scholarly journals Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance

2021 ◽  
Vol 22 (6) ◽  
pp. 2858
Author(s):  
Faustino Bisaccia ◽  
Prashant Koshal ◽  
Vittorio Abruzzese ◽  
Maria Antonietta Castiglione Morelli ◽  
Angela Ostuni
Keyword(s):  
Cancer Therapy ◽  
Functional Characterization ◽  
Physiological Role ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Functional Studies ◽  
Extracellular Milieu ◽  
Hepatic Cells ◽  
Ectopic Mineralization ◽  
Anti Cancer

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.

Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

2019 ◽  
Vol 24 (5) ◽  
pp. 461-464 ◽  
Author(s):  
Magali Devriese ◽  
Anne Legrand ◽  
Marie-Cécile Courtois ◽  
Xavier Jeunemaitre ◽  
Juliette Albuisson
Keyword(s):  
Vascular Calcification ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Elastic Fibers ◽  
Connective Tissues ◽  
Tibial Arteries ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Next Generation Sequencing Ngs ◽  
Eye Lesions

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by skin, eye, and cardiovascular lesions due to ectopic mineralization and fragmentation of elastic fibers of connective tissues. We present an atypical case of PXE with diffuse vascular calcification and negligible skin and eye lesions. The patient was a 37-year-old man suffering from severe bilateral arterial calcifications in superficial femoral and posterior tibial arteries. Eye fundoscopy and skin examination were first considered normal. This phenotype suggested first the diagnosis of Arterial Calcification due to Deficiency of CD73 (ACDC) characterized by mutations in NT5E gene. However, we found two variants in ABCC6 gene, and no variant in NT5E. Skin reexamination revealed few lateral skin papules confined to the scalp. Phenotypic overlap was described in vascular calcification disorders, between GACI and PXE phenotypes, and we discuss here expansion of this overlap, including ACDC phenotype. Identification of these expanding and overlapping phenotypes was enabled by genetic screening of the corresponding genes, in a systematic approach. We propose to create a calcification next generation sequencing (NGS) panel with NT5E, GGCX, ENPP1, and ABCC6 genes to improve the molecular diagnosis of vascular calcification.

scholarly journals Administration of vitamin K does not counteract the ectopic mineralization of connective tissues inAbcc6-/-mice, a model for pseudoxanthoma elasticum

Cell Cycle ◽  
2011 ◽  
Vol 10 (4) ◽  
pp. 701-707 ◽  
Author(s):  
Qiujie Jiang ◽  
Qiaoli Li ◽  
Alix E. Grand-Pierre ◽  
Leon J. Schurgers ◽  
Jouni Uitto
Keyword(s):  
Vitamin K ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Ectopic Mineralization

scholarly journals Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

2005 ◽  
Vol 25 (18) ◽  
pp. 8299-8310 ◽  
Author(s):  
John F. Klement ◽  
Yasushi Matsuzaki ◽  
Qiu-Jie Jiang ◽  
Joseph Terlizzi ◽  
Hae Young Choi ◽  
...  
Keyword(s):  
Complex Disease ◽  
Soft Tissues ◽  
Subcutaneous Tissue ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Alizarin Red ◽  
Arterial Blood ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Total Body

ABSTRACT Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6 −/− mice but was not observed in Abcc6 +/− or Abcc6 +/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6 −/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease.

Functional Characterization of a Variant Factor XII (F XII Locarno) in a Cross Reacting Material Positive F XII Deficient Plasma

1992 ◽  
Vol 67 (02) ◽  
pp. 219-225 ◽  
Author(s):  
Walter A Wuillemin ◽  
Miha Furlan ◽  
Hans Stricker ◽  
Bernhard Lämmle
Keyword(s):  
Dextran Sulfate ◽  
Functional Characterization ◽  
Healthy Woman ◽  
Chain Molecule ◽  
Plasma Kallikrein ◽  
Factor Xii ◽  
Single Chain ◽  
Sulfate Adsorption ◽  
Prolonged Incubation ◽  
Functional Studies

SummaryThe plasma of a healthy woman was found to contain half normal factor XII (FXII) antigen level (0.46 U/ml) without any FXII clotting activity (<0.01 U/ml). The variant FXII in this plasma, denoted as FXII Locarno, was partially characterized by immunological and functional studies on the proposita’s plasma. FXII Locarno is a single chain molecule with the same size (M r = 80 kDa) as normal FXII. Isoelectric focusing suggested an excess of negative charge in the variant FXII as compared to normal FXII. In contrast to FXII in normal plasma, FXII Locarno was not proteolytically cleaved upon prolonged incubation of proposita’s plasma with dextran sulfate. Adsorption to kaolin was similar for both, abnormal and normal FXII. Incubation of the proposita’s plasma with dextran sulfate and exogenous plasma kallikrein showed normal cleavage of FXII Locarno outside of the tentative disulfide loop Cys340-Cys467, but only partial cleavage within this disulfide loop. Furthermore, plasma kallikrein-cleaved abnormal FXII showed neither amidolytic activity nor proteolytic activity against factor XI and plasma prekallikrein.These results suggest a structural alteration of FXII Locarno, affecting the plasma kallikrein cleavage site Arg353-Val354 and thus formation of activated FXII (a-FXIIa).

Anticancer Properties of Essential Oils: An Overview

2018 ◽  
Vol 18 (10) ◽  
pp. 957-966 ◽  
Author(s):  
Milene Aparecida Andrade ◽  
Mariana Aparecida Braga ◽  
Pedro Henrique Souza Cesar ◽  
Marcus Vinicius Cardoso Trento ◽  
Mariana Araújo Espósito ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Essential Oils ◽  
Public Health Problem ◽  
Mechanisms Of Action ◽  
Low Molecular Weight ◽  
Anticancer Properties ◽  
Anti Cancer ◽  
Different Types ◽  
Antitumor Properties ◽  
Pharmaceutical Properties

Background: Essential oils are complex mixtures of low molecular weight compounds extracted from plants. Their main constituents are terpenes and phenylpropanoids, which are responsible for their biological and pharmaceutical properties, such as insecticidal, parasiticidal, antimicrobial, antioxidant, anti-inflammatory, analgesic, antinociceptive, anticarcinogenic, and antitumor properties. Cancer is a complex genetic disease considered as a serious public health problem worldwide, accounting for more than 8 million deaths annually. Objective: The activities of prevention and treatment of different types of cancer and the medicinal potential of essential oils are addressed in this review. Conclusion: Several studies have demonstrated anti-carcinogenic and antitumor activity for many essential oils obtained from various plant species. They may be used as a substitution to or in addition to conventional anti-cancer therapy. Although many studies report possible mechanisms of action for essential oils compounds, more studies are necessary in order to apply them safely and appropriately in cancer therapy.

Exploring Nanoemulsion for Liver Cancer Therapy

2020 ◽  
Vol 16 (4) ◽  
pp. 260-268
Author(s):  
Tanmay Upadhyay ◽  
Vaseem A. Ansari ◽  
Usama Ahmad ◽  
Nazneen Sultana ◽  
Juber Akhtar
Keyword(s):  
Cancer Therapy ◽  
Liver Cancer ◽  
Treatment Plan ◽  
Chemotherapeutic Drugs ◽  
Drug Delivery Vehicles ◽  
Chronic Hepatitis B Virus ◽  
Anti Cancer ◽  
B Virus ◽  
Delivery Vehicles ◽  
Liquid Dosage Form

Cancer is a leading cause of mortality worldwide, accounting for 8.8 million deaths in 2015. Among these, at least 0.78 million people died of liver cancer alone. The recognized risk factors for liver cancer include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, exposure to dietary aflatoxin, fatty liver disease, alcohol-induced cirrhosis, obesity, smoking, diabetes, and iron overload. The treatment plan for early diagnosed patients includes radiation therapy, tumour ablation, surgery, immunotherapy, and chemotherapy. Some sort of drug delivery vehicles has to be used when the treatment plan is targeted chemotherapy. Nanoemulsions are a class of biphasic liquid dosage form which are mixtures of oil and water stabilized by a surfactant. They are either transparent or bluish in hue and serve as a wonderful carrier system for chemotherapeutic drugs. These vehicles have a particle size in the range of 20-200 nm allowing them to be delivered successfully in the deepest of tissues. Recent publications on nanoemulsions reveal their acceptance and a popular choice for delivering both synthetic and herbal drugs to the liver. This work focuses on some anti-cancer agents that utilized the advantages of nanoemulsion for liver cancer therapy.

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