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Background: Diabetic gastrointestinal dysfunction (DGD) is a common complication in diabetic patients, and enteric glial cells (EGCs) found in the gastrointestinal tract have been shown to play an essential role in gastrointestinal dysfunction. Thus, targeting EGCs may be helpful for the control of DGD. This study aimed to evaluate the protective effect of Ginkgo biloba extract (GBE) from G. biloba dropping pills against hyperglycaemic stress-induced EGCs injury and its underlying mechanism. Methods: In vitro, the protective effect of GBE on CRL-2690 cells was evaluated by MTT assay and TUNEL assay. The expression of related markers was evaluated by RNA sequencing and validated by using western blotting. In vivo, STZ-induced C57BL/6J WT mice were used as models to evaluate the effects of GBE on blood glucose, body weight, and EGCs' activity and relevant signalling pathways were validated by immunofluorescence. Results: The results showed that GBE (25 μg/ml) treatment significantly attenuated hyperglycaemic stress-induced cytotoxicity and cell apoptosis in CRL-2690 cells, which was verified in an STZ-induced (100 mg/kg, 3 days) diabetic mouse model with continuous GBE administration (25/100 mg/kg/day, 6/12 weeks). Further mechanistic study based on transcriptomic data revealed that GBE exerted its beneficial effect by regulating immune-related pathways, and TLR2/BTK/NF-κB/IL-1α/IL-10 comprised the main targets of this drug. Conclusions: This study demonstrates the protective effect of GBE against hyperglycaemic stress-induced EGCs injury using both in vitro and in vivo models and further reveals that the effect was achieved by targeting TLR2 and its downstream molecules BTK/NF-κB/IL-1α/IL-10. This study may be helpful for expanding the clinical application of GBE in treating DGD. [ABSTRACT FROM AUTHOR]

Objectives: Retinal Müller glial cell loss is almost involved in all retinal diseases, especially diabetic retinopathy (DR). Oxidative stress significantly contributes to the development of Müller glial cell loss. Ginkgo biloba extracts (GBE) have been reported to possess antioxidant property, beneficial in treating human retinal diseases. However, little is known about its role in Müller glial cells. This study investigated the protective effect of GBE (prepared from ginkgo biloba dropping pills) in human Müller glial cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative stress and its underlying molecular mechanism. Methods: MIO-M1 cells were pretreated with or without GBE prior to the exposure to t-BHP-induced oxidative stress. Cell viability, cell death profile and lipid peroxidation were subsequently assessed. Protein expression of the key anti-oxidative signalling factors were investigated. Key findings: We showed that GBE can effectively protect human MIO-M1 cells from t-BHP-induced oxidative injury by improving cell viability, reducing intracellular ROS accumulation and suppressing lipid peroxidation, which effect is likely mediated through activating AMPK-Nrf2-NQO-1 antioxidant respondent axis. Conclusions: Our study is the first to reveal the great potentials of GBE in protecting human retinal Müller glial cell loss against oxidative stress. GBE might be used to prevent human retinal diseases particularly DR. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objectives: Age-related macular degeneration (AMD) is a prevalent ocular disease. Dry AMD accounts for most cases of blindness associated with AMD but there are no treatments. Oxidative stress-induced damage to retinal pigment epithelial (RPE) cells is a major contributor to the pathogenesis of dry AMD. This study investigated the protective actions of Ginkgo biloba extracts (GBE) in human RPE cells subjected to tert-butyl hydroperoxide (t-BHP)-mediated oxidative stress. Methods: The human ARPE-19 cells were pre-treated with or without GBE before the exposure to t-BHP. Cell viability, cell death profile and lipid peroxidation were assessed. The findings were verified using human primary RPE cultures. Key findings: GBE pre-treatment prevented the increase in lipid peroxidation and necrosis/ferroptosis, and the concurrent viability decrease in RPE cells exposed to t-BHP. It enabled the pronounced activation of Nrf2 and its downstream genes. We found that ERK1/2 phosphorylation was increased to a similar extent by t-BHP and GBE. Conclusion: This study revealed that GBE pre-treatment attenuates pro-oxidant stress and protects human RPE cells from oxidative injury by modulating ERK1/2-Nrf2 axis. These findings suggest that GBE has the potential to be developed as a agent that may be valuable in decreasing AMD progression. [ABSTRACT FROM AUTHOR]

Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories, hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17[beta]-estradiol ([E.sub.2]) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time- and concentration-dependent down-regulation of hOAT4 transport activity, whereas [E.sub.2] had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased [V.sub.max] without significant change in Kin. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, [P.sub.4] regulates hOAT4 activity by mechanisms independent of PKC pathway. acute regulation doi:10.1152/ajpendo.00696.2006

Zhou, Fanfan, Kunihiko Tanaka, Michael J. Soares, and Guofeng You. Characterization of an organic anion transport system in a placental cell line. Am J Physiol Endocrinol Metab 285: E1103-E1109, 2003. First published August 5, 2003; 10.1152/ajpendo.00182.2003.--Transporters within the placenta play a crucial role in the distribution of nutrients and xenobiotics across the maternal-fetal interface. An organic anion transport system was identified on the apical membrane of the rat placenta cell line HRP-1, a model for the placenta barrier. The apical uptake of [sup.3.H]-labeled organic anion estrone sulfate in HRP-1 cells was saturable ([K.sub.m] = 4.67 [micro]M), temperature and [Na.sup.+] dependent, [Li.sup.+] tolerant, and pH sensitive. The substrate specificity of the transport system includes various steroid sulfates, such as [beta]-estradiol 3,17-disulfate, 17[beta]-estradiol 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEAS) but does not include taurocholate, p-aminohippuric acid (PAH), and tetraethyl-ammonium. Preincubation of HRP-1 cells with 8-bromo-cAMP (a cAMP analog) and forskolin (an adenylyl cyclase activator) acutely stimulated the apical transport activity. This stimulation was further enhanced in the presence of IBMX (a phosphodiesterase inhibitor). Together these data show that the apical membrane of HRP-1 cells expresses an organic anion transport system that is regulated by cellular cAMP levels. This transport system appears to be different from the known taurocholate-transporting organic anion-transporting polypeptides and PAH-transporting organic anion transporters, both of which also mediate the transport of estrone sulfate and DHEAS. placenta; organic anion; transporters

Objectives Uveal melanoma (UM) is the most common primary intraocular tumour in adults. UM has a poor overall prognosis and ~50% of patients progress to metastatic disease that has a median survival of 5.2 months. There are currently no proven pharmacological treatments for primary or metastatic UM. Research efforts continue to seek new agents. Many natural compounds have shown promising anti-UM activity in in-vitro and/or in-vivo studies. This review summarises the current findings for natural compounds that may be potentially useful in treating UM. Key findings Literature suggests that natural compounds, such as pristimerin, picropodophyllin, oridonin, zeaxanthin, withaferin and FR-900359, may be promising candidate compounds to treat UM. Most of these compounds have demonstrated satisfactory efficacy in inhibiting in-vitro UM cell growth. Summary The evidence regarding the anti-UM effects of natural compounds is mainly limited to in-vitro studies; to date, only a small number of these agents have been evaluated in vivo. The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM. [ABSTRACT FROM AUTHOR]