Previously, we demonstrated that there is a marked reduction in the amount of ceramide in the stratum corneum of both lesional and nonlesional forearms in atopic dermatitis (AD), suggesting that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry and barrier-disrupted skin. In this study, we investigated, as a possible mechanism involved in the ceramide deficiency, whether sphingomyelin (SM) metabolism is altered in AD as compared to normal controls. In stripped stratum corneum and biopsied whole epidermis of patients with AD, SM hydrolysis as measured at pH 4.7 using [choline-methyl-14C]sphingomyelin as a substrate were markedly increased by 27- and 7-fold, respectively. Radio-thin-layer chromatography of the reaction products revealed that, whereas the SM hydrolysis in age-matched normal controls were associated with sphingomyelinase (SMase) that degrades SM to yield ceramides and phosphorylcholine (PC), most of the SM hydrolysis detected in AD were attributable not to the SMase but to a hitherto undiscovered epidermal enzyme, SM acylase, which releases free fatty acid and sphingosyl-PC (Sph-PC) instead of ceramides. The potential of this acylase-like enzyme to generate Sph-PC through SM hydrolysis was corroborated by thin-layer chromatographic analysis of the reaction products obtained using porcine kidney acylase, followed by high-performance liquid chromatography-mass spectrometry. Furthermore, Sph-PC was also detected by high-performance liquid chromatography-mass spectrometry after incubation of SM with atopic stratum corneum samples. On the other hand, the stratum corneum of patients with contact dermatitis or chronic eczema exhibited neither increased SM hydrolysis nor the generation of Sph-PC upon radio-thin-layer chromatographic analysis. These findings suggest that SM metabolism is altered in AD, resulting in a decrease in levels of ceramides, which could be an etiologic factor in the continuous generation of atopic dry and barrier disrupted skin observed in AD.
Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cell mechanisms mediating this relationship have not been elucidated. Th17 cells, which produce the proinflammatory cytokine interleukin 17 (IL-17), have been recognized as one of the key factors in the regulation of inflammatory bowel disease and rheumatoid arthritis. This study demonstrated that, in patients with various types of gastrointestinal cancer, IL-17 production was correlated with myeloid-derived suppressor cell (MDSC) levels and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with various types of gastrointestinal cancer compared to normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio (NLR) and significantly inversely correlated with cell-mediated immune response indicators [lymphocyte phytohemagglutinin (PHA)-blastogenesis and IL-12 induction] and patient nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism contributing to disease progression through enhancement of immune suppression or cachexia. Controlling the activation of Th17 cells may prove to be a valuable strategy for the treatment of gastrointestinal cancer patients.
Increased expression of p53R2 may predict gemcitabine resistance, and upregulated RNR activity may influence gemcitabine resistance in cholangiocarcinoma cells. Glutathione pathway-related genes were induced by continuous exposure to gemcitabine and may contribute to gemcitabine resistance.
Ischemia reperfusion (I-R) of the liver induces various events leading to cell death (apoptosis) and subsequent cells proliferation. Recent experimental studies have described the protective effect of ischemic preconditioning (IPC) on I-R injury of the liver. However, the mechanisms involved in this protection remain unknown. The protein products of immediate early genes (IEGs) behave as crucial transcriptional regulators not only in apoptosis but also in cell proliferation. Here, we evaluated the effects of IPC on IEG transcription after I-R injury, using a rat liver I-R injury model. Injury to hepatocytes was evaluated by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) and that to endothelial cells by plasma concentration of hyaluronic acid (HA). The extent of necrosis was evaluated by H&E staining, while cell proliferation and apoptosis were evaluated by proliferating cell nuclear antigen (PCNA) and terminal deoxy(d)-UTP nick end labelling (TUNEL) staining, respectively. Alterations in the transcription of IEGs (c-fos and c-jun) were examined by Northern blotting. Rats subjected to 40-min liver ischemia, preceded by 10-min preconditioning, showed significantly lower AST, ALT, LDH, and HA levels at 6 h after I-R than untreated animals (P < 0.05; n at least 5 rats per group). The percentage of necrotic areas at 24 h after I-R was significantly lower in IPC-treated animals than in the controls. The numbers of apoptotic cells at 24 h after I-R and the numbers of PCNA-positive cells at 24 and 48 h after I-R were significantly lower in IPC-treated rats than in controls. Transcription levels of IEGs were low in IPC-treated rats, particularly c-jun at 1 and 1.5 h after I-R (P < 0.05). Our results indicate that IPC provides a significant protective effect on for liver cells against I-R injury and that its effect is evidenced by a significant decrease in the transcription levels of IEGs following the insult.
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