Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.

Polycystic kidney diseases are a group of monogenically inherited disorders characterized by cyst development in the kidney with defects in primary cilia function central to pathogenesis. Autosomal dominant polycystic kidney disease (ADPKD) has progressive cystogenesis and accounts for 5-10% of kidney failure (KF) patients. There are two major ADPKD genes, PKD1 and PKD2, and seven minor loci.

The VUS Challenge in Cystic Kidney Disease: A Case-Based Review.

Genetic testing in nephrology is becoming increasingly important to diagnose patients and to provide appropriate care. This is especially true for autosomal dominant polycystic kidney disease (ADPKD) because this is a common cause of kidney failure and genetically complex. In addition to the major genes, PKD1 and PKD2 , there are at least six minor loci, and phenotypic, and in some cases, genetic overlap with other cystic disorders.

Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.

Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer-testing laboratory.

BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases.

The development of mutant BRAF inhibitors has improved the outcome for melanoma patients with BRAF mutations. Although the initial response to these inhibitors can be dramatic, sometimes resulting in complete tumor regression, the majority of melanomas become resistant. To study resistance to BRAF inhibition, we developed a novel mouse model of melanoma using a tetracycline/doxycycline-regulated system that permits control of mutant BRAF expression.

Effect of Korean Red Ginseng treatment on the gene expression profile of diabetic rat retina.

Background: Korean Red Ginseng (KRG) is a herbal medicine used in Asian countries and is very popular for its beneficial biological properties. Diabetes mellitus (DM) and its complications are rapidly becoming a global public health concern. The literature on transcriptional changes induced by KRG in rat models of diabetic retinopathy is limited.

Induction of Thioredoxin Reductase 1 by Korean Red Ginseng Water Extract Regulates Cytoprotective Effects on Human Endothelial Cells.

Korean Red Ginseng is a popular herbal medicine and is widely used in many food products. KRG has biological benefits related to vascular diseases including diabetes, hypertension, atherosclerosis, and other cardiac diseases and KRG has antioxidant and anti-hyperlipidemic actions. KRG decreases the level of oxidative stress and suppresses proinflammatory cytokines and cell adhesion molecules, thus protecting endothelial dysfunction.

Eriodictyol Protects Endothelial Cells against Oxidative Stress-Induced Cell Death through Modulating ERK/Nrf2/ARE-Dependent Heme Oxygenase-1 Expression.

The pathophysiology of cardiovascular diseases is complex and may involve oxidative stress-related pathways. Eriodictyol is a flavonoid present in citrus fruits that demonstrates anti-inflammatory, anti-cancer, neurotrophic, and antioxidant effects in a range of pathophysiological conditions including vascular diseases. Because oxidative stress plays a key role in the pathogenesis of cardiovascular disease, the present study was designed to verify whether eriodictyol has therapeutic potential.

Effects of Eicosapentaenoic Acid on the Cytoprotection Through Nrf2-Mediated Heme Oxygenase-1 in Human Endothelial Cells.

Consumption of omega-3 polyunsaturated fatty acid, particularly eicosapentaenoic acid (EPA), is associated with a significant reduction in the risk of developing cardiovascular disease. The aim of this study was to investigate whether heme oxygenase-1 (HO-1) induction contributes to the cytoprotective effects of EPA in endothelial cells threatened with oxidative damage. In this study, we investigated the effect of EPA on the induction of HO-1 by NF-E2-related factor 2 (Nrf2) in human umbilical vein endothelial cells.

β2 integrins (CD11/18) are essential for the chemosensory adhesion and migration of polymorphonuclear leukocytes on bacterial cellulose.

Bacterial cellulose (BC) has been studied widely for applications in biomedical materials such as prosthetic artificial blood vessels owing to its unique characteristics, which include nontoxicity and nonimmunogenicity as compared with synthetic biopolymers such as expanded polytetrafluorethylene (ePTFE). However, to date, studies on the relative effect of leukocytes on BC as a prosthetic vascular graft are insufficient. Polymorphonuclear leukocytes (PMN) play a pivotal role in early-phase immune response to bacterial or periprosthetic infection.

Crotonaldehyde induces heat shock protein 72 expression that mediates anti-apoptotic effects in human endothelial cells.

Crotonaldehyde is a highly reactive aldehyde and a common environmental pollutant. It occurs in cigarette smoke and automobile exhaust, and is also endogenously generated by lipid peroxidation. Reactive aldehydes, such as crotonaldehyde, are considered to be important mediators of cell damage.

Hemeoxygenase-1 mediates an adaptive response to spermidine-induced cell death in human endothelial cells.

Spermidine (SPD) is a ubiquitous polycation that is commonly distributed in living organisms. Intracellular levels of SPD are tightly regulated, and SPD controls cell proliferation and death. However, SPD undergoes oxidation in the presence of serum, producing aldehydes, hydrogen peroxide, and ammonia, which exert cytotoxic effect on cells.

Genome-wide profiling in melatonin-exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin.

Epigenetic alterations have emerged as an important mechanism involved in tumorigenesis. The epigenetic impact of DNA methylation in various types of human cancer is not completely understood. Previously, we observed melatonin-induced differential expression of miRNA and miRNA-related genes in human breast cancer cell lines that indicated an anticancer effect of melatonin.

Induction of heme oxygenase-1 inhibits cell death in crotonaldehyde-stimulated HepG2 cells via the PKC-δ-p38-Nrf2 pathway.

Background: Crotonaldehyde, an alpha, beta-unsaturated aldehyde present in cigarette smoke, is an environmental pollutant and a product of lipid peroxidation. It also produces adverse effects to humans and is considered as a risk factor for various diseases. Heme oxygenase-1 (HO-1) plays important roles in protecting cells against oxidative stress as a prime cellular defense mechanism.

Extract of Salvia miltiorrhiza (Danshen) induces Nrf2-mediated heme oxygenase-1 expression as a cytoprotective action in RAW 264.7 macrophages.

Ethnopharmacological Relevance: Danshen (Salvia miltiorrhiza) is widely used in traditional herbal medicines for relief of a variety of symptoms related to complications arising from vascular diseases such as hypertension, diabetes, and atherosclerosis. Induction of heme oxygenase-1 (HO-1) expression protects against oxidative stress-induced cell damage, which plays an important role in cytoprotection in a variety of pathological models.

Materials And Methods: In the present study, we investigated the effect of Danshen on the up-regulation of HO-1, an inducible and cytoprotective enzyme in RAW 264.

Up-regulation of Heme Oxygenase-1 by Korean Red Ginseng Water Extract as a Cytoprotective Effect in Human Endothelial Cells.

Korean red ginseng (KRG) is used worldwide as a popular traditional herbal medicine. KRG has shown beneficial effects on cardiovascular diseases, such as atherosclerosis, diabetes, and hypertension. Up-regulation of a cytoprotective protein, heme oxygenase (HO)-1, is considered to augment the cellular defense against various agents that may induce cytotoxic injury.

Fisetin induces Nrf2-mediated HO-1 expression through PKC-δ and p38 in human umbilical vein endothelial cells.

Fisetin is a natural flavonoid from fruits and vegetables that exhibits antioxidant, neurotrophic, anti-inflammatory, and anti-cancer effects in various disease models. Up-regulation of heme oxygenase-1 (HO-1) expression protects against oxidative stress-induced cell death, and therefore, plays a crucial role in cytoprotection in a variety of pathological models. In the present study, we investigated the effect of fisetin on the up-regulation of HO-1 in human umbilical vein endothelial cells (HUVECs).

Microinflammation in hemodialysis patients is associated with increased CD14CD16(+) pro-inflammatory monocytes: possible modification by on-line hemodiafiltration.

Background: An increased percentage of pro-inflammatory CD14(+)CD16(+) monocytes might contribute to inflammation in hemodialysis (HD) patients. The purpose of the study was to evaluate the possible contribution of pro-inflammatory monocytes to inflammation in HD patients and also to evaluate the effect of on-line hemodiafiltration (HDF).

Methods: Flow cytometric detection of monocytes in patients undergoing HD, on-line HDF and healthy controls as well as plasma cytokines and cytokine mRNA measurement were performed.

Upregulation of heme oxygenase-1 as an adaptive mechanism for protection against crotonaldehyde in human umbilical vein endothelial cells.

Crotonaldehyde, a highly reactive α, β-unsaturated aldehyde, is a ubiquitous environmental pollutant and a product of endogenous lipid peroxidation. It is also a major component of cigarette smoke and is present in many foods and beverages, and has also been linked to development of various diseases. Activation of endothelial cells by stimuli such as cigarette smoke is an important risk factor for cardiovascular diseases, including atherosclerosis.