Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2 2/2 ) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2 2/2 colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2 2/2 mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.-Ohnishi, T., Hashizume, C., Taniguchi, M., Furumoto, H., Han, J., Gao, R., Kinami, S., Kosaka, T., Okazaki, T. Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer. FASEB J. 31, 3816-3830 (2017). www.fasebj.orgIn the past decade, a positive correlation between inflammation and tumorigenesis has been identified, with supporting evidence from genetic, pharmacologic, and epidemiologic data in numerous organs, including colon, lungs, bladder, and ovaries (1, 2). Colorectal cancer (CRC) is one of the most common cancers worldwide. More than 1 million new cases of CRC are reported annually and the incidence rate has been increasing (3). Although most cases of CRC are sporadic, more than 20% of patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, develop colitis-associated colon cancer (CAC) (4). Thus, IBD is recognized as an important risk factor for the development of CRC. Experimental evidence suggests that inflammatory changes create a favorable microenvironment for initiation of CAC and tumor progression (5); however, the pathogenic mechanism that links IBD and CAC is not fully understood.It has been reported that dysregulation of lipid metabolism is a crucial factor in cancer initiation and contributes to the development of CRC (6). Among lipids, sphingolipids, including sphingomyelin (SM), ceramide, and sphingosine-1-phosphate (S1P), are a class of lipids that share sphingoid base as a structural backbone. Sphingolipids have been known as structur...
1. 17-β-oestradiol (E2) plays a critical role in neuroprotection through both genomic and non-genomic mechanisms. The aim of the present study was to investigate the role of G-protein-coupled receptor 30 (GPR30), a new kind of oestrogen receptor, in the neuroprotection against oxidative insult. 2. The neuroprotection evoked by GPR30 stimulation was examined in cultured cortical neurons. Hoechst 33258/propidium iodide double staining, flow cytometric analysis and western blotting were applied to assess neuronal apoptosis induced by H(2)O(2) . 3. We found that the GPR30 agonist, G1, and E2 attenuated apoptosis induced by H(2)O(2) exposure. Furthermore, G1 (1 nmol/L) or E2 (1 nmol/L) significantly increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bcl-2 and pro-caspase-3. Pretreatment with ICI182780, a highly selective nuclear oestrogen receptor antagonist that is used to block the classical ERα and ERβ receptors, did not totally block the neuroprotective effects of E2 (1 nmol/L) and had no effect on the neuroprotective effects of G1 (1 nmol/L). 4. Our data suggest that GPR30 is involved in the neuroprotection against oxidative insult. The neuroprotection evoked by GPR30 stimulation was associated with the signalling through the ERK1/2 kinase pathway. In addition, the anti-apoptotic activity of GPR30 was dependent on the expression of Bcl-2 and pro-caspase-3. GPR30 might be a potential therapeutic target for neuroprotection and oxidative stress.
The co-existence of de novo myelodysplastic syndrome (MDS) and non-Hodgkin lymphoma (NHL) prior to therapy is an extremely unusual finding. We report here a case of co-existent de novo MDS-refractory cytopenia with multilineage dysplasia and T-cell NHL, including clinical features, histopathological findings, molecular assessment, treatment course and outcomes. Other cases from the literature showing co-existence of both disorders are also reviewed; to date 19 similar cases have been reported. Among all cases (including the present patient), eight cases were diagnosed with de novo MDS and NHL simultaneously, which were considered to be true coincidences. The mechanisms responsible for the appearance of co-existence have not yet been ascertained, however in the present case a common chromosomal abnormality (20q deletion) was found in bone marrow and lymph node preparations. We conclude, therefore, that the co-existent de novo MDS and T-cell NHL seen in the present case may have a common origin.
ABSTRACT. We explored the correlation between serum YKL-40 levels and albuminuria in type 2 diabetes mellitus (T2DM) and its clinical significance. This study used a cross-sectional survey method. According to the American Diabetes Association 2007 Clinical Practice Recommendations, 738 patients with T2DM were divided into three groups: a normoalbuminuria group [albumin-to-creatinine ratio (ACR) <30 μg/mg, N = 360], a microalbuminuria group (ACR 30-300 μg/mg, N = 246), and a macroalbuminuria group (ACR ≥ 300 μg/mg, N = 332). The serum YKL-40 levels were determined by a quantitative sandwich enzyme-linked immunosorbent assay in all the cases and in 210 control subjects. Serum YKL-40 levels were significantly higher in the T2DM group vs the control group (P < 0.05), the macroalbuminuria group vs the microalbuminuria group (P < 0.05), and the microalbuminuria group vs the normoalbuminuria group (P < 0.05). Serum YKL-40 levels correlated with ACR in all 18597 Correlation between YKL-40 and albuminuria in T2DM ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 18596-18603 (2015) participants. Significant correlation of YKL-40 was found with ACR, 2-h plasma glucose, glycated hemoglobin, fasting blood glucose, homeostatic model assessment of insulin resistance index, systolic blood pressure, duration, diastolic blood pressure, age, triglycerides, and high-density lipoprotein cholesterol (r-values: 0.713, 0.524, 0.515, 0.467, 0.438, 0.409, 0.407, 0.374, 0.112, 0.097, and -0.123, respectively). ACR correlated with serum YKL-40 levels (Beta = 0.555, P < 0.001). YKL-40 may be involved in the occurrence and development of diabetic nephropathy and would be useful as a new marker for the disease.
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