ABCG2 Research Articles

Rhabdomyolysis induced by darolutamide and rosuvastatin.

Introduction: Darolutamide is a second-generation nonsteroidal androgen receptor antagonist approved for treatment of castrate-resistant, nonmetastatic prostate cancer and metastatic hormone-sensitive prostate cancer. Case report: A mid-70s man with castration-resistant prostate cancer was initiated on darolutamide. Due to impaired renal function and a history of poor tolerance to previous chemotherapy, the patient was started at 300 mg per day with a plan to titrate to the recommended renal-adjusted dose. He was admitted to the hospital for complaints of lower extremity weakness during week 11 of treatment. Physical examination and imaging did not indicate any significant pathology from cancer or other medical conditions causing his symptoms. The pharmacist identified and reported a significant drug interaction between darolutamide and rosuvastatin. Management & Outcome: The suggested change was rosuvastatin discontinuation. Limiting the rosuvastatin dose to 5 mg is recommended during concomitant use with darolutamide. Since the patient had been receiving rosuvastatin 40 mg daily, he was potentially receiving five times the maximum dose. Considering the patient's complaints of myalgia and a marked elevation in creatine phosphokinase, his condition confirmed the diagnosis of rosuvastatin-darolutamide-induced rhabdomyolysis. Clinical symptoms improved and creatinine phosphokinase (CPK) elevation subsided following rosuvastatin cessation. Discussion: Darolutamide inhibition of breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP), and other protein transporters impacts clearance of substrate drugs to varying extents. Clinical relevance of inhibition depends on the extent to which affected proteins and transporters contribute to the clearance of the substrate. Rosuvastatin's significant reliance on BCRP for active efflux leads to an elevated risk of statin-associated muscle symptoms when co-administered with darolutamide.

Causal Role of Phenylalanine and Cholesterol Metabolism in Bladder Cancer Chemoresistance: Insights from Mendelian Randomization and Targeted Molecular Docking.

Causal Role of Phenylalanine and Cholesterol Metabolism in Bladder Cancer Chemoresistance: Insights from Mendelian Randomization and Targeted Molecular Docking.

Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander?

Background: Several recent studies have documented an increased cardiovascular risk in patients with primary hyperparathyroidism (PHPT), thereby stimulating interest in the association with uric acid (UA), a metabolite linked to cardiovascular disease and chronic kidney disease (CKD) progression, whose role in these conditions is still the subject of study. The aim of this review is to summarize the underlying pathophysiological mechanisms of the PHPT-UA relation and discuss their potential clinical implications. Methods: We conducted a comprehensive literature review, with a focus on the physiological and clinical aspects of the relationship between PHPT and UA. Results: The evidence in the literature supports the association between PHPT and elevated UA levels, although the underlying mechanisms still need to be elucidated. Key mechanisms seem to involve tubular and intestinal transporters, particularly the ABCG2 transporter, as well as indirect effects mediated by hypercalcemia and inflammatory processes. Conclusions: The association between PHPT and UA, though recognized for years, highlights the existence of linked pathophysiological mechanisms between mineral and purine metabolism. However, the current knowledge does not clarify whether uric acid plays an active role in the development of complications related to hyperparathyroidism or if it just represents an indirect marker of metabolic dysfunction. In the absence of specific guidelines, measuring UA levels to screen for hyperuricemia, especially in patients with additional risk factors, should be considered to prevent related complications. Future studies could clarify the role of UA in PHPT, improving our understanding of the disease and potentially leading to new therapeutic strategies to prevent cardiovascular, renal and joint manifestations.

Elevated BCRP Transporter and Altered NF-кB Pathway Mediate Zoledronic Acid Resistance in MCF-7 Cells.

Zoledronic acid (ZA), a bisphosphonate derivate, became the standard for preserving bone structure in cancer. Using various intracellular signaling pathways, including NF-κB, ZA inhibits tumor cell proliferation, induces apoptosis, and has additive and synergistic effects with cytotoxic agents. However, it has been observed that resistance has developed against ZA. This study aims to explore the underlying mechanisms of ZA resistance in MCF-7 breast cancer cells by investigating the activity and localization of the human breast cancer resistance protein (BCRP), changes in the NF-κB pathway, and the markers of epithelial-mesenchymal transition (EMT). Previously, MCF-7 cells were stepwise selected in increasing concentrations of ZA and became resistant to 8 µM ZA (MCF-7/Zol). We determined that BCRP levels were elevated with altered intracellular localization in ZA resistant MCF-7 cells, and BCRP pump caused a decrease in the substrate accumulation in the MCF-7/Zol cells whereas no change in intercellular substrate accumulation was observed in parental cells. MCF-7/Zol cells have increased amount of phosphorylated IκB which is associated with increased nuclear translocation of NF-κB. Concordantly, BCRP upregulation may be associated with increased nuclear NF-κB in ZA resistant cells. MCF-7/Zol cells did not harbor EMT markers. Elucidation of molecular mechanisms of resistance developed against chemotherapeutic agents is important to target critical pathways and proteins to eliminate the resistant clones as well as for determining biomarkers for MDR.

Pretreatment of cancer cells with inhibitors of PKCδ, EGFR, and JNK increased intracellular hypericin content and enhanced the effectiveness of photodynamic therapy.

Pretreatment of cancer cells with inhibitors of PKCδ, EGFR, and JNK increased intracellular hypericin content and enhanced the effectiveness of photodynamic therapy.

Phytochemical intervention in BCRP-driven cancer drug resistance: A comprehensive review.

Phytochemical intervention in BCRP-driven cancer drug resistance: A comprehensive review.

Nano-pectic polysaccharide from vinegar-baked Radix Bupleuri enhances methotrexate efficacy against hepatocellular carcinoma via BCRP and MRP2 downregulation.

Nano-pectic polysaccharide from vinegar-baked Radix Bupleuri enhances methotrexate efficacy against hepatocellular carcinoma via BCRP and MRP2 downregulation.

2',6'-dihydroxy-3',4'-dimethoxydihydrochalcone counteracts cancer multidrug resistance by impeding STAT3 activation and ABC transporter-mediated drug efflux.

2',6'-dihydroxy-3',4'-dimethoxydihydrochalcone counteracts cancer multidrug resistance by impeding STAT3 activation and ABC transporter-mediated drug efflux.

A combination of dietary cholesterol and cholic acid induces hepatic expression of proinflammatory genes accompanied by changes in sterol metabolism and redox status.

A combination of dietary cholesterol and cholic acid induces hepatic expression of proinflammatory genes accompanied by changes in sterol metabolism and redox status.

Effect of Hepatic Impairment on the Pharmacokinetics of Baicalin in Rats: Critical Roles of Gut Microbiota and Hepatic Transporters

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic impairment. Methods: Carbon tetrachloride (CCl4)-induced rat models were used to simulate hepatic failure patients to assess the effect of hepatic impairment on the pharmacokinetics and distribution of BG. In vitro metabolism and transporter studies were employed to elucidate the potential mechanisms. Results: After intragastric administration of 10 mg/kg of BG, the peak plasma concentration and exposure (AUC0–t) of BG decreased by 64.6% and 52.6%, respectively, in CCl4-induced rats. After intravenous administration, the AUC0–t decreased by 73.6%, and unlike in the control group, the second absorption peak of BG was not obvious in the concentration–time curve of CCl4-induced rats. The cumulative excretion of BG in the feces increased, but that in the bile decreased. In vivo data indicated that the absorption and enterohepatic circulation of BG were affected. In vitro studies found that the hydrolysis of BG to the aglycone baicalein decreased significantly in the intestinal tissues and contents of the CCl4-induced rats. And BG was identified as a substrate for multiple efflux and uptake transporters, such as breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATP1B1, 1B3, 2B1), and organic anion transporters (OATs). The bile acids accumulated by liver injury inhibited the uptake of BG by OATPs, especially that by OATP2B1. Conclusions: Hepatic impairment reduced BG hydrolysis by intestinal microflora and inhibited its transporter-mediated biliary excretion, which synergistically led to the attenuation of the enterohepatic circulation of BG, which altered its pharmacokinetics.

ABCG2 Transporter: From Structure to Function-Current Insights and Open Questions.

ABCG2 is a crucial ATP-binding cassette (ABC) transporter involved in multidrug resistance and essential physiological and pharmacological processes. In recent years, multiple ABCG2 structures have been resolved using cryo-electron microscopy (cryo-EM), providing significant insights into its conformational states during its transport cycle. However, even more than 25 years after its description, a high-resolution X-ray crystallographic structure is still unavailable, limiting the understanding of its dynamic transitions, as well as leaving aspects of the transport cycle unresolved and open to discussion. Given the complexity of ABCG2, a multidisciplinary approach is essential in order to fully elucidate its mechanism. This review compiles recent advances in ABCG2 structural biology, highlights unresolved controversies, and explores future directions to bridge the gap between structure and function. Moving forward, integrating multiple structural and functional approaches will be key to uncovering the intricate workings of this enigmatic transporter. In particular, detailed structural insights will be crucial to identifying new ABCG2 substrates and designing selective inhibitors, with important implications for therapeutic development.

Contributions of pharmacogenetics to personalized precision therapy of diabetes and hypercholesterolemia.

Personalized medicine allows the selection of the drug and dose based on the patient's genetic information, which is imperative in the treatment of diabetes and hypercholesterolemia, diseases with high prevalence in Mexico. To integrate pharmacogenetic and genomic research on antidiabetic and antihypercholesterolemic drugs in Mexican patients. We integrated our research, relating it with similar research from national and foreign laboratories. For antidiabetic pharmacological treatments, variants in the ABCC8 and KCNJ11 genes were consistently associated with the response to sulfonylureas, while variants in the SLC47A1, SLC28A1 and ABCG2 genes explained up to 55% of the variability in the response to metformin. Regarding hypercholesterolemia, atorvastatin treatment is influenced by variants in the genes MTHFR, DRD3, GSTM3, TNFα MDR1, SLCO1BI, ABCB1, CYP2D6, CYP2B6, NAT2 and COMT. Our findings highlight the need to integrate pharmacogenetics into clinical practice to achieve greater therapeu tic success in diabetes and hypercholesterolemia.

Elacridar Inhibits BCRP Protein Activity in 2D and 3D Cell Culture Models of Ovarian Cancer and Re-Sensitizes Cells to Cytotoxic Drugs

Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. This study investigated the potential of elacridar (GG918), a potent dual P-gp and BCRP inhibitor, to overcome drug resistance in ovarian cancer cell lines. Both TOP-sensitive and TOP-resistant ovarian cancer cells were grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroid models to better mimic the tumor microenvironment. The expression of the ABCG2 gene was quantified via qPCR and BCRP protein levels were assessed by western blotting and immunofluorescence. Drug response was evaluated using MTT viability assays, while BCRP transporter activity was examined using flow cytometry and microscopic assessment of the intracellular retention of BCRP fluorescent substrates (Hoechst 33342 and MIT). In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models.

Abstract P4-03-24: Septin 9 isoform expression and response to taxane treatment in breast cancer patients

Abstract Drugs that disrupt the microtubule cytoskeleton, such as the microtubule stabilizing taxanes, are regularly used in the treatment of breast cancer in both the neoadjuvant and adjuvant setting. However, there are currently no molecular biomarkers that are used to guide which patients will respond to taxane treatment. Septins, a class of small GTPases, interact with both microtubules and actin to functionally link these cytoskeletal components and regulate cell biological processes shown to be critical for the invasion and migration of cancer cells. In particular, septin 9 (SEPT9) directly interacts directly with microtubules through an N-terminal domain on the longest isoform, SEPT9 isoform 1, which is sufficient to promote migration and invasion of breast cancer cells in vitro. Additionally, both SEPT9 isoform 1 and SEPT9 isoform 3 have been shown to play a role in taxane resistance in vitro, but the possible role in clinical taxane resistance had not been studied. We hypothesized that the relative expression of SEPT9 isoforms in breast tumors could play a role in their response to treatment with microtubule-targeted chemotherapy, specifically to taxanes in the neoadjuvant setting. We performed a prospective clinical trial to correlate the expression of SEPT9 isoforms in breast tumors with pathological response to taxanes in the neoadjuvant setting. Pretreatment levels of SEPT9 isoforms, as well as other genes associated with clinically relevant drug resistance mechanisms, including the MDR1, ABCG2, and ABCG11 drug efflux transporters and the βIII-isoform of tubulin, were determined from FFPE biopsy samples using Biomark multiplexed PCR. RNA was isolated from 3 scrolls per patient biopsy sample using the Puregen automated RNA extraction platform. Expression was normalized between patients referencing actin using the ΔCt method and the average expression for each gene was set at 1. Protein levels of total SEPT9 as well as isoforms 1 and 3 were also determined by immunohistochemistry and quantified by calculating the cytoplasm and nucleus H-scores using the Aperio eSlide Manager analysis. Patients were treated in the neoadjuvant setting with either paclitaxel (dose dense or weekly), docetaxel or nab-paclitaxel. The expression of markers was reevaluated in the post-treatment surgical samples of patients who did not have a complete pathological response. We found that the expression of SEPT9 isoforms and drug resistance genes differed amongst the pre-treatment patient samples and are determining the correlation of initial SEPT9 isoform levels with pathological response to taxane treatment as well as whether SEPT9 isoform expression changes after treatment with taxanes. Preliminary results suggest that higher initial SEPT9 isoform 3 levels correspond with better tumor response to taxane treatment compared to those with lower initial SEPT9 isoform 3 levels and that total SEPT9 and SEPT9 isoform 1 levels decrease after taxane treatment while SEPT9 isoform 3 levels increase after taxane treatment. Overall, the data support the hypothesis that the relative expression of SEPT9 isoforms in breast tumors plays a role in their response to treatment with taxanes in the neoadjuvant setting. Citation Format: Jacob Essif, April Risinger, Kate Lathrop, Rebecca Thompson, Virginia Kaklamani, Marcela Mazo, Jessica Jones, Saba Shaikh, Jo Ann Meekins, Kyrsten Kawazoe. Septin 9 isoform expression and response to taxane treatment in breast cancer patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-03-24.

778-P: Pemvidutide, a Balanced GLP-1/Glucagon Dual Receptor Agonist, Enhances Reverse Cholesterol Transport in a Golden Syrian Hamster Model

Introduction and Objective: Pemvidutide is a long-acting, peptide-based GLP-1/glucagon dual receptor agonist that elicits significant reductions in body weight and serum lipids in preclinical and clinical studies. Reverse cholesterol transport (RCT) is an important process for removing excess cholesterol from peripheral tissues. Preclinical studies have suggested that glucagon may enhance the elimination of cholesterol, possibly due to enhanced RCT. Here, we investigated the effects of pemvidutide on RCT via cholesterol excretion in a preclinical model. Methods: Obese male Golden Syrian hamsters were treated daily with pemvidutide or vehicle for 35 days. On Day 35, macrophages labelled with 3H-cholesterol were injected intraperitoneally, and the appearance of the 3H-cholesterol in plasma, liver, and feces was quantitated over 72 hours. In an independent study, changes in the hepatic expression of genes involved in cholesterol transport were measured by reverse transcription-polymerase chain reaction (RT-PCR) following pemvidutide treatment. Results: Pemvidutide treatment significantly reduced total plasma triglycerides, total cholesterol, and LDL-cholesterol as compared to vehicle controls. Specifically, pemvidutide significantly reduced plasma 3H-cholesterol and increased the excretion of 3H-cholesterol and its metabolites in feces over 72 hours. RT-PCR analysis showed significantly increased hepatic gene expression of the cholesterol transporters ABCG5 and ABCG8 in the pemvidutide treated group compared to vehicle. Conclusion: Pemvidutide treatment increased excretion of cholesterol into feces and upregulated transporters of cellular cholesterol in the liver, consistent with increased RCT. These findings suggest that in addition to other mechanisms, pemvidutide improves serum cholesterol through enhanced cholesterol excretion. Disclosure M. Lucca Andrade: Employee; Altimmune Inc. J.J. Suschak: Employee; Altimmune Inc. B. Georges: Employee; Altimmune Inc. F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. M.S. Roberts: Employee; Altimmune Inc.

Abstract P3-01-25: Molecular and immunological characterization of HER2-low, HER2 ultra-low, and HER2-null male breast cancer

Abstract Background: Human epidermal growth factor receptor 2 (HER2) gene expression is an important predictive and prognostic biomarker in breast cancer (BC), which also guides treatment recommendations. The expression of HER2 is a continuum from null to positive and includes HER2-low and ultra-low as targets for anti-HER2 antibody–drug conjugates (ADC). However, HER2-low and ultra-low have not been studied in male BC. Here, we analyze whether there are any differences in molecular and immunological features between HER2-low, ultra-low and HER2-null/negative expression in males with BC. Methods: 199 male breast tumor samples were included in this study. HER2-null expression was defined as infiltrating cancer cells completely free of HER2 immunohistochemistry (IHC) staining. HER2 ultra-low expression was defined as ≤10% cancer cell showing incomplete and faint/weak membrane staining. HER2-low expression was defined as HER2 (IHC) 1+ or 2+ with negative chromogenic in situ hybridization (CISH) assay. HER2-positive expression was defined as HER2 IHC 3+ staining or 2+ with positive CISH assay. Mutations and gene expression were detected by next-generation sequencing (NextSeq; WES, NovaSeq) and Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ), respectively; tumor mutational burden (TMB) totaled somatic mutations per tumor (high>10 mt/MB). Immune cell fractions were calculated by deconvolution of WTS:Quantiseq. Statistical significance was determined using chi-square and Mann-Whitney U test and p-value <0.05 was considered significant. Results: Of 199 samples, there were 70 (35.2%) HER2-null tumors, 49 (24.6%) HER2 ultra-low tumors, 64 (32.2%) HER2-low tumors, and 16 (8.0%) HER2-positive. The proportion of HR+ was 81.4% in HER2-null, 93.8% in HER2 ultra-low, 87.5% in HER2-low and 81.2% in HER2-positive tumors. HER2 ultra-low male BC had higher frequency of PIK3CA (44.19% vs 23.64%) compared to HER2-null and KMT2D (7.5% vs 0%) compared to HER2-low, all p<0.05. HER2-low male BC had numerically lower frequency of TP53 (8.7% vs 16.6%, p=0.2) and ESR1 (1.6% vs 5.4%, p=0.2) compared to HER2-null. No significant differences were noted in TMB-high frequency (7.1% vs 5.0% vs 6.9%) and PD-L1 positivity (22C3) (8.11% vs 9.0% vs 10.6%) between HER2 ultra-low, HER2-low and HER2-null (all p=1.0). Analysis of inferred immune cells revealed that HER2 ultra-low and HER2-low male BC had higher infiltration of B cells (6.6% vs 5.8% vs 4.9%) but lower infiltration of neutrophil (2.4% vs 2.0% vs 3.8%) (all p<0.05). HER2-low had lower expression of immune checkpoint gene LAG3 (fold change (FC): 1.6), stem cell-related genes (KLF4, POU5F1; FC: 1.3-1.7) and drug-efflux gene ABCB5 (FC: 2.2) compared to HER2-null tumors (all p<0.05). HER2 ultra-low had lower expression of drug-efflux gene ABCG2 (FC: 1.5) compared to HER2-null tumors (p<0.05). Data adjusted for HR-subtype will be presented at the meeting. Conclusions: Our findings add valuable information to the current understanding of the HER2 spectrum in the male breast cancer, including frequency distribution and molecular characterization. With some exceptions, HER2-low, ultra-low and null breast cancer in men shared genomic features, suggesting that the disease biology may not be different across the spectrum of what historically has been considered HER2-negative disease. Interestingly, HER2 ultra-low, HER2-low and HER2-null had differential tumor immune microenvironment that warrant further exploration. Citation Format: Dario Trapani, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Priya Jayachandran, Nancy U. Lin, Giuseppe Curigliano, Milan Radovich, Maryam Lustberg, Stephanie L. Graff, George W. Sledge Jr, Sara M. Tolaney, Jose P. Leone. Molecular and immunological characterization of HER2-low, HER2 ultra-low, and HER2-null male breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-01-25.

Implementation of an Online Drug–Drug Interaction Screener for the STRIVE Ensitrelvir Trial for COVID-19

BackgroundEnsitrelvir is an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with associated drug–drug interactions (DDIs) through CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporter-3 (OAT-3) inhibition. We present the development and implementation of an online DDI screener to assess interactions during the STRIVE ensitrelvir trial.MethodsThe STRIVE Network is conducting a randomized, double-blind, placebo-controlled trial evaluating ensitrelvir's efficacy and safety in hospitalized adults with coronavirus disease 2019 (COVID-19) and lower respiratory tract involvement. DDI guidance was compiled into a database accessed via a web portal where a multidisciplinary team categorized medications as permitted, prohibited, or conditionally permitted. For prohibited medications, washout periods and start/restart criteria were provided with alternative medication suggestions. Sites could request new medications for addition. After 18 months, a survey was conducted to assess the tool's usefulness.ResultsVersion 1 of the DDI screener launched in December 2022 with 615 medications, expanding to 1182 through 6 updates by version 7. In 11 cases, prohibited medications were revised to conditionally permit enrollment after dosage adjustments (antihypertensives, anti-infectives, and psychiatric medications). Anticoagulants, immunosuppressants, and emergency use medications posed the greatest challenges due to trial blinding. With 334 participants enrolled across 150 sites in 13 countries, 117192 screener searches were completed by May 2024. The most searched medication classes were antihypertensive, antibiotics, corticosteroids, and anticoagulants. Sites found the DDI screener most helpful during screening/enrollment and valued the washout guidance.ConclusionsDDI resources for investigational medications like ensitrelvir, with high DDI potential, are crucial for safe conduct of clinical trials. Effective implementation requires a multidisciplinary, iterative approach that incorporates real-time feedback from trial sites.

Curcumin ameliorates hyperuricemia and gout‐induced damage via modulating the ROS‐dependent NEK7‐NLRP3 inflammasome activation

Abstract Curcumin, a bioactive compound extracted from Curcuma longa. L., demonstrates significant therapeutic potential in inflammatory diseases. This study aims to explore the effects of curcumin on hyperuricemia with acute gout and associated renal dysfunction in a mouse model. The results show that curcumin treatment alleviates ankle joint swelling, reduces inflammatory cytokines IL‐1β and TNF‐α, and lowers serum uric acid concentrations. High‐dose curcumin notably inhibits xanthine oxidase (XOD) activity, a key enzyme in uric acid production, while it enhances the renal expression of the urate transporter ABCG2, thereby promoting uric acid excretion. Furthermore, curcumin effectively mitigates renal injury as evidenced by reduced serum creatinineand blood urea nitrogen levels and suppresses renal inflammation. At the molecular level, curcumin exerts potent antioxidant effects by lowering reactive oxygen species (ROS) levels in both cultured HK‐2 human renal tubular epithelial cells and RAW264.7 mouse macrophages. The curcumin‐mediated effects are associated with the disruption of NEK7‐NLRP3 complex formation, leading to the suppression of the ROS/NEK7‐NLRP3 inflammasome pathway. This, in turn, inhibits pyroptosis and the subsequent release of mature IL‐1β. These findings suggest that curcumin not only reduces uric acid production but also modulates inflammation through ROS‐scavenging properties and its ability to inhibit the NLRP3 inflammasome.

Effect of luteolin on ceftiofur intestinal absorption: the rational use of Caco-2 monolayer cell model and everted gut sac model

Effect of luteolin on ceftiofur intestinal absorption: the rational use of Caco-2 monolayer cell model and everted gut sac model

Folate transfer in placental choriocarcinoma cells treated with valproic acid: Insights gained through comparisons with the amide derivative sec-butylpropylacetamide and its individual stereoisomers.

We have previously shown that valproic acid (VPA) alters the expression of placental carriers of essential nutrients, including folates. Here, we exposed a placental cell line to VPA, its central nervous system-active amide derivative sec-butylpropylacetamide (SPD), and its individual stereoisomers to address the question of whether folate carrier expression can predict the teratogenicity of VPA-related compounds. We additionally conducted a pilot analysis of folate transfer across placental cell monolayers to estimate the translation of altered carrier expression to carrier activity. BeWo cells were incubated for 2 or 5 days with racemic SPD, its stereoisomers (2S,3S)-SPD, (2R,3S)-SPD, and (2R,3R)-SPD (previously found to be teratogenic at high doses in mice; .5 or 1 mmol·L-1), VPA (1 mmol·L-1 = 144 mg/L), or their vehicle. Expression of FOLR1 (folate receptor alpha), SLC19A1 (reduced folate carrier), and ABCG2 (breast cancer resistance protein) was measured by real-time polymerase chain reaction. Folate transfer across monolayers of BeWo b30 cells exposed to .5 mmol·L-1 (2R,3R)-SPD or 1 mmol·L-1 VPA was quantified by liquid chromatography-mass spectrometry analysis. At 1 mmol·L-1, racemic SPD, (2S,3S)-SPD, and (2R,3S)-SPD reduced by twofold SLC19A1 expression, similar to VPA (p < .001). SPD and its enantiomers induced FOLR1 expression by up to twofold (p < .05) or did not significantly affect it, and racemic SPD increased ABCG2 expression (p < .01). After 5 days, VPA, but not (2R,3R)-SPD, enhanced both maternal-to-fetal and fetal-to-maternal folate transfer (p < .01), resulting in a 15% increase in net transfer in the fetal direction. Altered expression of the studied carriers could not explain the folate transfer kinetics across placental cell monolayers. Future studies should assess the effects of VPA and other antiseizure medications on transplacental transfer of essential compounds invivo and the ability to predict it by functional invitro assays.