Dihydropyrazine induces endoplasmic reticulum stress and inhibits autophagy in HepG2 human hepatoma cells.

Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which is a methyl-substituted DHP, caused severe oxidative stress and cytotoxicity. However, the molecular mechanisms underlying the cytotoxic pathways of the DHP response remain elusive.

Exploring simple ways to avoid collecting highly 137Cs-contaminated Aralia elata buds for the revival of local wild vegetable cultures.

Collection and cooking of wild vegetables have provided seasonal enjoyments for Japanese local people as provisioning and cultural ecosystem services. However, the Fukushima Daiichi Nuclear Power Plant accident in March 2011 caused extensive radiocesium contamination of wild vegetables. Restrictions on commercial shipments of wild vegetables have been in place for the last 10 years.

A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the for ATP.

Diphosphene with a phosphineborane tether and its rhodium complex.

A diphosphene ligand possessing a PP bond and a phosphineborane moiety in its molecule was synthesized. The reaction of the new bidentate diphosphene-phosphineborane ligand with [Rh(cod)]BF provided a cationic diphosphene-rhodium complex with -coordination through the η-PP and η-BH moieties. The complex was applied to the coupling reaction of benzimidazole with cyclohexylallene.

Explaining the variation in Cs aggregated transfer factor for wild edible plants as a case study on Koshiabura (Eleutherococcus sciadophylloides) buds.

The aggregated transfer factor (T) is commonly used to represent the actual transfer of radiocesium from soil to wild edible plants, but the values have shown substantial variation since the Fukushima nuclear accident. To elucidate the factors causing this variation, we investigated the effects of spatial scale and vertical Cs distribution in the soil on the variation of T-Cs values for one of the most severely contaminated wild edible plants, Eleutherococcus sciadophylloides Franch. et Sav.

Oxidative stress and cellular toxicity induced by dihydropyrazine: a comparative study with other Maillard reaction products.

Glycation products are generated during the Maillard reaction, a non-enzymatic reaction between reducing sugars and the amino groups of proteins, which accumulate in the body with aging and cause many diseases. Herein, we have focused on dihydropyrazines (DHPs), which are glycation products formed by the dimerization of D-glucosamine or 5-aminolevulinic acid, and have reported that DHPs can produce several kinds of radicals and induce cytotoxicity via oxidative stress. To advance our understanding of DHP-mediated cytotoxicity, we selected a DHP, 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), and two major Maillard reaction products, N-(carboxymethyl)-L-lysine (CML) and acrylamide, and performed comparative experiments focusing on their cytotoxicity and their ability to induce oxidative stress.

Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.

Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner.

Dihydropyrazine suppresses TLR4-dependent inflammatory responses by blocking MAPK signaling in human hepatoma HepG2 cells.

Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products generated through non-enzymatic reactions in vivo and in food. They are recognized as compounds that are toxic to organisms as they produce radicals. However, our previous study indicated that DHP-3 suppressed Toll-like receptor 4 (TLR4) expression and decreased the phosphorylation of nuclear factor-κB (NF-κB) in lipopolysaccharide (LPS)-treated HepG2 cells.

Use of a Baculovirus-Mammalian Cell Expression-System for Expression of Drug-Metabolizing Enzymes: Optimization of Infection With a Focus on Cytochrome P450 3A4.

Heterologous expression systems are important for analyzing the effects of genetic factors including single nucleotide polymorphisms on the functions of drug-metabolizing enzymes. In this study, we focused on a baculovirus-mammalian cell (Bac-Mam) expression system as a safer and more efficient approach for this purpose. The baculovirus-insect cell expression system is widely utilized in large-scale protein expression.

Functional Interaction between Cytochrome P450 and UDP-Glucuronosyltransferase on the Endoplasmic Reticulum Membrane: One of Post-translational Factors Which Possibly Contributes to Their Inter-Individual Differences.

Cytochrome P450 (P450) and uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) catalyze oxidation and glucuronidation in drug metabolism, respectively. It is believed that P450 and UGT work separately because they perform distinct reactions and exhibit opposite membrane topologies on the endoplasmic reticulum (ER). However, given that some chemicals are sequentially metabolized by P450 and UGT, it is reasonable to consider that the enzymes may interact and work cooperatively.

Molecular mechanism of dihydropyrazine-induced cytotoxicity: the possibility of an independent pathway from the receptor for advanced glycation end products.

Dihydropyrazines (DHPs) are one of glycation products that are non-enzymatically generated in vivo and in food. We had previously revealed that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), a methyl-substituted DHP, elicited redox imbalance and cytotoxicity in cultured cells. However, the molecular mechanisms underlying DHP-3-induced cytotoxicity remain unclear.

Untangling radiocesium dynamics of forest-stream ecosystems: A review of Fukushima studies in the decade after the accident.

Forest-stream ecosystems are widespread and biodiverse terrestrial landscapes with physical and social connections to downstream human activities. After radiocesium is introduced into these ecosystems, various material flows cause its accumulation or dispersal. We review studies conducted in the decade after the Fukushima nuclear accident to clarify the mechanisms of radiocesium transfer within ecosystems and to downstream areas through biological, hydrological, and geomorphological processes.

The carboxyl-terminal di-lysine motif is essential for catalytic activity of UDP-glucuronosyltransferase 1A9.

UDP-Glucuronosyltransferase (UGT) is a type I membrane protein localized to the endoplasmic reticulum (ER). UGT has a di-lysine motif (KKXX/KXKXX) in its cytoplasmic domain, which is defined as an ER retention signal. However, our previous study has revealed that UGT2B7, one of the major UGT isoform in human, localizes to the ER in a manner that is independent of this motif.

The effect of dihydropyrazines on lipopolysaccharide-stimulated human hepatoma HepG2 cells via regulating the TLR4-MyD88-mediated NF-κB signaling pathway.

Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products that are spontaneously generated in vivo and ingested via food. DHPs generate various radicals and reactive oxygen species (ROS), which can induce the expression of several antioxidant genes in HepG2 cells. However, detailed information on DHP-response pathways remains elusive.

Relation of Reduction of Antibodies against Hepatitis B Virus to Hepatocellular Carcinoma Recurrence in the Patients with Resolved Hepatitis B Virus Infection Following Direct-acting Antiviral Therapy for Hepatitis C Virus Infection.

Background: A possible interaction of hepatitis viruses at cellular and molecular levels has been suggested. Eradication of hepatitis C virus (HCV) has been reported to induce activation of hepatitis B virus (HBV)-related liver diseases.

Materials And Methods: The present study examined association of HBV markers with recurrence of hepatocellular carcinoma (HCC) in patients with resolved HCV infection by direct-acting antiviral (DAA) therapy.

β-Naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor, disrupts zinc homeostasis in human hepatoma HepG2 cells.

Recent studies have demonstrated a relationship between the disruption of zinc homeostasis and the onset of diseases. However, little is known about the factors that disrupt zinc homeostasis. Here, we investigated the effects of β-naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor (AHR), on intracellular zinc levels.

Atypical Familial Amyotrophic Lateral Sclerosis with Slowly Progressing Lower Extremities-predominant Late-onset Muscular Weakness and Atrophy.

Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS).

A rare case of acute pancreatitis caused by Candida Albicans.

We experienced a rare case of acute pancreatitis caused by Candida infection. A 52-year-old man was admitted to our hospital with a chief complaint of abdominal pain. Blood tests revealed high amylase and hepatobiliary enzyme abnormalities, and the patient was hospitalized for acute pancreatitis.

Impact of lifestyle intervention on dry eye disease in office workers: a randomized controlled trial.

Objectives: To evaluate the effects of a 2-month lifestyle intervention for dry eye disease in office workers.

Methods: Prospective interventional study (randomized controlled study). Forty-one middle-aged Japanese office workers (men, 22; women, 19; 39.

Exercise program improved subjective dry eye symptoms for office workers.

Introduction: We investigated the benefits of a cognitive behavior therapy-based exercise program to reduce the dry eye symptoms of office workers.

Materials And Methods: We recruited 11 office workers with dry eye symptoms, aged 31-64 years, who voluntarily participated in group health guidance at a manufacturing company. Participants learned about the role of physical activity and exercise in enhancing wellness and performed an exercise program at home 3 days per week for 10 weeks.

Nrf2-ARE-Dependent Alterations in Zinc Transporter mRNA Expression in HepG2 Cells.

Zinc transporters are solute carrier family members. To date, 10 zinc transporters (ZnTs) and 14 Zrt-, Irt-like proteins (ZIPs) have been identified. ZnTs control intracellular zinc levels by effluxing zinc from the cytoplasm into the extracellular fluid, intracellular vesicles, and organelles; ZIPs also contribute to control intracellular zinc levels with influxing zinc into the cytoplasm.