels of urate and plasma and urinary levels of indoxyl sulfate excreted via the urate excretion transporter ATP binding cassette subfamily G member 2 (ABCG2), as indices, with baseline levels after switching from febuxostat to dotinurad. This single-center, single-arm, open-label, prospective, exploratory study aims to evaluate the effect of switching from febuxostat to dotinurad on serum urate levels and its background factors. The study will include 50 hyperuricemic patients with type 2 diabetic kidney disease and urate levels exceeding 6 mg/dL despite administration of febuxostat 20 mg/day for at least 3 months. The primary outcome is the achievement rate of serum urate levels of ≤6 mg/dL after 24 weeks of treatment with dotinurad at 0.5 mg to a maximum of 4 mg once daily. Secondary outcomes include the changes in serum urate levels, plasma and urinary indoxyl sulfate levels, and renal injury-related markers from baseline to observation points at weeks 4, 12, and 24. The study hypothesizes that switching to dotinurad may reduce the plasma levels of indoxyl sulfate and increase its urinary levels in patients with hyperuricemia. These suggest that dotinurad can potently lower the serum urate level by inhibiting URAT1 without adversely affecting ABCG2. Thus, findings of this study are expected to provide useful insights into the treatment of hyperuricemia associated with type 2 diabetic kidney disease and the discovery of new possibilities for dotinurad. Prior to the study, its study protocol was scientifically and ethically reviewed and approved by the Japan Physicians Association Clinical Research Review Board (approval number: JPA007-2204-02). In addition, patients who provide written informed consent will participate in the study. The results of this study will be published through submission to a peer-reviewed scientific journal. https://jrct.niph.go.jp/en-latest-detail/jRCTs031220080, identifier jRCTs031220080.

The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors.

The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.

The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance.

Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.

A diet supplemented with cholic acid elevates blood pressure accompanied by albuminuria in rats.

A diet supplemented with cholic acid (CA), the primary 12α-hydroxylated bile acid, can induce hepatic lipid accumulation in rats without obesity. This study examined the effects of a CA-supplemented diet on blood pressure (BP). After acclimation, WKAH/HkmSlc rats (3 weeks old) were divided into two groups and fed with a control AIN-93-based diet or a CA-supplemented diet (0.5g CA/kg) for 13 weeks. The CA diet increased systolic and diastolic BP as well as hepatic lipid concentrations in the rats. No changes were found in the blood sodium concentration. Urinary albumin concentration increased in CA-fed rats. An increase was observed in the hepatic expression of ATP-binding cassette subfamily B member 1B that correlated BPs and urinary albumin concentration accompanied by an increase in portal taurocholic acid concentration. These results suggest that 12α-hydroxylated bile acids are involved in increased BP and albuminuria via alteration of hepatic function.

Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases.

ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.

Association of pro-inflammatory cytokines, inflammatory proteins with atherosclerosis index in obese male subjects.

Investigation the association of pro-inflammatory markers interleukin (IL)-1β and IL- 10 expression, serum levels of C-reactive protein (CRP), cyclooxygenase-2 (COX2), High-density lipoprotein (HDL), Apolipoprotein A1 (ApoA1), and ATP Binding Cassette Subfamily A Member 1 (ABCA1) inflammatory proteins with atherosclerosis index (homocysteine) in normal-weight and obese male subjects. 59 males including 30 obese (Body mass index (BMI) of≥30kg/m2) and 29 normal-weight (BMI of 18.5-24.9kg/m2) were joined to this study. Plasma levels of IL-1β and IL-10 (pg/mL), CRP (pg/mL), COX-2 (ng/mL), APOA1 (mg/dL), ABCA1 (ng/mL), HDL, Cholesterol, and Triglyceride (TG) (mg/dL), and homocysteine (µmol/L) was measured. Association of these biomarkers with homocysteine was determined. Obese subjects had higher serum levels of IL10, IL1β, CRP, COX-2, TG, and cholesterol concentrations (allp<0.05 except IL-10 and cholesterol) and low levels of HDL, APOA1, and ABCA1 (non-significant differences) in comparison to normal-weight group. Homocysteine levels were high in obese men with no significant differences between the two groups. In obese subjects, homocysteine had a significant inverse correlation with APOA1, ABCA1, and HDL, and a strong and moderate positive correlation was found with CRP and TG levels, respectively. High level of homocysteine and its correlation with inflammation proteins and markers in obese subjects appear to be contributed with atherosclerosis development.

ABCC8 is correlated with immune cell infiltration and overall survival in lower grade glioma

ATP binding cassette subfamily C member 8 (ABCC8) encodes a protein regulating the ATP-sensitive potassium channel. Whether the level of ABCC8 mRNA in lower grade glioma (LGG) correlates with immune cell infiltration and patient outcomes has not been evaluated until now. Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets. The association between ABCC8 and tumor immune cell infiltration, diverse gene mutation characteristics, tumor mutation burden (TMB), and survival in LGG was also investigated in several independent datasets. Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways. Through an online database, we found that ABCC8 expression in LGG was lower than in normal tissues. Then, the association of ABCC8 expression and immune cell infiltration in LGG was discussed. As we expected, the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets. Consistently, TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis. Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB. The high expression of ABCC8 was linked to improved survival of LGG patients. A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG. Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.

Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.

Clopidogrel is an antiplatelet prodrug primarily prescribed to prevent or treat acute coronary syndrome (ACS) or acute ischemic stroke (IS), polymorphisms of genes encoding cytochrome P-450 (CYP) and P-glycoprotein transporter, could affect the efficiency of clopidogrel absorption and biotransformation, especially during the first critical hours following its administration. The present study was designed to investigate the potential association of clopidogrel responsiveness and 14 polymorphisms in the genes encoding the CYPs (CYP2C9, 2C19, 3A4, 3A5, 1A2, and 2B6), the ATP binding cassette subfamily B member 1 (ABCB1). Platelet aggregation activity was measured after 8h of 300mg clopidogrel administration for fifty-five ACS patients. There was no significant association between polymorphism of the studied CYPs and clopidogrel responsiveness (P>0.05). The frequency of the ABCB1 3435 T allele in clopidogrel non-responders was higher (78.9%) compared to responders (52.8%), but this difference was not significant (P=0.057). Demographic characteristics, comorbidities, concomitant treatments were not associated with clopidogrel response. There was no effect of the studied genetic variations and demographic factors on the platelet activity of clopidogrel in Moroccan ACS patients.

Pyroglutamylproline purified from fermented barley extract increases ABCG2 expression in Caco-2 cells

Fermented barley extract P (FBEP) prepared from barley shochu distillation by-product has been reported to lower serum uric acid (UA) by increasing urinary excretion of UA. ATP-binding cassette subfamily G member 2 (ABCG2) is a transporter responsible for UA efflux from the intestinal tract and kidneys. This study aimed to identify, among the compounds isolated from FBEP using high-performance liquid chromatography, the components that promote ABCG2 expression in Caco-2 cells. Pyroglutamylproline (pEP) increased the expression of ABCG2 in Caco-2 cells at the gene and protein levels. These results suggest that the pEP contained in FBEP may decrease serum UA levels by increasing the expression of urate efflux transporters in the intestinal epithelium and promoting UA excretion.

Biochemical and Molecular Characterization of Prochloraz Resistance in Lasiodiplodia theobromae Field Isolates.

Stem-end rot (SER), caused by Lasiodiplodia theobromae, is one of the most critical diseases of mango in China. The demethylation inhibitor fungicide prochloraz has been widely used in China to control mango diseases. Isolates (n = 139) of L. theobromae were collected in 2019 from six mango-producing regions in Hainan Province, China. The fungicide sensitivity of L. theobromae isolates to prochloraz revealed that the EC50 (50% effective concentration) values ranged from 0.0006 to 16.4131 µg/ml. In total, 21 of the 139 isolates were categorized as resistant to prochloraz. The resistant isolates sprayed with prochloraz could not be effectively controlled in detached fruit. The mycelial growth, conidia germination, and ability to grow at temperatures ranging from 12 to 35°C of resistant isolates decreased, suggesting fitness penalties. The experiment showed that, after treatment with prochloraz at 10 µg/ml, the content of ergosterol in the mycelia of the sensitive isolate decreased by 80.23%, whereas the resistant strain decreased by only 57.52%. The damage to membranes in the sensitive isolates was more serious than for resistant isolates. The target gene CYP51 and the ATP-binding cassette (ABC) subfamily ABCG gene were cloned but no mutation was found. When treated with prochloraz, the expression of CYP51 and ABCG in resistant isolates was significantly higher than in the sensitive isolates. Thus, induced expression of its target gene combined with the induction of expression drug efflux transporters appeared to mediate the prochloraz resistance of L. theobromae.

Nanobodies targeting ABCC3 for immunotargeted applications in glioblastoma

The cancer “omics” reveal many clinically relevant alterations that are transforming the molecular characterization of glioblastomas. However, many of these findings are not yet translated into clinical practice due, in part, to the lack of non-invasive biomarkers and the limitations imposed by the blood–brain barrier. Nanobodies, camelid single-domain antibody fragments, emerge as a promising tool for immunotargeted applications for diagnosing and treating glioblastomas. Performing agnostic bioinformatic analysis from glioblastoma patient datasets, we identified ATP Binding Cassette subfamily C member 3 (ABCC3) as a suitable target for immunotargeted applications. The expression of ABCC3 is associated with poor survival and impaired response to temozolomide. Importantly, high expression of ABCC3 is restricted to glioblastoma, with negligible levels in healthy brain tissue, and further correlates with tumor grade and stemness markers. We identified three immunogenic epitopes of ABCC3 which were used to isolate nanobodies from a glioblastoma-specific phage-display nanobody library. Two nanobodies targeting ABCC3 (NbA42 and NbA213) were further characterized and demonstrated in vivo selective recognition of ABCC3 in glioblastoma xenograft mouse models upon systemic administration. We designate NbA42 and NbA213 as new candidates to implement immunotargeted applications guiding a more personalized and precise diagnosis, monitoring, and treatment of glioblastoma patients.

Functional characterization of ABCA4 genetic variants related to Stargardt disease

The ATP-binding cassette subfamily 4 (ABCA4), a transporter, is localized within the photoreceptors of the retina, and its genetic variants cause retinal dystrophy. Despite the clinical importance of the ABCA4 transporter, a few studies have investigated the function of each variant. In this study, we functionally characterized ABCA4 variants found in Korean patients with Stargardt disease or variants of the ABCA4 promoter region. We observed that four missense variants—p.Arg290Gln, p.Thr1117Ala, p.Cys1140Trp, and p.Asn1588Tyr—significantly decreased ABCA4 expression on the plasma membrane, which could be due to intracellular degradation. There are four major haplotypes in the ABCA4 proximal promoter. We observed that the H1 haplotype (c.-761C>A) indicated significantly increased luciferase activity compared to that of the wild-type, whereas the H3 haplotype (c.-1086A>C) indicated significantly decreased luciferase activity (P < 0.01 and 0.001, respectively). In addition, c.-900A>T in the H2 haplotype exhibited significantly increased luciferase activity compared with that of the wild-type. Two transcription factors, GATA-2 and HLF, were found to function as enhancers of ABCA4 transcription. Our findings suggest that ABCA4 variants in patients with Stargardt disease affect ABCA4 expression. Furthermore, common variants of the ABCA4 proximal promoter alter the ABCA4 transcriptional activity, which is regulated by GATA-2 and HLF transcription factors.

Impact of Genetic Variants on Postoperative Pain and Fentanyl Dose Requirement in Patients Undergoing Major Breast Surgery: A Candidate Gene Association Study.

Postoperative analgesia is crucial for the early and effective recovery of patients undergoing surgery. Although postoperative multimodal analgesia is widely practiced, opioids such as fentanyl are still one of the best analgesics. The analgesic response of fentanyl varies widely among individuals, probably due to genetic and nongenetic factors. Among genetic factors, single nucleotide polymorphisms (SNPs) may influence its analgesic response by altering the structure or function of genes involved in nociceptive, fentanyl pharmacodynamic, and pharmacokinetic pathways. Thus, it is necessary to comprehensively ascertain if the SNPs present in the aforementioned pathways are associated with interindividual differences in fentanyl requirement. In this study, we evaluated the association between 10 candidate SNPs in 9 genes and 24-hour postoperative fentanyl dose (primary outcome) and also with postoperative pain scores and time for first analgesia (secondary outcomes). A total of 257 South Indian women, aged 18-70 years, with American Society of Anesthesiologists (ASA) physical status I-III, undergoing major breast surgery under general anesthesia, were included in the study. Patients were genotyped for candidate SNPs using real-time polymerase chain reaction. All patients received a standardized intravenous fentanyl infusion through a patient-controlled analgesic (PCA) pump, and the 24-hour postoperative fentanyl dose requirement was measured using PCA. The median 24-hour postoperative fentanyl requirement was higher in rs1799971 carriers (G/G versus A/A + A/G-620 μg [500-700] vs 460 μg [400-580]) with a geometric mean (GM) ratio of 1.91 (95% confidence interval [CI], 1.071-1.327). The median 24-hour pain scores were higher in rs4680 carriers (A/G + A/A versus G/G-34 [30-38] vs 31 [30-38]) with a GM ratio of 1.059 (95% CI, 1.018-1.101) and were lower in rs1045642 carriers (A/A + A/G versus G/G-34 [30-38] vs 30 [30-34]) with a GM ratio of 0.936 (95% CI, 0.889-0.987). The median time for first analgesic was lower in rs734784 carriers [C/C versus T/T + C/T-240 minutes (180-270) vs 240 minutes (210-270)] with a GM ratio of 0.902 (95% CI, 0.837-0.972). Five of 9 clinical factors, namely, history of diabetes, hypertension, hypothyroidism, anesthesia duration, and intraoperative fentanyl requirement were associated with different outcomes individually ( P < .05) and were used to adjust the respective associations. The SNP opioid receptor mu-1 ( OPRM1 ) (rs1799971) was associated with higher postoperative fentanyl requirement in South Indian patients undergoing major breast surgery. Twenty-four hour postoperative pain scores were higher in catechol-O-methyl transferase ( COMT ) (rs4680) carriers and lower in ATP binding cassette subfamily B member 1 ( ABCB1 ) (rs1045642) carriers, whereas time for first analgesic was lower in potassium channel subunit 1 ( KCNS1 ) (rs734784) carriers. However, these exploratory findings must be confirmed in a larger study.

The Functionality of Apigenin as a Novel Cardioprotective Nutraceutical with Emphasize on Regulating Cardiac Micro RNAs:.

Cardiovascular diseases (CVDs) are considered the most common disorder and the leading cause of mortality globally. The etiology of CVDs depends on a variety of genetic and acquired parameters. Nowadays, a dramatic surge appeared in published reports to find the association between microRNAs (miRNAs) and CVDs in order to understand the cause of the disease, rapid diagnosis with the introduction of valid biomarkers, and target as a therapeutic approach. Apigenin is a novel nutraceutical flavonoid that cardioprotective properties are suggested. The current review aimed to evaluate the beneficial features of this phytochemical against CVDs with an emphasis on its ability to regulate the miRNAs. The findings demonstrated that Apigenin could regulate cardiac miRNAs, including miR-103, miR-122-5p, miR-15b, miR-155, and miR-33. Consequently, preventing CVDs is possible through different effects such as the promotion of cholesterol efflux, prevention of hyperlipidemia, alteration in ATP Binding Cassette Subfamily A Member 1 (ABCA1) levels, reducing of cardiocytes apoptosis, and retarding myocytes fibrosis. Also, it can regulate signaling pathways, protect against endothelial dysfunction, maintain oxidative balance, and decrease inflammatory factors and reactive oxygen species. Hence, apigenin regulatory characteristics affecting miRNAs expression could introduce this flavonoid as a novel cardioprotective phytochemical against different CVDs.