Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in the development of experimental ...steatohepatitis in rodents. In this study, to evaluate the effect of oltipraz on lipid and bile acid metabolism, wild-type and Nrf2-null mice were fed the standard diet (containing 4% soybean oil) with or without oltipraz. Based on these results, we examined the effect of oltipraz on the experimental steatohepatitis in high-fat diet (containing 4% soybean oil and 20% lard) fed Nrf2-null mice. Oltipraz induced hepatic mRNA expression of peroxisome proliferator-activated receptor α, carnitine palmityl transferase 1, and bile salt export pump by Nrf2 independent mechanisms. In Nrf2-null mice fed a high-fat diet for 12 weeks, moderate to severe inflammation and fibrosis were observed. Oral administration of oltipraz suppressed the degree of inflammation and fibrosis in Nrf2-null mouse liver fed a high-fat diet. These histopathological findings approximately corresponded to the data of mRNA expression of tumor necrosis factor α, monocyte chemoattractant protein-1, Timp-1, and collagen type 1α1. These results indicated that oltipraz administration ameliorated liver injury by Nrf2 independent manner in a model of steatohepatitis generated by Nrf2-null mice with high-fat diet.
Myxedema coma is a life-threatening and emergency presentation of hypothyroidism. However, the clinical features and outcomes of this condition have been poorly defined because of its rarity.
We ...conducted a retrospective observational study of patients diagnosed with myxedema coma from July 2010 through March 2013 using a national inpatient database in Japan. We investigated characteristics, comorbidities, treatments, and in-hospital mortality of patients with myxedema coma.
We identified 149 patients diagnosed with myxedema coma out of approximately 19 million inpatients in the database. The mean (standard deviation) age was 77 (12) years, and two-thirds of the patients were female. The overall proportion of in-hospital mortality among cases was 29.5%. The number of patients was highest in the winter season. Patients treated with steroids, catecholamines, or mechanical ventilation showed higher in-hospital mortality than those without. Variations in type and dosage of thyroid hormone replacement were not associated with in-hospital mortality. The most common comorbidity was cardiovascular diseases (40.3%). The estimated incidence of myxedema coma was 1.08 per million people per year in Japan. Multivariable logistic regression analysis revealed that higher age and use of catecholamines (with or without steroids) were significantly associated with higher in-hospital mortality.
The present study identified the clinical characteristics and outcomes of patients with myxedema coma using a large-scale database. Myxedema coma mortality was independently associated with age and severe conditions requiring treatment with catecholamines.
•Two-thirds of patients with myxedema coma were female, and the mean age was 77 years.•The mortality rate was 29.5%, and the incidence was 1.08/million people/year.•Older age and use of catecholamines, with or without steroids, were related to death.
We previously reported that lysine-demethylase 2A (KDM2A), a Jumonji-C histone demethylase, is activated by gallic acid to reduce H3K36me2 levels in the rRNA gene promoter and consequently inhibit ...rRNA transcription and cell proliferation in the breast cancer cell line MCF-7. Gallic acid activates AMP-activated protein kinase (AMPK) and increases reactive oxygen species (ROS) production to activate KDM2A. Esters of gallic acid, propyl gallate (PG) and epigallocatechin gallate (EGCG), and other chemicals, reduce cancer cell proliferation. However, whether these compounds activate KDM2A has yet to be tested. In this study, we found that PG and EGCG decreased rRNA transcription and cell proliferation through KDM2A in MCF-7 cells. The activation of both AMPK and ROS production by PG or EGCG was required to activate KDM2A. Of note, while the elevation of ROS production by PG or EGCG was limited in time, it was sufficient to activate KDM2A. Importantly, the inhibition of rRNA transcription and cell proliferation by gallic acid, PG, or EGCG was specifically observed in MCF-7 cells, whereas it was not observed in non-tumorigenic MCF10A cells. Altogether, these results suggest that the derivatization of gallic acid may be used to obtain new compounds with anti-cancer activity.
Metformin is used to treat type 2 diabetes. Metformin activates AMP-activated kinase (AMPK), which may contribute to the action of metformin. Metformin also shows anti-proliferation activity. ...However, the mechanism is remained unknown. We found that treatment of MCF-7 cells with metformin induced the demethylase activity of KDM2A in the rDNA promoter, which resulted in reductions of rRNA transcription and cell proliferation. AMPK activity was required for activation of KDM2A by metformin. Because demethylase activities of JmjC-type enzymes require a side reaction converting α-ketoglutarate to succinate, these organic acids may affect their demethylase activities. We found that metformin did not induce KDM2A demethylase activity in conditions of a reduced level of α-ketoglutarate. A four-hour treatment of metformin specifically reduced succinate, and the replenishment of succinate inhibited the activation of KDM2A by metformin, but did not inhibit the activation of AMPK. Metformin reduced succinate even in the conditions suppressing AMPK activity. These results indicate that metformin activates AMPK and reduces the intracellular succinate level, both of which are required for the activation of KDM2A to reduce rRNA transcription. The results presented here uncover a novel factor of metformin actions, reduction of the intracellular succinate, which contributes to the anti-proliferation activity of metformin.
Two of the Arabidopsis thaliana SEC23 homologs, AtSEC23A and AtSEC23D, are expressed in the tapetum and play essential roles in pollen wall formation, exine patterning, and tapetum development.
...Abstract
The specialized multilayered pollen wall plays multiple roles to ensure normal microspore development. The major components of the pollen wall (e.g. sporopollenin and lipidic precursors) are provided from the tapetum. Material export from the endoplasmic reticulum (ER) is mediated by coat protein complex II (COPII) vesicles. The Arabidopsis thaliana genome encodes seven homologs of SEC23, a COPII component. However, the functional importance of this diversity remains elusive. Here, we analyzed knockout and knockdown lines for AtSEC23A and AtSEC23D, two of the A. thaliana SEC23 homologs, respectively. Single atsec23a and atsec23d mutant plants, despite normal fertility, showed an impaired exine pattern. Double atsec23ad mutant plants were semi-sterile and exhibited developmental defects in pollen and tapetal cells. Pollen grains of atsec23ad had defective exine and intine, and showed signs of cell degeneration. Moreover, the development of tapetal cells was altered, with structural abnormalities in organelles. AtSEC23A and AtSEC23D exhibited the characteristic localization pattern of COPII proteins and were highly expressed in the tapetum. Our work suggests that AtSEC23A and AtSEC23D may organize pollen wall development and exine patterning by regulating ER export of lipids and proteins necessary for pollen wall formation. Also, our results shed light on the functional heterogeneity of SEC23 homologs.
Excessive pressure and shear stress while walking cause a risk of callus formation, which eventually causes foot ulcers in patients with diabetes mellitus. Callus under the second metatarsal head ...(MTH) has been associated with increased shear stress/pressure ratios (SPR). Callus under the fifth MTH has been associated with increased peak shear stress (PSS). The purpose of this study is to examine whether the effect of the suitable size and width of shoes prevents diabetic foot ulcers under the second and fifth MTH. We measured the pressure and shear stress by testing three kinds of sizes and two types of width of shoes. Significant difference was not observed in the SPR under the second MTH among different sizes of shoes. However, the pressure and shear stress were significantly lower when putting on shoes of fit size compared with larger sizes. The PSS under the fifth MTH was significantly smaller when putting on shoes of fit width compared with those of narrow width. Wearing shoes of fit size and width has the potential to prevent callus formation by reducing the pressure and shear stress constituting SPR under the second MTH and PSS under the fifth MTH.
Glaucoma is an ocular disease characterized by progressive retinal ganglion cell (RGC) death caused by axonal injury. However, the underlying mechanisms involved in RGC death remain unclear. In this ...study, we investigated changes in the transcriptome profile following axonal injury in mice (C57BL/6) with RNA sequencing (RNA-seq) technology. The experiment group underwent an optic nerve crush (ONC) procedure to induce axonal injury in the right eye, and the control group underwent a sham procedure. Two days later, we extracted the retinas and performed RNA-seq and a pathway analysis. We identified 177 differentially expressed genes with RNA-seq, notably the endoplasmic reticulum (ER) stress-related genes Atf3, Atf4, Atf5, Chac1, Chop, Egr1 and Trb3, which were significantly upregulated. The pathway analysis revealed that ATF4 was the most significant upstream regulator. The antioxidative response-related genes Hmox1 and Srxn1, as well as the immune response-related genes C1qa, C1qb and C1qc, were also significantly upregulated. To our knowledge, this is the first reported RNA-seq investigation of the retinal transcriptome and molecular pathways in the early stages after axonal injury. Our results indicated that ER stress plays a key role under these conditions. Furthermore, the antioxidative defense and immune responses occurred concurrently in the early stages after axonal injury. We believe that our study will lead to a better understanding of and insight into the molecular mechanisms underlying RGC death after axonal injury.
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