Valproic Acid-Induced Upregulation of Multidrug Efflux Transporter ABCG2/BCRP via PPARα-Dependent Mechanism in Human Brain Endothelial Cells.

Despite the progress made in the development of new antiepileptic drugs (AEDs), poor response to them is a rising concern in epilepsy treatment. Of several hypotheses explaining AED treatment failure, the most promising theory is the overexpression of multidrug transporters belonging to ATP-binding cassette (ABC) transporter family at blood-brain barrier. Previous data show that AEDs themselves can induce these transporters, in turn affecting their own brain bioavailability. Presently, this induction and the underlying regulatory mechanism involved at human blood-brain barrier is not well elucidated. Herein, we sought to explore the effect of most prescribed first- and second-line AEDs on multidrug transporters in human cerebral microvascular endothelial cells, hCMEC/D3. Our work demonstrated that exposure of these cells to valproic acid (VPA) induced mRNA, protein, and functional activity of breast cancer resistance protein (BCRP/ABCG2). On examining the substrate interaction status of AEDs with BCRP, VPA, phenytoin, and lamotrigine were found to be potential BCRP substrates. Furthermore, we observed that siRNA-mediated knockdown of peroxisome proliferator-activated receptor alpha (PPARα) or use of PPARα antagonist, resulted in attenuation of VPA-induced BCRP expression and transporter activity. VPA was found to increase PPARα expression and trigger its translocation from cytoplasm to nucleus. Findings from chromatin immunoprecipitation and luciferase assays showed that VPA enhances the binding of PPARα to its response element in the ABCG2 promoter, resulting in elevated ABCG2 transcriptional activity. Taken together, these in vitro findings highlight PPARα as the potential molecular target to prevent VPA-mediated BCRP induction, which may have important implications in VPA pharmacoresistance. SIGNIFICANCE STATEMENT: Induction of multidrug transporters at blood-brain barrier can largely affect the bioavailability of the substrate antiepileptic drugs in the brains of patients with epilepsy, thus affecting their therapeutic efficacy. The present study reports a mechanistic pathway of breast cancer resistance protein (BCRP/ABCG2) upregulation by valproic acid in human brain endothelial cells via peroxisome proliferator-activated receptor alpha involvement, thereby providing a potential strategy to prevent valproic acid pharmacoresistance in epilepsy.

Correlates of depression, anxiety, self-esteem, and suicidal ideas in COVID-associated mucormycosis patients and the effects of treatment.

AIM: The aim was to study the correlates of depression, anxiety, self-esteem, and suicidal ideas in patients of COVID-associated mucormycosis (CAM) and effects of treatment. MATERIALS AND METHODS: A cross-sectional, analytical study was performed in a tertiary care center in Western Maharashtra. By purposive sampling, 34 patients of CAM were included in the study with their informed consent and after obtaining ethical clearance. A self-made questionnaire to include demographic and clinical details was filled. Hospital Anxiety and Depression Scale (HADS), Rosenberg Self-Esteem Scale (RSES), and Suicidal Ideation Attributes Scale (SIDAS) were applied after initial diagnosis. The HADS, RSES, and SIDAS were reapplied after their operative treatment. RESULTS: A significant reduction in anxiety and depression scores postoperatively was seen. No significant difference was found in self-esteem or suicidal ideas postoperatively in the study population. However, patients who underwent orbital exenteration showed a significant reduction in level of self-esteem with anxiety and depression postoperatively. No specific correlation was found between the computed tomography score, family history, intensive care unit admission, or orbital exenteration with anxiety, depression, self-esteem, and suicidal ideas. CONCLUSION: Levels of anxiety and depression in patients of CAM reduced significantly after treatment, but self-esteem worsened in males more than females owing to disfigurement. There is a need of psychological counseling in patients of mucormycosis undergoing a debilitating surgery both pre- and postoperatively for a better outcome and recovery.

Multidrug efflux transporter ABCG2: expression and regulation.

The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/ß-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.

Clinical profile, treatment and outcome of Kawasaki disease: A single-center experience from a tertiary care referral center of Assam, north-east India.

AIM: This is a retrospective study to report our experience with a cohort of 73 patients with Kawasaki disease (KD) over 2.5 years. METHOD: The study was conducted in the Department of Pediatrics. Data were retrieved from medical records of Pediatric Rheumatology and Immunodeficiency Clinic collected from April 2017 to October 2019 and analyzed. RESULTS: Male-to-female ratio in our cohort was 2:1. The median age at diagnosis of KD was 3 years (IQR, 4.25). Fever was present in all patients. Oral mucosal changes are the second most common symptom (N = 64, 87%) followed by extremity changes (N = 58, 79%), and rash (N = 56, 76%). Nineteen (26%) children had cardiovascular complications like coronary artery abnormalities (N = 15, 20%), cardiac tamponade (N = 2, 2%), and shock (N = 1, 1%). The effusion in the patients with cardiac tamponade contained inflammatory cells and plenty of red blood cells. Sixty-eight (93%) patients with KD had received treatment with IVIg. Patients in our cohort had completed a mean follow-up of 13.6 ± 9.4 months. No fatality or any long term adverse effects were observed on follow-up. CONCLUSION: Kawasaki disease is a common rheumatological disorder in children at our center with diverse clinical presentations. The disease needs to be considered as a differential diagnosis in an acute febrile illness in children persisting up to 5 days.

Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Corrigendum: Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

[This corrects the article DOI: 10.3389/fphar.2019.00839.].

Global Text Mining and Development of Pharmacogenomic Knowledge Resource for Precision Medicine.

Understanding patients' genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype-phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease-drug-gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility.