ABCC2 Gene Research Articles

Curcumol Synergizes with Cisplatin in Osteosarcoma by Inhibiting M2-like Polarization of Tumor-Associated Macrophages.

Osteosarcoma is the most prevalent bone cancer, and chemotherapy is still an indispensable treatment in its clinical practice. Cisplatin (CDDP) has become the most commonly used agent for osteosarcoma, although the outcomes of CDDP chemotherapy remain unsatisfactory because of frequent resistance. Here, we report on a promising combination therapy where curcumol, a bioactive sesquiterpenoid, enhanced CDDP-induced apoptosis to eradicate osteosarcoma cells, and revealed that M2-like macrophages might be the underlying associated mechanisms. First, we observed that curcumol enhanced the CDDP-mediated inhibition of cell proliferation and augmented the apoptosis in osteosarcoma cell lines. Curcumol contributed to preventing the migration of osteosarcoma cells when combined with CDDP. Moreover, this drug combination showed more potent tumor-growth suppression in the orthotopic transplantation of osteosarcoma K7M2 WT cells. We then estimated chemotherapy-associated drug-resistant genes, including ABCB1, ABCC1 and ABCG2, and found that curcumol significantly reversed the mRNA levels of CDDP-induced ABCB1, ABCC1 and ABCG2 genes in the tumor tissue. Moreover, M2-like macrophages were enriched in osteosarcoma tissues, and were largely decreased after curcumol and CDDP treatment. Taken together, these findings suggest that curcumol inhibits the polarization of M2-like macrophages and could be a promising combination strategy to synergize with CDDP in the osteosarcoma.

Population pharmacokinetics of oxcarbazepine 10-monohydroxy derivative in Chinese adult epileptic patients

ObjectiveOxcarbazepine (OXC) is metabolised to active 10-monohydroxy derivative (MHD) after oral administration. Using this fact we aimed to develop an MHD population pharmacokinetic (PPK) model in Chinese adult epileptic patients...

The role of ATP-binding cassette transporter genes expression in treatment failure cutaneous leishmaniasis

Leishmaniasis is one of the common diseases transmitted by sand flies in tropical and subtropical regions of the world. Currently, antimonial derivatives are the first line of treatment. Some of the members of the ATP-binding cassette (ABC) family of Leishmania are shown to be associated with no response to treatment. In this study, we evaluated ABCI4, ABCG2, ABCC7, ABCB4, and ABCC3 genes expression in Leishmania isolated from patients with non-healing cutaneous leishmaniasis and treatment response isolates. We selected 17 clinical isolates including 8 treatment failure and 9 treatment response samples from September 2020 to March 2021. The isolates were obtained from patients of Health Center Laboratory of Varzaneh, Isfahan, Iran with cutaneous leishmaniasis. The diagnosis was performed using microscopic observation. The samples were directly collected from the lesions. The expression profiling of genes was assessed using SYBR Green real-time PCR that was analyzed with delta-delta Ct. All treatment failure clinical isolates were L. major. Gene expression analysis in treatment failure isolates showed that the ABC transported genes had a different pattern in each isolate. Treatment failure has been reported for cutaneous leishmaniasis worldwide. Knowledge of the molecular mechanisms of treatment failure could solve this problem. ABC transporter genes are considered controversial over the mechanisms of treatment failure outcomes. In this study, we showed that ABC transporter genes could be considered one of the important mechanisms.

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice.

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(−/−) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

FAT1 downregulation enhances stemness and cisplatin resistance in esophageal squamous cell carcinoma.

Primary or acquired drug resistance accounts for the failure of chemotherapy and cancer recurrence in esophageal squamous cell carcinoma (ESCC). However, the aberrant mechanisms driving drug resistance are not fully understood in ESCC. In our previous study, FAT Atypical Cadherin 1 (FAT1) was found to inhibit the epithelial-mesenchymal transition (EMT) process in ESCC. EMT plays a critical role in the development of drug resistance in multiple cancer types. Besides, it equips cancer cells with cancer stem cell (CSC)-like characters that also are associated with chemotherapy resistance. Whether FAT1 regulates the stemness or drug resistance of ESCC cells is worth being explored. Here we found that FAT1 was downregulated in ESCC spheres and negatively correlated with stemness-associated markers including ALDH1A1 and KLF4. Knocking down FAT1 enhanced the sphere-forming ability, resistance to cisplatin and drug efflux of ESCC cells. Additionally, FAT1 knockdown upregulated the expression of drug resistance-related gene ABCC3. Furtherly, we found FAT1 knockdown induced the translocation of β-catenin into nucleus and enhanced its transcriptional activity. The result of ChIP showed that β-catenin was enriched in ABCC3 promoter. Furthermore, β-catenin promoted expression of ABCC3. In conclusion, FAT1 knockdown might enhance the stemness and ABCC3-related cisplatin resistance of ESCC cells via Wnt/β-catenin signaling pathway. FAT1 and its downstream gene ABCC3 might be potential targets for overcoming chemoresistance in ESCC.

The Association between Single Nucleotide Polymorphisms, including miR-499a Genetic Variants, and Dyslipidemia in Subjects Treated with Pharmacological or Phytochemical Lipid-Lowering Agents.

Disorders of lipoprotein metabolism are among the major risk factors for cardiovascular disease (CVD) development. Single nucleotide polymorphisms (SNPs) have been associated with the individual variability in blood lipid profile and response to lipid-lowering treatments. Here, we genotyped 34 selected SNPs located in coding genes related to lipid metabolism, inflammation, coagulation, and a polymorphism in the MIR499 gene—a microRNA previously linked to CVD—to evaluate the association with lipid trait in subjects with moderate dyslipidemia not on lipid-lowering treatment (Treatment-naïve (TN) cohort, n = 125) and in patients treated with statins (STAT cohort, n = 302). We also explored the association between SNPs and the effect of a novel phytochemical lipid-lowering treatment in the TN cohort. We found that 6 SNPs (in the MIR499, TNFA, CETP, SOD2, and VEGFA genes) were associated with lipid traits in the TN cohort, while no association was found with the response to twelve-week phytochemical treatment. In the STAT cohort, nine SNPs (in the MIR499, CETP, CYP2C9, IL6, ABCC2, PON1, IL10, and VEGFA genes) were associated with lipid traits, three of which were in common with the TN cohort. Interestingly, in both cohorts, the presence of the rs3746444 MIR499 SNP was associated with a more favorable blood lipid profile. Our findings could add information to better understand the individual genetic variability in maintaining a low atherogenic lipid profile and the response to different lipid-lowering therapies.

Potential genetic biomarker of Saudi Arabian patients with colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer deaths globally. We implemented a comprehensive literature review regarding CRC genetics studies to offer a perception into the genes associated with CRC recognized in Saudi patients. Definite genetic variants in ABCB1, ADIPOQ, CTNNB1, SFRP3, LRP6, CYP19A1, PARP-1, TDG genes exhibited significant protection against CRC development in Saudi population. Whereas, other gene mutations in ABCB1, ABCC1, CASR, IL-17F, NOTCH1, NOTCH4, PRNCR1, TDG, TLR2, TLR4, TLR-9, TSLP, TSLPR and TNF-α genes showed irrelevant correlation with CRC risk in Saudi Arabia. On the other hand, specific mutations in ABCC1, ADIPOQ, CYP1A1, KIR, IL-17A, MMP2, NOTCH3, PRNCR1, RETN, TDG, TLR2, BRAF, PARP-1, TLR4, TLR-9, TNF-α, TSLP and XRCC1 genes demonstrated a substantial augmented CRC risk development in Saudi patients. Furthermore, ATR, ATM, BMI1, CCAT1, Chk1, Chk2, COX-2, FoxM1, FSCN1, Ki67, MALAT1, miR-29, miR-34a, miR-92, miR-182-5, PANDAR, PIK3CA, TIGAR over-expression revealed a robust association with CRC in Saudi Arabia (KSA). Moreover, gene alterations in APC, EGFR, FBXW7, TP53, PTEN, K-ras genes were concomitant in CRC. As well as, lower expression of MLH1, MSH2, MSH6, PMS2, EPCAM and MUTYH genes were recognized in LS patients and future CRC Saudi patients. These gene mutations may be used as diagnostic and/or prognostic genetic markers in CRC Saudi patients and could offer a potential therapeutic target for CRC management.

In silico screening and analysis of single-nucleotide polymorphic variants of the ABCC2 gene affecting Dubin–Johnson syndrome

Background and Study AimsDubin–Johnson syndrome (DJS) is a benevolent genetic disorder of the liver with autosomal inheritance. It is a rare disorder characterized by an increase in conjugated bilirubin and anomaly in coproporphyrin clearance. DJS is caused by deleterious mutations in the ABCC2 gene. A polymorphism in the ABCC2 gene causes malfunctions in its ability to regulate the efflux of different organic anions, such as bilirubin, from hepatocytes to the canaliculi. Multidrug resistance protein 2 (MRP2) encoded by the ABCC2 gene is one of the main regulators of the export of bilirubin to respective sites. ABCC2 gene mutations have widely drawn attention in the pathology of DJS in various populations. Patients and MethodsThe ABCC2 gene was subjected to the National Center for Biotechnology Information (NCBI) database in 2020, and non-synonymous single-nucleotide polymorphisms (nsSNPs) and variants in untranslated regions were studied using different computational servers. SIFT, Protein variation effect analyzer, and PolyPhen-2 were used to retrieve the damaging Single-nucleotide polymorphisms (SNPs); PhD-SNP, SNPs&GO, and Protein Analysis Through Evolutionary Relationships were used to predict the association of nsSNPs with DJS; Mutation3D illustrated the location of variants in the protein; SNAP2, MutPred2, ELASPIC, and HOPE were used to predict the structural and functional effects of these mutations on MRP2; and I-mutant 3.0 and MuPro were used to determine the effects of polymorphism on the function of MRP2. ResultsIn this study, 18,947 SNPs were screened from the NCBI database, followed by a series of refinement of variants using online available servers. We concluded that 41 ABCC2 gene variants are vital etiological candidates for DJS in humans. These 41 variants had highly damaging effects on the MRP2 protein, which may lead to deficient transportation capacity, thereby affecting the efflux of bilirubin across the canalicular membrane. ConclusionIn silico tools are an alternative approach for predicting the target SNPs. Hence, previously unreported variants can be considered strong etiological candidates for diseases related to MRP2.

Miniature Inverted-Repeat Transposable Elements (MITEs) in the Two Lepidopteran Genomes of Helicoverpa armigera and Helicoverpa zea.

Simple SummaryMiniature inverted-repeat transposable elements (MITEs) are non-autonomous transposable elements that play important roles in genome organization and evolution. Helicoverpa armigera and Helicoverpa zea shows a high number of reported cases of insecticide resistance worldwide, having evolved resistance against pyrethroids, organophosphates, carbamates, organochlorines, and recently to macrocyclic lactone spinosad and several Bacillus thuringiensis toxins. In the present study, we conducted a genome screening of MITEs in the H. armigera and H. zea genomes using bioinformatics approaches, and the results revealed a total of 3570 and 7405 MITE sequences in the H. armigera and H. zea genomes, respectively. Among these MITEs, we highlighted eleven MITE insertions in the H. armigera defensome genes and only one MITE insertion in those of H. zea.Miniature inverted-repeat transposable elements MITEs are ubiquitous, non-autonomous class II transposable elements. The moths, Helicoverpa armigera and Helicoverpa zea, are recognized as the two most serious pest species within the genus. Moreover, these pests have the ability to develop insecticide resistance. In the present study, we conducted a genome-wide analysis of MITEs present in H. armigera and H. zea genomes using the bioinformatics tool, MITE tracker. Overall, 3570 and 7405 MITE sequences were identified in H. armigera and H. zea genomes, respectively. Comparative analysis of identified MITE sequences in the two genomes led to the identification of 18 families, comprising 140 MITE members in H. armigera and 161 MITE members in H. zea. Based on target site duplication (TSD) sequences, the identified families were classified into three superfamilies (PIF/harbinger, Tc1/mariner and CACTA). Copy numbers varied from 6 to 469 for each MITE family. Finally, the analysis of MITE insertion sites in defensome genes showed intronic insertions of 11 MITEs in the cytochrome P450, ATP-binding cassette transporter (ABC) and esterase genes in H. armigera whereas for H. zea, only one MITE was retrieved in the ABC-C2 gene. These insertions could thus be involved in the insecticide resistance observed in these pests.

Map-based cloning and functional analysis revealed ABCC2 is responsible for Cry1Ac toxin resistance in Bombyx mori.

Bt toxins are parasporal crystals produced by Bacillus thuringiensis (Bt).They have specific killing activity against various insects and have been widely used to control agricultural pests. However, their widespread use has developed the resistance of many target insects. To maintain the sustainable use of Bt products, the resistance mechanism of insects to Bt toxins must be fully clarified. In this study, Bt-resistant and Bt-susceptible silkworm strains were used to construct genetic populations, and the genetic pattern of silkworm resistance to Cry1Ac toxin was determined. Sequence-tagged sitemolecular marker technology was used to finely map the resistance gene and to draw a molecular genetic linkage map, and the two closest markers were T1590 and T1581, indicating the resistance gene located in the 155 kb genetic region. After analyzing the sequence of the predicted gene in the genetic region, an ATP binding cassette transporter (ABCC2) was identified as the candidate gene. Molecular modeling and protein-protein docking result showed that a tyrosine insertion in the mutant ABCC2 might be responsible for the interaction between Cry1Ac and ABCC2. Moreover, CRISPR/Cas9-mediated genome editing technology was used to knockout ABCC2 gene. The homozygous mutant ABCC2 silkworm was resistant to Cry1Ac toxin, which indicated ABCC2 is the key gene that controls silkworm resistance to Cry1Ac toxin. The results have laid the foundation for elucidating the molecular resistance mechanism of silkworms to Cry1Ac toxin and could provide a theoretical basis for the biological control of lepidopteran pests.

Association Study of SLCO1B3 and ABCC3 Genetic Variants in Gallstone Disease.

There is growing evidence that gallstone formation may be genetically determined. Recent studies have shown that polymorphism of genes encoding proteins involved in bile acid transport may be associated with the risk of gallstone disease. The aim of this study was to investigate the association between SLCO1B3 (rs4149117:G>T, rs7311358:A>G) and ABCC3 (rs4793665:T>C, rs11568591:G>A) genetic variants and susceptibility to cholesterol gallstone disease, as well as gallstone composition. The study included 317 patients suffering from cholelithiasis who underwent cholecystostomy and 249 controls with no evidence of stones, confirmed by ultrasound examination. There were no statistically significant differences in the distribution of studied gene polymorphisms between patients with gallstone disease and healthy controls. No significant associations were observed between studied genotypes and the content of analyzed gallstone components: total cholesterol, bilirubin, CaCO3, nor the total bile acids. There was also no association between bile acid content in gallstones and the polymorphisms studied. The results of this study suggest that polymorphisms of SLCO1B3 and ABCC3 genes are not a valuable marker of gallstone disease susceptibility and do not influence gallstone composition.

Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up.

Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the relation between highly-evidenced genetic polymorphisms located in relevant pharmacogenes and the risk of suffering premature death and other comorbidities such as cancer, diabetes mellitus, arterial hypertension, graft rejection, infections and nephrotoxicities in a cohort of 87 patients (8 were excluded due to early loss of follow-up) transplanted at Hospital La Fe in Valencia (Spain) during a 12-year follow-up. Employing a logistic regression model with false discovery rate penalization and Kaplan–Meier analyses, we observed significant association between survival rates and metabolizer genes. In this sense, our results show an association between MTHFR gene variants in donor rs1801133 (HR: 7.90; p-value: 0.032) and recipient rs1801131 (HR: 7.34; p-value: 0.036) and the group of patients who died during the follow-up period, supporting the interest of confirming these results with larger patient cohorts. In addition, donor polymorphisms in UGT1A9 metabolizer gene rs6714486 (OR: 0.13; p-value: 0.032) were associated with a lower risk of suffering from de novo cancer. Genetic variants in CYP2B6 metabolizer gene rs2279343 demonstrated an association with a risk of infection. Other variants in different locations of SLCO1A2, ABCC2 and ABCB1 transporter genes were associated with a lower risk of suffering from type 2 diabetes mellitus, chronic and acute nephrotoxicities and arterial hypertension. Results suggest that pharmacogenetics-derived information may be an important support for personalized drug prescription, clinical follow-up and the evolution of liver-transplanted patients.

Association between single nucleotide genetic polymorphisms in ABC transporter genes with drug-resistant epilepsy in the Spanish population

Almost a third of all patients with epilepsy (30%) fail to respond to pharmacological treatment. The presence of single nucleotide polymorphisms (SNPs) in the individual may influence the variability of the response to drug treatment. The transporter hypothesis posits that the presence of SNPs in the genes encoding ABC proteins would affect the bioavailability of antiseizure drugs at the epileptogenic focus, giving rise to refractoriness. The aim of the present study was to evaluate the association of 13 polymorphisms in the ABCB1, ABCC2, ABCC5 and ABCG2 genes with drug-resistant epilepsy (DRE) in a Spanish population. A case-control study was conducted involving 327 patients with epilepsy: 227 resistant to drug therapy and 100 in whom their medication enabled them to control their symptoms, according to International League Against Epilepsy criteria. In the peripheral blood leukocyte DNA that was extracted, polymorphisms in the ABC transporter genes were studied. The iPlex® Gold and Mass ARRAY technology platform was used. The allele and genotypic frequencies of the case and control groups, p-value, odds ratio and 95% confidence intervals were compared. The allele and genotypic frequency of the present study was similar to that reported in population-based databases. For the SNPs studied, no significant differences (p > 0.05) were found in any of the inheritance models analysed. Our results suggest that there is no association between the polymorphisms analysed in the ABC genes and DRE in the Spanish population. Nevertheless, further studies will confirm or refute these results.

Risk Factors of Renal Tubular Dysfunction in Thai People Living with HIV Receiving Tenofovir Disoproxil Fumarate.

Tenofovir disoproxil fumarate (TDF) associates with renal tubular dysfunction (RTD) in some people living with HIV (PLWH). We studied clinical and genetic factors associated with RTD in Thai PLWH receiving TDF. RTD was diagnosed in 13 of 65 (20%) patients. The median (interquartile range) age and CD4 cell counts were 43.8 (40.4-50.9) years and 554 (437-716) cells/mm3, respectively. The median duration of TDF use was 46.9 (31.5-54.1) months. Univariate logistic regression demonstrated body mass index (BMI), concomitant use of protease inhibitor (PI), hyperlipidemia, and homozygous C/C SNP rs1059751 of ABCC4 gene as predisposing factors of RTD. In multivariate model, concomitant use of PI [adjusted odds ratio (aOR) 11.39; 95% confidence interval (CI), 1.59- 81.56; P = 0.015], hyperlipidemia (aOR 8.59; 95% CI, 1.46-50.40; P = 0.017), and BMI (aOR 0.76; 95% CI, 0.59-0.98; P = 0.037) remained associated with RTD in patients receiving TDF. PLWH receiving TDF with the presence of these factors should be closely monitored for RTD.

Clinicopathological and Prognostic Significance of ABCC3 in Human Glioma.

Glioma is the most common malignant primary brain tumor with an inferior survival period and unsatisfactory prognoses. Identification of novel biomarkers is important for the improvements of clinical outcomes of glioma patients. In recent years, more and more biomarkers were identified in many types of tumors. However, the sensitive markers for diagnoses and prognoses of patients with glioma remained unknown. In the present research, our team intended to explore the expression and clinical significance of ABCC3 in glioma patients. Sequential data filtration (survival analyses, independent prognosis analyses, ROC curve analyses, and clinical association analyses) was completed, which gave rise to the determination of the relationship between glioma and the ABCC3 gene. Clinical assays on the foundation of CGGA and TCGA datasets unveiled that ABCC3 expression was distinctly upregulated in glioma and predicted a shorter overall survival. In the multivariable Cox analysis, our team discovered that the expression of ABCC3 was an independent prognosis marker for both 5-year OS (HR = 1.118, 95% CI: 1.052–1.188; P < 0.001). Moreover, our team also studied the association between ABCC3 expression and clinical features of glioma patients, finding that differential expression of ABCC3 was remarkably related to age, 1p19q codeletion, PRS type, chemo status, grade, IDH mutation state, and histology. Overall, our findings suggested ABCC3 might be a novel prognosis marker in glioma.

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

Bt Cry1Ac resistance in Trichoplusia ni is conferred by multi-gene mutations

The three-domain Cry toxin Cry1Ac from Bacillus thuringiensis （Bt） is an important insecticidal toxin in Bt sprays and has been used in transgenic Bt-crops to confer insect resistance. The cabbage looper, Trichoplusia ni, has developed resistance to Bt sprays in commercial greenhouses, and the resistance to Cry1Ac has been previously identified to be associated with altered expression of the APN1 and APN6 genes and be genetically linked to a locus on chromosome 15. In this study, the Cry1Ac resistance locus in T. ni was further finely mapped, and the specific Cry1Ac resistance-conferring mutation in the resistance locus was identified to be a 4 bp frameshift insertion in the ABCC2 gene by whole genome resequencing, midgut transcriptome analysis, candidate gene cDNA sequencing and mutation site genomic DNA sequencing. By CRISPR/Cas9 mutagenesis, a series of ABCC2 and ABCC3 mutant T. ni strains were generated, and the role of ABCC2 in the toxicity of Cry1Ac in T. ni was confirmed. The results from this study also showed that knockout of ABCC2 in T. ni conferred resistance to Cry1Ac at a level lower than that in the greenhouse-derived resistant T. ni strain and that the Cry1Ac resistance-associated alteration of APN1 and APN6 expression was independent of ABCC2 gene mutations, indicating that the altered expression of APN1 and APN6 was controlled by another gene mutation in Cry1Ac resistant T. ni. Furthermore, T. ni larval bioassays showed that the level of Cry1Ac resistance in F1 families from reciprocal crosses of the Cry1Ac resistant strain with an ABCC2 knockout CRISPR strain was significantly higher than that in ABCC2 knockout strain, indicating the presence of additional Cry1Ac resistance-conferring mutation(s) in the Cry1Ac resistant strain. Therefore, the resistance to Cry1Ac in T. ni is conferred by a mutation in ABCC2 and an additional mutation (or mutations) which leads to altered expression of APN1 and APN6. The additional Cry1Ac resistance mutation or mutations remain to be identified.

Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin-Johnson Syndrome in a Large Case Series From the Arabs.

Background: There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe.Objectives: In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS.Methods: We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in ABCC2 gene.Results: Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3–6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5–14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes (p < 0.001). The median urinary coproporphyrin I% was 88% (IQ1–IQ3 = 84.2–92.7%). We identified four homozygous variants in the ABCC2 gene (from 22 unrelated families), one splicing variant (c.3258+1G>A; p.?), and three were missense variants; two of which were novel missense variants [c.1594G>A (p.Glu532Lys) and c.2439G>C (p.Lys813Asn)]. The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families).Conclusions: Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with “founder effects.” Identification of the predominant ABCC2 variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.

Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample

BackgroundResearchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. MethodsWe conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. ResultsThe GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide–significant (p < 5 × 10−8) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10−10), the AKAP6 gene (rs3784187, p = 1.2 × 10−8), and near the MFSD1 gene (rs340315, p = 4.5 × 10−8). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). ConclusionsIn this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.

Melatonin has favorable preventive effects on experimental chronic pancreatitis rat model.

Background/aim Currently, there is not any specific treatment for chronic pancreatitis (CP). It was aimed to investigate the effects of melatonin administration on endoplasmic reticulum (ER) stress, oxidative stress, fibrosis, biochemical and histopathological parameters, and Abcc2,Abcc5, and Abcg2 gene levels in an experimental rat CP model.Materials and methods Forty rats were randomized into five groups: Sham, CP, CP+25 mg/kg melatonin, CP+50 mg/kg melatonin, and CP+placebo. In all rats, except the sham group, a model of chronic pancreatitis was accomplished with intraperitoneal caerulein administration. In treatment groups, melatonin was used as a therapeutic agent. Serum TGF-β, TNF-α, MDA and GPx levels were studied. Pancreatic tissues were evaluated histopathologically. The expression levels of αSma,IR1α,Perk,Abcc2,Abcc5, and Abcg2 genes were measured with the qRT-PCR.Results Biochemical results of the melatonin groups exhibited favorable changes compared to the CP and placebo groups. α Sma,IR1α,Perk expression levels were significantly lower in the melatonin groups. The expression levels of Abcc2, Abcc5, and Abcg2 were significantly higher in the CP group compared to the sham group, and these gene levels were significantly lower in the melatonin groups compared to the CP group (p < 0.01, p < 0.05, p < 0.05, respectively).Conclusion In light of these favorable positive results, melatonin may be a useful preventive agent in the course of CP.