Effect of proton pump inhibitors versus histamine-2 receptor antagonists on acute kidney injury in septic patients at high risk for developing stress ulcers.

BACKGROUND: To compare the effects of proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) use on the occurrence of acute kidney injury (AKI) in septic patients at high risk for developing stress ulcers. METHODS: Using the Medical Information Mart for Intensive Care IV version 2.2 database, septic patients with high-risk factors for stress ulcers (i.e., shock, coagulopathy, invasive mechanical ventilation, or chronic liver diseases) were included. Exposures included PPIs and H2RAs within 24 h of intensive care unit (ICU) admission or prior to ICU admission. The primary end point was severe sepsis-associated AKI as defined by the Kidney Disease Improving Global Outcomes criteria stage 3 (KDIGO-3). Propensity score matching (PSM) was performed to balance baseline characteristics. Multivariable Cox proportional hazards regression was used to estimate the effect size. RESULTS: 4731 PPI users and 4903 H2RA users were included. After PSM, there were 1785 pairs exposed to PPIs and H2RAs. In the PSM cohort, the cumulative incident KDIGO-3 rate was higher in the PPI group than in the H2RA group (log-rank test, p = 0.009). Regression analyses showed that PPI exposure [adjusted hazard ratio 1.32, 95% confidence interval (CI) 1.11-1.58, p = 0.002] was associated with incident KDIGO-3 compared with H2RA use. This association remained consistent in sensitivity analyses. Additionally, the PPI group had a higher need for kidney replacement therapy compared with the H2RA group (3.6% vs. 2.1%, P = 0.012). CONCLUSIONS: Among septic patients at high risk for developing stress ulcers, PPI exposure was associated with incident KDIGO-3 AKI compared with H2RA use.

SIRT2, a direct target of miR-212-5p, suppresses the proliferation and metastasis of colorectal cancer cells.

The aberrant expression of human sirtuin 2 (SIRT2) has been detected in various types of cancer; however, the biological roles, underlying mechanisms and clinical significance of SIRT2 dysregulation in human colorectal cancer (CRC) remain unclear. The results of this study demonstrate that compared with paired normal tissues, SIRT2 expression is significantly decreased in CRC tissues. SIRT2 loss has been correlated with clinicopathological characteristics, including distant metastasis, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage; this loss serves as an independent factor that indicates a poor prognosis for patients with CRC. Further gain- and loss-of-function analyses have demonstrated that SIRT2 suppresses CRC cell proliferation and metastasis both in vivo and in vitro. Mechanistically, miR-212-5p was identified to directly target the SIRT2 3'-untranslated region (3'-UTR), leading to SIRT2 down-regulation. The ectopic expression of SIRT2 reverses the effect of miR-212-5p overexpression on CRC cell colony formation, invasion, migration and proliferation. Clinically, an inverse correlation was found between miR-212-5p and SIRT2 expression. High miR-212-5p expression has been found to result in a poor prognosis and aggressive clinicopathological characteristics in patients with CRC. Taken together, these results suggest that SIRT2, targeted by miR-212-5p, acts as a tumour suppressor in CRC and that the miR-212-5p/SIRT2 axis is a promising prognostic factor and potential therapeutic target in CRC.

Effect of newly identified hTERT-interacting proteins on telomerase activity.

There is a close relationship between telomeres-telomerase and age-related disease. Human telomerase reverse transcriptase (hTERT) is both the catalytic component of human telomerase and the rate-limiting determinant of telomerase activity. Its transcriptional regulation is the primary mode of control of telomerase activity. It is critical to find the proteins interacting with hTERT for exploring the regulatory mechanisms of the hTERT expression and the telomerase activity. In this study, the yeast two-hybrid system was used to screen the potential interactive proteins of hTERT. Six proteins were obtained, among which T-STAR, LOXL3, HKR3, and Par-4 were further confirmed as the interacting proteins of hTERT by co-immunoprecipitation. Then the sense and antisense gene eukaryotic expression vectors containing these four genes were constructed and transfected into tumor cell lines. The correlations among the expression levels of these four proteins, the expression level of hTERT, and the telomerase activity were analyzed. Results showed that the up-regulation of T-STAR expression and down-regulation of HKR3 expression led to the increase of hTERT expression and telomerase activity, while the up- and down-regulation of LOXL3 and Par-4 expressions had no obvious effect. Our results suggested that T-STAR has a positive correlation with the telomerase activity while HKR3 may be a negative regulator. This conclusion is important to further explore the influencing factors or regulation pathways of human telomerase activity, which may be of great importance for the potential clinical application.