BackgroundDiabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown.MethodsSCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser database (https://genome-cancer.ucsc.edu/). CRC cell lines stably transfected with SCD1 shRNAs or vector were established to investigate the role of SCD1 in modulating migration and invasion of CRC cells. A glucose concentration gradient was set to investigate regulation of SCD1 in CRC relevant to diabetic conditions.ResultsThe clinical data analysis showed high expression of SCD1 in CRC tissues with a negative correlation with the prognosis of CRC. In vitro experiments revealed that SCD1 increased CRC progression through promoting epithelial–mesenchymal transition (EMT). Lipidomic analysis demonstrated that SCD1 increased MUFA levels and MUFA administration could rescue migration and invasion defect of CRC cells induced by SCD1 knockdown. Furthermore, SCD1-mediated progression of CRC was promoted by carbohydrate response-element binding protein (ChREBP) in response to high glucose. Mechanistically, hyperglycemia-SCD1-MUFA induced CRC cell migration and invasion by regulating PTEN.ConclusionsOur findings show that SCD1 promotes metastasis of CRC cells through MUFA production and suppressing PTEN in response to glucose, which may be a novel mechanism for diabetes-induced CRC metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0711-9) contains supplementary material, which is available to authorized users.

Background and objectives The notion that oral intestinal sorbent AST-120 slows renal disease progression has not been evaluated thoroughly. In this study, we investigated the long-term effect of AST-120 on renal disease progression (doubling of serum creatinine, eGFR decrease .50%, or initiation of RRT) in patients with advanced CKD.Design, setting, participants, & measurements We prospectively recruited 579 patients (CKD stage 3 or 4) from 11 medical centers in Korea from March 4, 2009 to August 31, 2010 and randomized them into an AST-120 arm and a control arm. Patients in the AST-120 arm were given 6 g AST-120 in three divided doses per day, and those in the control arm received only standard conventional treatment (open-label design) for 36 months or until the occurrence of primary outcomes.Results Levels of serum and urine indoxyl sulfate and b2-microglobulin decreased throughout the study period in both treatment arms; however, there was not a significant difference in change in uremic toxins in the AST-120 and control arms. The two arms were not different in the occurrence of composite primary outcomes (100 events in 272 individuals in the AST-120 arm and 100 events in 266 individuals in the control arm; hazard ratio, 1.12; 95% confidence interval, 0.85 to 1.48; log-rank P=0.45). The decline in eGFR and change in proteinuria were similar in the two treatment arms over time (P randomization-time =0.64 and P randomization-time =0.16, respectively). There was no difference in mortality (nine deaths in the AST-120 arm and 11 deaths in the control arm; log-rank P=0.73) or unplanned hospitalizations (102 in the AST-120 arm and 109 in the control arm; log-rank P=0.76) in the two treatment arms. There was no significant difference of the health-related quality of life score between the two arms.Conclusions Long-term use of AST-120 added to standard treatment did not change renal disease progression, proteinuria, mortality, and health-related quality of life in patients with advanced renal dysfunction.

BackgroundWe investigated the long-term effect of AST-120, which has been proposed as a therapeutic option against renal disease progression, in patients with advanced chronic kidney disease (CKD).MethodsWe performed post-hoc analysis with a per-protocol group of the K-STAR study (Kremezin study against renal disease progression in Korea) that randomized participants into an AST-120 and a control arm. Patients in the AST-120 arm were given 6 g of AST-120 in three divided doses, and those in both arms received standard conventional treatment.ResultsThe two arms did not differ significantly in the occurrence of composite primary outcomes (log-rank P = 0.41). For AST-120 patients with higher compliance, there were fewer composite primary outcomes: intermediate tertile hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.38 to 1.01, P = 0.05; highest tertile HR 0.436, 95% CI 0.25 to 0.76, P = 0.003. The estimated glomerular filtration rate level was more stable in the AST-120 arm, especially in diabetic patients. At one year, the AST-120-induced decrease in the serum indoxyl sulfate concentration inversely correlated with the occurrence of composite primary outcomes: second tertile HR 1.59, 95% CI 0.82 to 3.07, P = 0.17; third tertile HR 2.11, 95% CI 1.07 to 4.17, P = 0.031. Furthermore, AST-120 showed a protective effect against the major cardiovascular adverse events (HR 0.51, 95% CI 0.26 to 0.99, P = 0.046).ConclusionLong-term use of AST-120 has potential for renal protection, especially in diabetic patients, as well as cardiovascular benefits. Reduction of the serum indoxyl sulfate level may be used to identify patients who would benefit from AST-120 administration.

Endothelial cell damage and impaired angiogenesis substantially contribute to the progression of chronic renal failure (CRF). The effect of endothelial progenitor cell (EPC) treatment on the progression of CRF is yet to be determined. We performed 5/6 nephrectomy to induce CRF in C57BL/6 mice. EPCs were isolated from bone marrow, grown in conditioned medium, and characterized with surface marker analysis. The serial changes in kidney function and histological features were scrutinized in CRF mice and EPC-treated CRF (EPC-CRF) mice. Adoptively transferred EPCs were present at the glomeruli and the tubulointerstitial area until week 8 after transfer. In CRF mice, renal function deteriorated steadily over time, whereas the EPC-CRF group showed less deterioration of renal function as well as reduced proteinuria along with a relatively preserved kidney structure. Renal expression of proinflammatory cytokines and adhesion molecules was already decreased in the EPC-CRF group at the early stage of disease, at which point the renal function and histology of CRF and EPC-CRF mice were not different. Angiogenic molecules including VEGF, KDR, and thrombospondin-1, which were decreased in the CRF group, were restored by EPC treatment. In conclusion, EPCs trafficked into the injured kidney protected the kidney from the inflammatory condition and consequently resulted in functional and structural renal preservation. Our study suggests EPCs as a potential candidate for a novel therapeutic approach in CRF.