Elevated Adenylyl Cyclase 9 Expression Is a Potential Prognostic Biomarker for Patients with Colon Cancer.

BACKGROUND Adenylyl cyclase 9 (ADCY9) is an enzyme that modulates signal transduction by producing the second messenger, cyclic adenosine monophosphate (cAMP). The aim of the present study was to investigate the association of ADCY9 expression with clinicopathological features and disease-free survival of colon cancer patients. MATERIAL AND METHODS Immunohistochemistry staining with ADCY9 antibody was performed on a tissue microarray. Immunoreactivity scores (IRS) were recorded and applied for association analysis. ADCY9 mRNA expression and clinicopathogical information were also extracted from TCGA colon cancer dataset and analyzed using univariate and multivariate Cox proportional hazards models.  RESULTS ADCY9 IRS was significantly higher (P=0.002) in tumor tissues (6.40±1.26, n=200) than in adjacent normal samples (4.13±0.83, n=8). The IRS and mRNA expression of ADCY9 were correlated to colon cancer TNM staging. Longer disease-free survival was observed in patients with lower ADCY9 expression (P=0.001). In the multivariate models, ADCY9 expression level (hazard ratio [HR] 5.495, 95% confidence interval [CI] 1.753-17.227, P=0.003), and distant metastasis (HR 4.329, 95% CI 1.374-13.636, P=0.012) were still associated with disease-free survival. CONCLUSIONS High ADCY9 expression is a poor prognostic factor for disease-free survival in colon cancer.

Salvianolic Acid B Attenuates Iopromide-Induced Renal Tubular Epithelial Cell Injury by Inhibiting the TLR4/NF-κB/NLRP3 Signaling Pathway.

Postcontrast acute kidney injury (PC-AKI) is directly caused by the use of contrast, indicating a clear causal relationship between the contrast and the injury. Salvianolic acid B (Sal B), a water-soluble compound of Salvia miltiorrhiza, has a potent anti-inflammatory effect. We conducted a study to explore whether the protective effect of Sal B on iopromide-induced injury in human proximal tubular epithelial cells (HK-2 cells) is related to inhibition of the TLR4/NF-κB/NLRP3 signal pathway. The results showed that 100 µmol/L Sal B counteracted the decrease in cell viability, the increase of ROS and the number of apoptotic cells, and the decrease of mitochondrial membrane potential (ΔΨm) induced by iopromide. Molecular docking analysis showed that Sal B binds TLR4 and NLRP3 proteins. Moreover, 100 µmol/L Sal B also decreased the expression of TLR4, NLRP3, ASC, Caspase-1, IL-18, IL-1ß, TNF-α, p-NF-κB, cleaved caspase-3, and the ratio of Bax/Bcl-2 induced by iopromide. TAK-242, a TLR4 antagonist, was added to further explore the mechanism of Sal B. However, the cotreatment group with TAK-242 and Sal B had no significant difference in cell viability and apoptosis rate compared to the treatment group with TAK-242 or Sal B alone. These results indicated that Sal B can inhibit the TLR4/NF-κB/NLRP3 signal pathway, resulting in the alleviation of iopromide-induced HK-2 cell injury.

Effects and Mechanism of Salvianolic Acid B on the Injury of Human Renal Tubular Epithelial Cells Induced by Iopromide.

With the increasing application of medical imaging contrast materials, contrast-induced nephropathy (CIN) has become the third major cause of iatrogenic renal insufficiency. CIN is defined as an absolute increase in serum creatinine levels of at least 0.50 mg/dl or an increase >25% of serum creatinine from baseline after exposure to contrast. In this study, the protective effects of salvianolic acid B (Sal B) were detected in human renal tubular epithelial cells (HK-2) exposed to iopromide. The results showed that different concentrations of Sal B counteract the loss of cell viability induced by iopromide, and reduce cell apoptosis, the reactive oxygen species (ROS) levels, and the levels of endoplasmic reticulum stress (ERS)-related and apoptosis-related proteins such as p-IRE-1α, p-eIF-2α/eIF-2α, p-JNK, CHOP, Bax/Bcl-2, and cleaved caspase-3. In addition, Sal B at a concentration of 100 µmol/L inhibited ERS and reduced cell damage to a similar extent as the ERS inhibitor 4-PBA. Importantly, treatment with Sal B could abolish the injury induced by ERS agonist tunicamycin, increasing cell viability and the mitochondrial membrane potential, as well as significantly reducing ROS levels and the expression of Bax/Bcl-2, cleaved-caspase-3, GRP78, p-eIF2α, p-JNK, and CHOP. These results suggested that the protective effect of Sal B against HK-2 cell injury induced by iopromide may be related to the inhibition of ERS.