Although reactive oxygen species (ROS) has been established as important signaling molecules in transforming growth factor-beta1 (TGF-β1)-mediated apoptosis, its underlying molecular mechanisms are not well understood. Here, we demonstrate that TGF-β1 induces apoptotic cell death through decreasing the expression and activity of glutaredoxin (Grx), a thiol antioxidant enzyme, in hepatoma cells. Down-regulation of Grx by TGF-β1 was highly dependent on Smad3, a major TGF-β signaling transducer. Western blot analysis and chromatin immunoprecipitation (ChIP) assay revealed that endogenous Smad3 physically interacts with histone deacetylase 1 (HDAC1) and its co-repressor, mSin3A in response to TGF-β1 stimulation and this complex binds to Grx1 promoter region -1872/-1662 bp containing two CAGA boxes. Deletion or mutation of these sites abolished binding of Smad3 to Grx1 promoter and subsequent down-regulation of Grx1 promoter activity in TGF-β1-stimulated hepatoma cells. Notably, hepatoma cells which stably express hepatitis B virus X (HBx) displayed increased Grx activity and level of Grx protein, and showed resistance to TGF-β1-induced apoptosis. Importantly, HBx inhibited binding of Smad3 to Grx1 promoter by inducing phosphoprylation of serine 208 in linker region of Smad3. Expression of a mutant Smad3 in which linker phosphorylation sites were ablated caused a marked attenuation in inhibition by HBx of TGF-β1-induced apoptosis. Finally, elevated levels of Grx and phosphorylated Smad3 at linker regions were observed in the hepatocellular carcinoma (HCC) tissues compared to normal tissues. Taken together, these findings suggest that Smad3 is a transcriptional repressor of Grx and increased Smad3 phosphorylation at linker regions in HCC may intercept the tumor suppressor function of TGF-β through transcriptional activation of Grx, thereby providing new mechanistic insight into the development of anti-cancer drug-resistant HCC. This work was supported by the “Human Resource Development Center for Economic Region Leading Industry” Project, the Ministry of Education, Science & Technology (MEST), and the National Research Foundation of Korea (NRF). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2011-4766

The present study investigated the microbial etiologies and clinical impact of extended-spectrum β-lactamase (ESBL)-producing bacteria according to urine and blood cultures from patients with acute pyelonephritis (APN). Data of all patients (age >15 years) who had been hospitalized at a single hospital with APN were collected between January, 2010 and December, 2018. Overall, 882 patients with APN were included. Patients were divided into an ESBL-producing and non-ESBL-producing group. In addition, each group was further stratified in accordance with positive ESBL cultures from a urine sample (U-ESBL group and U-non-ESBL group) or from either blood or urine samples (UB-ESBL group and UB-non-ESBL group). In 651 (74%) of these cases, bacteria were isolated from either urine or blood samples. The prevalence of ESBL-producing bacteria from either urine or blood samples (UB-ESBL) was found to steadily increase over the 9-year study period from 6.3 to 37.8%. The male sex [odds ratio (OR), 2.572; 95% confidence interval (CI), 1.295-5.108] and previous antibiotic exposure (OR, 2.275; 95% CI, 1.105-4.680) were significant risk factors for UB-ESBL in the multivariable analysis. The patients in the UB-ESBL group exhibited a significantly higher mortality rate (OR, 1.654; 95% CI, 1.106-2.474) and a higher continuous renal replacement therapy (CRRT) rate. By multivariable analysis, UB-ESBL and not U-ESBL was an independent prognostic indicator for mortality and recurrence. Consequently, the use of carbapenems as a first-line therapy for APN is expected to rapidly increase, and there is concern regarding the emergence of new antibiotic-resistance bacteria. Global efforts to reduce resistance bacteria and the development of novel treatment methods other than the use of antibiotics to treat bacteria are urgently required. In addition, the results of the present study emphasize the importance of blood culture tests, as well as urine culture tests for the successful treatment of APN.