scholarly journals Organic Anion Transporting Polypeptide 2B1 in Human Fetal Membranes: A Novel Gatekeeper for Drug Transport During Pregnancy?

2021 ◽  
Vol 12 ◽  
Author(s):  
Esha Ganguly ◽  
Ananth Kumar Kammala ◽  
Meagan Benson ◽  
Lauren S. Richardson ◽  
Arum Han ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Delivery ◽  
Pregnancy Complications ◽  
Drug Transport ◽  
Organic Anion ◽  
Fetal Membrane ◽  
Organic Anion Transporting Polypeptide ◽  
Decidual Cells ◽  
Adverse Pregnancy

Current intervention strategies have not been successful in reducing the risks of adverse pregnancy complications nor maternal and fetal morbidities associated with pregnancy complications. Improving pregnancy and neonatal outcomes requires a better understanding of drug transport mechanisms at the feto-maternal interfaces, specifically the placenta and fetal membrane (FM). The role of several solute carrier uptake transporter proteins (TPs), such as the organic anion transporting polypeptide 2B1 (OATP2B1) in transporting drug across the placenta, is well-established. However, the mechanistic role of FMs in this drug transport has not yet been elucidated. We hypothesize that human FMs express OATP2B1 and functions as an alternate gatekeeper for drug transport at the feto-maternal interface. We determined the expression of OATP2B1 in term, not-in-labor, FM tissues and human FM cells [amnion epithelial cell (AEC), chorion trophoblast cell (CTC), and mesenchymal cells] using western blot analyses and their localization using immunohistochemistry. Changes in OATP2B1 expression was determined for up to 48 h after stimulation with cigarette smoke extract (CSE), an inducer of oxidative stress. The functional role of OATP2B1 was determined by flow cytometry using a zombie violet dye substrate assay. After OATP2B1 gene silencing, its functional relevance in drug transport through the feto-maternal interface was tested using a recently developed feto-maternal interface organ-on-a-chip (OOC) system that contained both FM and maternal decidual cells. Propagation of a drug (Rosuvastatin, that can be transported by OATP2B1) within the feto-maternal interface OOC system was determined by mass spectrometry. FMs express OATP2B1 in the CTC and AEC layers. In FM explants, OATP2B1 expression was not impacted by oxidative stress. Uptake of the zombie violet dye within AECs and CTCs showed OATP2B1 is functionally active. Silencing OATP2B1 in CTCs reduced Rosuvastatin propagation from the decidua to the fetal AEC layer within the feto-maternal interface-OOC model. Our data suggest that TPs in FMs may function as a drug transport system at the feto-maternal interface, a function that was previously thought to be performed exclusively by the placenta. This new knowledge will help improve drug delivery testing during pregnancy and contribute to designing drug delivery strategies to treat adverse pregnancy outcomes.

scholarly journals Novel Insights into the Regulatory Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 in Oxidative Stress and Inflammation of Human Fetal Membranes

2020 ◽  
Vol 21 (17) ◽  
pp. 6139 ◽  
Author(s):  
Ramkumar Menon ◽  
Morgan R Peltier
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Water Soluble ◽  
Fetal Membrane ◽  
Fetal Membranes ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Western Blots ◽  
Adverse Pregnancy ◽  
Nrf2 Expression

Fetal membrane dysfunction in response to oxidative stress (OS) is associated with adverse pregnancy outcomes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is one of the regulators of innate OS response. This study evaluated changes in Nrf2 expression and its downstream targets heme oxygenase (HO-1) and peroxisome proliferator-activated receptor gamma (PPARγ) in fetal membranes during OS and infection in vitro. Furthermore, we tested the roles of sulforaphane (SFN; an extract from cruciferous vegetables) and trigonelline (TRN; an aromatic compound in coffee) in regulating Nrf2 and its targets. Fetal membranes (n = 6) collected at term were placed in an organ explant system were treated with water-soluble cigarette smoke extract (CSE), an OS inducer (1:10), and lipopolysaccharide (LPS; 100 ng/mL). Nrf2 expression, expression, its enhancement by sulforaphane (SFN, 10 µM/mL) and down regulation by TRN (10uM/mL) was determined by western blots. Expression of Nrf2 response elements PPARγ (western) heme oxygenase (HO-1), and IL-6 were quantified by ELISA. CSE and LPS treatment of fetal membranes increased nrf2, but reduced HO-1 and PPARγ and increased IL-6. Co-treatment of SFN, but not with TRN, with CSE and LPS increased Nrf2 substantially, as well as increased HO-1 and PPARγ and reduced IL-6 expression. Risk factor-induced Nrf2 increase is insufficient to generate an antioxidant response in fetal membranes. Sulforaphane may enhance innate antioxidant and anti-inflammatory capacity by increasing NRF-2 expression.

scholarly journals Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

2011 ◽  
Vol 25 (1) ◽  
pp. 1-14 ◽  
Author(s):  
W. Edward Visser ◽  
Edith C. H. Friesema ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Psychomotor Retardation ◽  
Cellular Level ◽  
Monocarboxylate Transporter ◽  
Causative Role ◽  
Organic Anion Transporting Polypeptide ◽  
Neurological Abnormalities ◽  
Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

scholarly journals Role of Liposomes Composite as Drug Transport Mechanism

2021 ◽  
pp. 230-243
Keyword(s):  
Drug Delivery ◽  
Lipid Bilayers ◽  
Transport Mechanism ◽  
Drug Transport ◽  
Phospholipid Bilayer ◽  
Drug Transporter ◽  
Delivery Methods ◽  
Second Stage ◽  
Novel Drug

Liposomes are spherical shaped vesicles comprising of at least one phospholipid bilayer that serve as a novel drug delivery framework. They are microscopic structures in which a fluid system is totally encased by a film made out of lipid bilayers. It varies in size, conformation, charge and drug transporter stacked with assortment of particles, for example, small molecules of drug, plasmids, nucleotides or proteins and so on. Ongoing advances in nanotherapeutics have brought about engineered liposomes rising in nanomedicine, giving better restorative control of diseased states. This has made ready for the improvement of second-stage liposomes for increased efficiency and could at last lead to a change in perspective from the regular drug delivery methods.

scholarly journals Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

2019 ◽  
Vol 20 (24) ◽  
pp. 6358 ◽  
Author(s):  
Giuseppina Emanuela Grieco ◽  
Noemi Brusco ◽  
Giada Licata ◽  
Laura Nigi ◽  
Caterina Formichi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Delivery ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Delivery Methods ◽  
Cell Dysfunction ◽  
Single Cell Type ◽  
Chronic Hyperglycaemia ◽  
Target Effects

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases.

scholarly journals The Importance of Antioxidant Micronutrients in Pregnancy

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Hiten D. Mistry ◽  
Paula J. Williams
Keyword(s):  
Oxidative Stress ◽  
Placental Development ◽  
Maternal Circulation ◽  
Copper Zinc ◽  
Adverse Pregnancy ◽  
Intervention Trials ◽  
Peroxidase Enzymes ◽  
Reduced Activity ◽  
In Pregnancy

Pregnancy places increased demands on the mother to provide adequate nutrition to the growing conceptus. A number of micronutrients function as essential cofactors for or themselves acting as antioxidants. Oxidative stress is generated during normal placental development; however, when supply of antioxidant micronutrients is limited, exaggerated oxidative stress within both the placenta and maternal circulation occurs, resulting in adverse pregnancy outcomes. The present paper summarises the current understanding of selected micronutrient antioxidants selenium, copper, zinc, manganese, and vitamins C and E in pregnancy. To summarise antioxidant activity of selenium is via its incorporation into the glutathione peroxidase enzymes, levels of which have been shown to be reduced in miscarriage and preeclampsia. Copper, zinc, and manganese are all essential cofactors for superoxide dismutases, which has reduced activity in pathological pregnancy. Larger intervention trials are required to reinforce or refute a beneficial role of micronutrient supplementation in disorders of pregnancies.

scholarly journals Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

2014 ◽  
Vol 34 (4) ◽  
pp. 699-707 ◽  
Author(s):  
Brandon J Thompson ◽  
Lucy Sanchez-Covarrubias ◽  
Lauren M Slosky ◽  
Yifeng Zhang ◽  
Mei-li Laracuente ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Transforming Growth Factor ◽  
Organic Anion ◽  
Functional Expression ◽  
Brain Barrier ◽  
Parp Cleavage ◽  
Organic Anion Transporting Polypeptide ◽  
Cns Drug Delivery ◽  
Blood Brain

Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood–brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor- β (TGF- β)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF- β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

scholarly journals Role of Vitamin E in Pregnancy

2021 ◽  
Author(s):  
Mohd Aftab Siddiqui ◽  
Usama Ahmad ◽  
Asad Ali ◽  
Farogh Ahsan ◽  
Md. Faheem Haider
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Vitamin E ◽  
Pregnancy Complications ◽  
Blood Cells ◽  
Egg Quality ◽  
Healthy Skin ◽  
In Pregnancy ◽  
Vitamin E Supplementation

Vitamins play important roles in female health. They are essential for many functions, including menstruation and ovulation, oocyte (egg) quality and maturation. Vitamin E was first discovered in 1922 as a substance necessary for reproduction. It has become widely known as a powerful lipid-soluble antioxidant. There are various reports on the benefits of vitamin E on health in general. Vitamin E helps your body create and maintain red blood cells, healthy skin, eyes and strengthens your natural immune system. However, despite it being initially discovered as a vitamin necessary for reproduction, to date studies relating to its effects in this area are lacking. Vitamin E supplementation may help reduce the risk of pregnancy complications involving oxidative stress, such as pre-eclampsia. This chapter is written to provide a review of the known roles of vitamin E in pregnancy.

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