Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation

AbstractThe C4-hydroxylation of dihydrosphingosine or dihydroceramide is a key reaction in the biosynthesis of phytosphingolipids, both in yeasts and in mammalian cells. Mouse DES2 (mDES2) was recently cloned and shown to work as a Δ4-desaturase/C4-hydroxylase, when expressed in yeast cells. Here, we cloned a human homologue of mDES2, hDES2, by homology search utilizing a BLAST program. When expressed in HEK 293 cells, hDES2 exhibited hydroxylase activity for dihydroceramide. Northern blot analyses of hDES2 revealed high expression in skin, intestines, and kidney, sites reportedly possessing high levels of phytosphingolipids. Furthermore, up-regulation of hDES2 mRNA expression and subsequent phytoceramide production were observed during vitamin C/serum-induced differentiation of human keratinocytes. These results suggest that the newly cloned hDES2 plays an essential role in phytosphingolipid synthesis in human skin and other phytosphingolipid-containing tissues

Observed Features of Langmuir Turbulence Forced by Misaligned Wind and Waves Under Destabilizing Buoyancy Flux

Several features of Langmuir turbulence remain unquantified despite its potentially large impacts on ocean surface mixing. For example, its vertical velocity variance, expected to be proportional to based on numerical simulations, was proportional to in recent field observations, where is the friction velocity and is surface Stokes velocity. To investigate unquantified features of Langmuir turbulence, we conducted a field experiment around a marine observation tower in a shallow sea off the southern coast of Japan in early winter when winds and waves (often swells) were often misaligned. Coherent structures similar to Langmuir cells were successfully identified in the horizontal and vertical structures of turbulent flows measured with upward- and horizontally looking acoustic Doppler current profilers (ADCPs). ADCPs and several anemometers attached at the tower showed that turbulent vertical velocity variance was large when the Langmuir number and Hoenikker number (; where B is surface buoyancy flux and H is the water depth) were both small and that the orientation of the cells was generally aligned in the direction of Lagrangian current shear. These results agree well with the previous numerical results. As in the previous observations, however, the vertical velocity variance appeared to be proportional to . In our experiment, this curious feature was explained by compensatory effects between waves and convection. Misaligned wind with waves also seems to characterize the observed Langmuir turbulence, though further quantitative analysis is required to confirm this result

Phytoceramide and sphingoid bases derived from brewer's yeast Saccharomyces pastorianus activate peroxisome proliferator-activated receptors

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid and glucose metabolism. PPARα is highly expressed in the liver and controls genes involved in lipid catabolism. We previously reported that synthetic sphingolipid analogs, part of which contains shorter-length fatty acid chains than natural sphingolipids, stimulated the transcriptional activities of PPARs. Sphingosine and dihydrosphingosine (DHS) are abundant sphingoid bases, and ceramide and dihydroceramide are major ceramide species in mammals. In contrast, phytosphingosine (PHS) and DHS are the main sphingoid bases in fungi. PHS and phytoceramide exist in particular tissues such as the epidermis in mammals, and involvement of ceramide species in PPARβ activation in cultured keratinocytes has been reported. The purpose of the present study is to investigate whether natural sphingolipids with C18 fatty acid and yeast-derived sphingoid bases activate PPARs as PPAR agonists.</p> <p>Method</p> <p>Lipids of brewer's yeast contain PHS- and DHS-based sphingolipids. To obtain the sphingoid bases, lipids were extracted from brewer's yeast and acid-hydrolyzed. The sphingoid base fraction was purified and quantified. To assess the effects of sphingolipids on PPAR activation, luciferase reporter assay was carried out. NIH/3T3 and human hepatoma (HepG2) cells were transfected with expression vectors for PPARs and retinoid × receptors, and PPAR responsive element reporter vector. When indicated, the PPAR/Gal4 chimera system was performed to enhance the credibility of experiments. Sphingolipids were added to the cells and the dual luciferase reporter assay was performed to determine the transcriptional activity of PPARs.</p> <p>Results</p> <p>We observed that phytoceramide increased the transcriptional activities of PPARs significantly, whereas ceramide and dihydroceramide did not change PPAR activities. Phytoceramide also increased transactivation of PPAR/Gal4 chimera receptors. Yeast-derived sphingoid base fraction, which contained PHS and DHS, or authentic PHS or DHS increased PPAR-dependent transcription. Additionally, phytoceramide stimulated PPARα activity in HepG2 hepatocytes, suggesting that phytoceramide activates genes regulated by PPARα.</p> <p>Conclusions</p> <p>Phytoceramide and yeast-derived sphingoid bases activate PPARs, whereas ceramide and dihydroceramide do not change the PPAR activity. The present findings suggest that phytoceramide acts as a PPAR ligand that would regulate PPAR-targeted genes.</p

Análisis de las comorbilidades en pacientes con colitis ulcerosa: una herramienta para prevenir las exacerbaciones en casos de colitis ulcerosa

There have been previous studies, especially in Western countries and even in some areas in Asia, about extra-intestinal manifestations (EIMs) and its link with the outcome of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD), and ulcerative colitis (UC). This link is crucial when discussing a patient’s prognosis and important when dealing with UC management. The aim of this study was to clarify the most common comorbidities associated with UC, emphasizing immunologic comorbidities in Japan. This study was a retrospective analysis performed at Nagoya University Hospital. The data collection started in March, 2019, and continued for two years. We retrieved the medical records of 105 patients with UC diagnosis, from which the data of 176 EIMs were extracted and analyzed. Results showed that EIMs with UC in the active phase accounted for 43.7% of total EIMs. Twenty-six patients with immune-mediated inflammatory disease frequently had an active phase (odds ratio [OR] 3.84, 99% CI, 1.44–10.27). Comorbidities showing an active manifestation of symptoms and UC in the active phase were significantly correlated in patients with immunological comorbidities, such as peripheral arthritis (r = 0.97, p < 0.01) and rheumatoid arthritis (RA) (r = 0.99, p < 0.01), as well as in patients with primary sclerosis cholangitis (PSC) (r = 0.98, p < 0.01). In conclusion, this analysis suggests the importance of having full comprehension of how immunological comorbidities affect the natural development of UC, which is of vital importance to prevent further UC complications and properly adjust the management of the disease.Se trata de un análisis retrospectivo que estudia múltiples comorbilidades de índole inmunológico que se da en pacientes con colitis ulcerosa. Este estudio se llevó a cabo en el hospital universitario de la Universidad de Nagoya. Se recolectó datos de 105 pacientes con colitis ulcerosa, de los cuales 176 comorbilidades extraintestinales fueron analizadas. Se encontró que comorbilidades con manifestación activa de síntomas y con colitis ulcerosa en fase activa fueron significativamente correlacionadas en pacientes con comorbilidades inmunológicas, tales como artritis periféricas (r=O.97, P<O.OI ), artritis reumatoide (r=O.99, P<O.OI ), así como pacientes con colangitis esclerosa primaria (r=O.98, P<O.OI ). En conclusión, este análisis sugiere la importancia de tener plena comprensión de cómo las comorbilidades inmunológicas afectan el desarrollo natural de la colitis ulcerosa, lo cual es de vital importancia para prevenir mayores complicaciones de la colitis ulcerosa y ajustar adecuadamente el manejo de la enfermedad.Japón. Ministerio de Educación, Cultura, Deportes, Ciencia y Tecnología (Monbukagakusho)Artículo de investigació

Relationship of Grade of Malignant Brain Tumor to Cancer Stem Cells and Survivin Expression

Glioblastoma (GBM) is difficult to completely cure by surgical treatment alone, and it is generally treated with a combination of surgery, radiotherapy, and chemotherapy. However, GBM is resistant to radiotherapy and chemotherapy, and complete cure cannot be achieved. Cancer stem cells (CSC) and survivin, which inhibit apoptosis, are considered as factors underlying tumor recurrence and the radiation- and drug-resistance of these tumors. We analyzed CSC and survivin expression in surgically excised specimens of malignant brain tumors to establish the relationships between the grades and CSC and survivin expression and between MIB-1 (Ki-67) expression and resistance. No relationship was noted between the grades and CSC or survivin expression, or between MIB-1 and CSC expression or between Grade 3 and 4 MIB-1 and survivin expression, although a correlation was noted between MIB-1 and survivin expression in Grade II tumors. These findings suggested that CSC are consistently contained in tumor tissue at a specific rate regardless of the histological grade, and the apoptosis of cells with low-level proliferative and cell cycling activities does not occur because these cells do not respond to chemotherapy or radiation, being resistant to treatment

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC

First detection of two superoutbursts during rebrightening phase of a WZ Sge-type Dwarf Nova : TCP J21040470+4631129

We report on photometric and spectroscopic observations and analysis of the 2019 superoutburst of TCP J21040470+4631129. This object showed a 9 mag superoutburst with early superhumps and ordinary superhumps, which are the features of WZ Sge-type dwarf novae. Five rebrightenings were observed after the main superoutburst. The spectra during the post-superoutburst stage showed Balmer, He I, and possible sodium doublet features. The mass ratio is derived as 0.0880(9) from the period of the superhump. During the third and fifth rebrightenings, growing superhumps and superoutbursts were observed, which have never been detected during a rebrightening phase among WZ Sge-type dwarf novae with multiple rebrightenings. To induce a superoutburst during the brightening phase, the accretion disk needs to have expanded beyond the 3 : 1 resonance radius of the system again after the main superoutburst. These peculiar phenomena can be explained by the enhanced viscosity and large radius of the accretion disk suggested by the higher luminosity and the presence of late-stage superhumps during the post-superoutburst stage, plus by more mass supply from the cool mass reservoir and/or from the secondary because of the enhanced mass transfer than those of other WZ Sge-type dwarf novae.peer-reviewe

First Detection of Two Superoutbursts during Rebrightening Phase of a WZ Sge-type Dwarf Nova: TCP J21040470+4631129

We report photometric and spectroscopic observations and analysis of the 2019 superoutburst of TCP J21040470+4631129. This object showed a 9-mag superoutburst with early superhumps and ordinary superhumps, which are the features of WZ Sge-type dwarf novae. Five rebrightenings were observed after the main superoutburst. The spectra during the post-superoutburst stage showed the Balmer, He I and possible sodium doublet features. The mass ratio is derived as 0.0880(9) from the period of the superhump. During the third and fifth rebrightenings, growing superhumps and superoutbursts were observed, which have never been detected during a rebrightening phase among WZ Sge-type dwarf novae with multiple rebrightenings. To induce a superoutburst during the brightening phase, the accretion disk was needed to expand beyond the 3:1 resonance radius of the system again after the main superoutburst. These peculiar phenomena can be explained by the enhanced viscosity and large radius of the disk suggested by the higher luminosity and the presence of late-stage superhumps during the post-superoutburst stage, plus by more mass supply from the cool mass reservoir and/or from the secondary because of the enhanced mass transfer than those of other WZ Sge-type dwarf novae.Comment: 13 pages, 10 figures, accepted for publication in PAS