Pterostilbene, a Dimethyl Derivative of Resveratrol, Exerts Cytotoxic Effects on Melanin-Producing Cells through Metabolic Activation by Tyrosinase.

Pterostilbene (PTS), which is abundant in blueberries, is a dimethyl derivative of the natural polyphenol resveratrol (RES). Several plant species, including peanuts and grapes, also produce PTS. Although RES has a wide range of health benefits, including anti-cancer properties, PTS has a robust pharmacological profile that includes a better intestinal absorption and an increased hepatic stability compared to RES.

Novel machine learning method allerStat identifies statistically significant allergen-specific patterns in protein sequences.

Cutting-edge technologies such as genome editing and synthetic biology allow us to produce novel foods and functional proteins. However, their toxicity and allergenicity must be accurately evaluated. It is known that specific amino acid sequences in proteins make some proteins allergic, but many of these sequences remain uncharacterized.

A cell-based evaluation of human tyrosinase-mediated metabolic activation of leukoderma-inducing phenolic compounds.

Background: Chemical leukoderma is a skin depigmentation disorder induced through contact with certain chemicals, most of which have a p-substituted phenol structure similar to the melanin precursor tyrosine. The tyrosinase-catalyzed oxidation of phenols to highly reactive o-quinone metabolites is a critical step in inducing leukoderma through the production of melanocyte-specific damage and immunological responses.

Objective: Our aim was to find an effective method to evaluate the formation of o-quinone by human tyrosinase and subsequent cellular reactions.

Statins repress needle-like carbon nanotube- or cholesterol crystal-stimulated IL-1β production by inhibiting the uptake of crystals by macrophages.

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower atherogenic LDL-cholesterol levels. Statins exert clinically relevant anti-inflammatory effects; however, the underlying molecular mechanism remains unclear. Studies have shown that endogenous and exogenous pathogenic crystals, such as cholesterol and monosodium urate (MSU), and needle-like nanomaterials, such as multi-wall carbon nanotubes (MWCNT), induce the production of IL-1β and play a critical role in the development of crystal-associated sterile inflammatory pathologies.

Assessment of Immune Responses in an Animal Model of Wheat Food Allergy via Epicutaneous Sensitization.

Wheat allergy is a pathological event involving immunocompetent cells against ingested wheat allergen and is clearly associated with transdermal sensitization. However, the molecular mechanisms involved in the disease etiology are not completely understood. A complex cellular and tissue network linking to food allergy makes it difficult to understand the molecular mechanism of allergenicity.

Real-time PCR Detection Methods for Food Allergens (Wheat, Buckwheat, and Peanuts) Using Reference Plasmids.

Specific and sensitive real-time qualitative polymerase chain reaction (PCR) methods for the detection of food allergens including wheat, buckwheat, and peanuts were developed that could cancel between instrument effects and avoid risks of false-positives and false-negatives. In these real-time PCR analysis, the cutoff for determination of positive samples was set in every PCR run by using reference plasmids containing known copies of the target sequences. The copy numbers of the plasmids were used to detect the allergenic ingredients corresponding to 10 ppm (w/w) protein in highly processed foods (cooked for more than 30 min at 122 °C).

Cross-allergenicity of crustacean and the edible insect Gryllus bimaculatus in patients with shrimp allergy.

Food scarcity is a serious problem for many developing as well as developed countries. Edible insects have attracted attention recently as a novel food source. Crickets are especially high in nutritional value and easy to breed and harvest.

Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting T17 cell polarization.

Background: Ras homolog gene family H (RhoH) is a membrane-bound adaptor protein involved in proximal T-cell receptor signaling. Therefore RhoH plays critical roles in the differentiation of T cells; however, the function of RhoH in the effecter phase of the T-cell response has not been fully characterized.

Objective: We sought to explore the role of RhoH in inflammatory immune responses and investigated the involvement of RhoH in the pathogenesis of psoriasis.

Determining Food Allergens by Skin Sensitization in Mice.

A food allergy is a chronic inflammatory disease against dietary antigens with high prevalence in industrialized countries. Because there is currently no cure for food allergies, avoiding the allergen is crucial for the prevention of an allergic reaction. Therefore, a further understanding of the pathogenesis and risk factors that augment the sensitization to food allergens is required.

T-cell activation RhoGTPase-activating protein plays an important role in T17-cell differentiation.

T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear.

LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux.

Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many of the data assessing the function of the ABCA1-syntrophin interaction are based on overexpression in nonmacrophage cells.

Overexpression of RhoH Permits to Bypass the Pre-TCR Checkpoint.

RhoH, an atypical small Rho-family GTPase, critically regulates thymocyte differentiation through the coordinated interaction with Lck and Zap70. Therefore, RhoH deficiency causes defective T cell development, leading to a paucity of mature T cells. Since there has been no gain-of-function study on RhoH before, we decided to take a transgenic approach to assess how the overexpression of RhoH affects the development of T cells.

Differential function of Themis CABIT domains during T cell development.

Themis (also named Gasp) is a newly identified Grb2-binding protein that is essential for thymocyte positive selection. Despite the possible involvement of Themis in TCR-mediated signal transduction, its function remains unresolved and controversial. Themis contains two functionally uncharacterized regions called CABIT (cysteine-containing, all-β in Themis) domains, a nuclear localization signal (NLS), and a proline-rich sequence (PRS).

Differential requirement for RhoH in development of TCRαβ CD8αα IELs and other types of T cells.

RhoH is a new member of the atypical G proteins exclusively expressed in hematopoietic lineage cells. It has been shown to act as an adaptor for ZAP70, Syk, Lck and Csk kinases in signal transduction, and is required for positive selection of thymocytes as well as activation of peripheral T cells and mast cells. In the present study, we showed that RhoH is required not only for positive selection but also for negative selection of thymocytes.

Mutation of the ATP cassette binding transporter A1 (ABCA1) C-terminus disrupts HIV-1 Nef binding but does not block the Nef enhancement of ABCA1 protein degradation.

HIV-1 infection and antiretroviral therapy are associated with a dyslipidemia marked by low levels of high-density lipoprotein and increased cardiovascular disease, but it is unclear whether virion replication plays a causative role in these changes. The HIV-1 Nef protein can impair ATP cassette binding transporter A1 (ABCA1) cholesterol efflux from macrophages, a potentially pro-atherosclerotic effect. This viral inhibition of efflux was correlated with a direct interaction between ABCA1 and Nef.

MiR-33 contributes to the regulation of cholesterol homeostasis.

Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1.

Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation.

ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux to apolipoprotein A1 (apoA-I) initiates the biogenesis of high density lipoprotein. Here we show that the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG bind to the C terminus of ABCA1 by a PDZ-PDZ interaction and prevent ABCA1 protein degradation by activating RhoA. ABCA1 is a protein with a short half-life, and apoA-I stabilizes ABCA1 protein; however, depletion of PDZ-RhoGEF/LARG by RNA interference suppressed the apoA-I stabilization of ABCA1 protein in human primary fibroblasts.

ABC transporters, atherosclerosis and inflammation.

Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT).

Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis.

Elevated sphingolipids have been associated with increased cardiovascular disease. Conversely, atherosclerosis is reduced in mice by blocking de novo synthesis of sphingolipids catalyzed by serine palmitoyltransferase (SPT). The SPT enzyme is composed of the SPTLC1 and -2 subunits, and here we describe a novel protein-protein interaction between SPTLC1 and the PDZ protein Par3 (partitioning defective protein 3).

The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines.

Release of cellular cholesterol by ATP-binding cassette transporter (ABC)A1 and apolipoproteins is a major source of plasma high-density lipoprotein (HDL). Expression of ABC transporter A1 (ABCA1) is directly stimulated by liver X receptor (LXR)/retinoid X receptor (RXR) activation. We evaluated the abilities of two RXR agonists, PA024 and HX630, to increase ABCA1 expression.

The novel compounds that activate farnesoid X receptor: the diversity of their effects on gene expression.

Farnesoid X receptor (FXR) controls the expression of critical genes in bile acid and cholesterol homeostasis. To study FXR and to develop a regulator of cholesterol, some non-steroidal and steroidal ligands have been found in addition to endogenous ligands for FXR. In this study, we discovered five bile acid derivatives (methyl cholate, methyl deoxycholate, 5beta-cholanic acid, 5beta-cholanic acid-7alpha,12alpha-diol, and NIHS700) and two natural products (marchantin A and marchantin E) that activated FXR in the reporter assay.

SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter.

ABCA1 transport of cholesterol and phospholipids to nascent HDL particles plays a central role in lipoprotein metabolism and macrophage cholesterol homeostasis. ABCA1 activity is regulated both at the transcriptional level and at the post-translational level. To explore mechanisms involved in the post-translational regulation of the transporter, we have used affinity purification and mass spectrometry to identify proteins that bind ABCA1 and influence its activity.

Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status.

ABC transporter A1 (ABCA1) mediates and rate-limits biogenesis of high density lipoprotein (HDL), and hepatic ABCA1 plays a major role in regulating plasma HDL levels. HDL generation is also responsible for release of cellular cholesterol. In peripheral cells ABCA1 is up-regulated by the liver X receptor (LXR) system when cell cholesterol increases.