Background/Aims: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. Methods: In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. Results: CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. Conclusion: Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.
Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin–angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.
Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using Sult1a1-deficient (Sult1a1-/- KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in Sult1a1-/- (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in Sult1a1-/- (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress.
The current chemotherapy has been able to give us many options to treat for lung cancer and recent studies have showed that perioperative chemotherapy may improve survival. In this study, we compared 2 groups with locally advanced lung cancers (stage III, T3N0M0, inclusive of ipsilateral PM2, D1 and D2) ; group A, which had been treated by chemotherapy for downstaging prior to surgery (n = 23), and group B, which had been treated by surgery alone (n = 48). The postoperative 3- and 5-year overall survival rates analyzed using the Kaplan-Meier method were 64.7 and 29.4% for group A, 32.5 and 10% for group B, respectively. And there was a significant difference between 2 groups. Further on patients with pN2, 3-year survival rate was 60% for group A and 36.7% for group B. In view of the progress of chemotherapy, even if the locally advanced lung cancer, which may be suspected of invasion to pulmonary artery, pulmonary vein and central bronchus, is not classified as T4, a patient with it should be performed an induction chemotherapy for downstaging and an operation for complete resection of the tumor and preserving lung function.
The vitamin B12 (B12) content in seven species of seaweed that are consumed frequently in Hokkaido, Japan, was microbiologically measured using Escherichia coil 215. Asakusanori (Porphyra tenera), maruba-amanori (Porphyra suborbiculata) and akaba-gin-nansou (Rhodogtossum pulcherum) showed higher B12 content than the other species, although the content varied greatly among samples in the same species. A bioautography on a thin-layer plate holding a mixture of silica gel and cellulose, differentiation of B12 and its analogues using a binding specificity of intrinsic factor and haptocorrin, and comparison of the B12 concentra tion determined by the radioisotope dilution assay method using the intrinsic factor as the B12-binding protein with that by the bioassay method, predominantly showed B12 in maruba-amanori and B12 analogues in wakame (Undaria pinnatifida) and akaba-gin-nansou. The B12 uptake of akaba-gin-nansou from artificial seawater was similar to that of asaku sanori that contained only B12.
【INTRODUCTION】Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer. Since TNBC exhibits a significantly lower 5-year survival rate than other subtypes, development of novel therapeutic strategies for TNBC is urgently needed. Tumor suppressor gene Cylindromatosis (CYLD) is associated with acquisition of malignant traits in various malignant tumors as a negative regulator for intracellular signals, such as nuclear factor-κB (NF-κB) signaling. The aim of this study was to clarify the clinical and biological significance of reduced CYLD expression in TNBC and to explore novel pharmacotherapy CYLD-negative poor-prognosis TNBC patients.
Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis.
