Embelia ribes (False Black Pepper) and Gymnema sylvestre (Sugar Destroyer)
Azamal Husen in Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
G. sylvestre ethanolic extract has potent activity against human skin melanoma and skin papilloma models, but has no toxic effect on normal liver cell lines (Chakraborty et al., 2013). It also has a significant inhibitory effect on breast cancer resistant protein (BCRP). The administration of flavonoids from G. sylvestre effectively suppresses BCRP expression, which improves the activity of BCRP substrates methotrexate, topotecan, epirubicin, and daunorubicin, resulting in increased systemic absorption. Several studies have revealed G. sylvestre hypolipidemic activity. The administration of a G. sylvestre leaf extract to Wister female rats significantly reduced cholesterol, low-density lipoprotein, and triglyceride levels while increasing HDL levels (Singh et al., 2017). G. sylvestre hydroalcoholic leaf extract also significantly lowers LDL. The study was conducted with supplements of a higher level of cholesterol, LDL, triglyceride, and effectively lowering the level of HDL for seven days, after which the mice were treated with G. sylvestre leaf extract, which results in lowering the level of triglycerides, LDL, and cholesterol and also increasing the level of HDL due to the presence of chemical constituents such as saponins, tannins, and flavonoids (Rachh et al., 2010; Dholi and Raparla, 2014). Similar results were reported in several studies with diabetic rats (Bishayee and Chatterjee, 1994; Kumar et al., 2013).
Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery *
Valerio Voliani in Nanomaterials and Neoplasms, 2021
Although drug resistance can indeed be multifactorial, arising from combined mechanisms, such as activation of detoxifying systems and defective apoptotic pathways, classic MDR is effected through the efflux action of ATP-dependent transporters that are members of a superfamily of proteins that possess an ATP-binding cassette (ABC) [78]. MDR in cancer frequently arises from the overexpressed ABC transporter, P-glycoprotein, an efflux pump capable of binding several distinct hydrophobic chemotherapeutics [79]. Although it is found overexpressed in cancer and arises from cellular adaptations to stress, such as hypoxia, P-glycoprotein is normally found in organs, such as the brain, testis, placenta, liver, gastrointestinal tract and kidneys, tasked with protecting these organs from toxins [80]. Further insights into MDR in cells not expressing P-glycoprotein led to the discovery of MDR-associated protein-1 and the breast cancer resistance protein (BCRP) [81]. Consequently, research efforts have been devoted to the investigation of efflux pump inhibitors, with verapamil (Covera) and cyclosporine A emerging as first-generation antagonists [82].
Companion Animals Models of Human Disease
Rebecca A. Krimins in Learning from Disease in Pets, 2020
Canine lymphoma (cL) is a common type of neoplasia in dogs with an estimated incidence rate of 20–100 cases per 100,000 dogs and is in many respects comparable to non-Hodgkin lymphoma in humans(75–77). Although the exact cause is unknown, environmental factors and genetic susceptibility are thought to play an important role. cL is not a single disease, and a wide variation in clinical presentations and histological subtypes is recognized. Despite this potential variation, most dogs present with generalized lymphadenopathy (multicentric form) and intermediate to high-grade lymphoma, more commonly of B-cell origin. The most common paraneoplastic sign is hypercalcemia that is associated with the T-cell immunophenotype. Chemotherapy is the treatment of choice and a doxorubicin-based multidrug protocol is currently the standard of care. A complete remission is obtained for most dogs and lasts for a median period of 7–10 months, resulting in a median survival of 10–14 months. Many prognostic factors have been reported, but stage, immunophenotype, tumor grade, and response to chemotherapy appear of particular importance. Failure to respond to chemotherapy suggests drug resistance, which can be partly attributed to the expression of drug transporters of the ABC-transporter superfamily, including P-gp and BCRP. Ultimately, most lymphomas will become drug resistant and the development of treatments aimed at reversing drug resistance or alternative treatment modalities (e.g. immunotherapy and targeted therapy) are of major importance.
Regulation of BCRP expression and sulfasalazine pharmacokinetics by the nuclear receptor REV-ERBα
Published in Xenobiotica, 2023
Chunhong Wu, Yifei Xiao, Caimei Wu, Dihao Xie, Meixue Luo, Dingyi Yao, Min Chen, Danyi Lu
Breast cancer resistance protein (BCRP, also known as ABCG2) belongs to membrane efflux transporters of the ATP-binding cassette (ABC) superfamily. It is highly expressed in barrier tissues such as the liver, small intestine, kidney, and brain, and plays an important role in the transport of a wide range of endogenous and exogenous substances including drugs (e.g. sulfasalazine, topotecan, and methotrexate) (Meyer zu Schwabedissen and Kroemer 2011; Jani et al. 2014; Mao and Unadkat 2015). Since BCRP is localised on the luminal membrane of enterocytes and on the canalicular membrane of hepatocytes, it restricts intestinal absorption and facilitates the hepatobiliary excretion of substrate drugs (Maliepaard et al. 2001). Due to the critical roles of BCRP in drug pharmacokinetics and pharmacodynamics, identification of a new regulator of BCRP expression and understanding the regulatory mechanism thereof may have potential significance for precise drug therapy. To date, several transcription factors (e.g. HIF1, NRF2, and PPARγ) have been reported to regulate BCRP transcription and expression by interacting with specific cis-acting elements located in the proximal promoter region of the BCRP gene (Nakanishi and Ross 2012; Zattoni et al. 2022). In addition, the expression of BCRP is controlled at epigenetic and posttranslational levels (Chen et al. 2019). However, it is still unknown whether and how REV-ERBα regulates BCRP expression and activity.
Basic physiology of the blood-brain barrier in health and disease: a brief overview
Published in Tissue Barriers, 2021
The barrier type endothelial cells of the brain capillaries express certain efflux transporters, designated as multidrug-resistance transporters localized predominantly on the luminal plasma membrane.46,47 These transporters include P-gp, also called mdr-1, and breast cancer resistance protein which extrude the administered xenobiotics, compounds that include lipophilic and cationic drugs, from the brain capillary endothelial cells back to the circulation and hence reduce the delivery of drugs into the brain parenchyma at effective doses thereby posing an obstacle to the treatment of neurodegenerative disorders/diseases. A number of chemical compounds and chemotherapeutic agents used in daily clinical practice have been described as the substrates of these transporters.48,49 Successful management of tumors and refractory epilepsy is reported to be overwhelmed by the activity of P-gp.50,51 Although inhibitors of P-gp and breast cancer resistance protein have been used effectively to overcome the drug resistance in experimental animals, human data are still lacking.52–54
Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity
Published in Drug Metabolism Reviews, 2021
UPA binds extensively (>98%) to serum proteins, specially to albumin, α1-acid glycoprotein, globulins, and cholesterol binding proteins such as very low density, low density, and high-density lipoproteins (Blithe et al. 2003). On the other hand, UPA does not bind to the sex hormone or corticosteroid-binding globulin (Larner et al. 2000). As observed during the drug development, UPA is not a substrate of transporters such as the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and -B3), bile salt export pump, organic anion transporter 1 and 3 (OAT1 and -3) and the P-glycoprotein (P-gp) (Pohl et al. 2015). Nevertheless, inhibition of the breast cancer resistance protein (BCRP) in hepatic cells was reported (Pohl et al. 2015). Following intravenous and oral administration of 14C-UPA to monkeys, radioactivity was widely distributed and even 14 days radioactivity was measurable, the liver exhibiting the highest accumulation.
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