High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In vivo Compared with Monotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in Vitro and in vivo. MATERIALS AND METHODS: We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of 5×105 U87 cells and treatedwith metformin, TMZ, and the combination for 4weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway. RESULTS: The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ. CONCLUSION: The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in Vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.

Erratum: Age-related Changes in the Sirtuin1-NFE2-related Factor 2 Signaling System in the Kidney / 대한내과학회지

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Age-related Changes in the Sirtuin1-NFE2-related Factor 2 Signaling System in the Kidney / 대한내과학회지

BACKGROUND/AIMS: Renal aging-related changes are characterized by oxidative stress. SIRT1 regulates cellular conditions by activating Nrf2. The present study investigated the processes of renal changes by antioxidant enzymes and the relationship between SIRT1 and Nrf2. METHODS: We used male 2-, 12-, and 24-month-old C57BL/6 mice. We measured renal function, histological changes, oxidative stress, and expression of SIRT1–Nrf2 signaling in the kidneys. RESULTS: 24-month-old mice exhibited increased albuminuria and serum creatinine. Creatinine clearance was decreased in 24-month-old mice compared with 12-month-old mice. There were increases in mesangial volume and tubulointerstitial fibrosis in 24-month-old mice. Moreover, oxidative stress marker, 3-Nitrotyrosine, expression and apoptosis were increased in 24-month-old mice. The 24 h urinary 8-isoprostane and 8-hydroxy-deoxyguanosine excretion increased with aging. The levels of expression of SIRT1 and nuclear Nrf2 were decreased in 24-month-old mice. The antioxidant enzymes HO-1 and NQO-1 were down-regulated in 24-month-old mice. Another antioxidant enzyme, SOD2, was decreased in 24-month-old mice. CONCLUSIONS: Our results demonstrated that SIRT1 was down-regulated with aging, and this may be related to changes in the expression of target molecules including Nrf2. As a result, oxidative stress was induced. The pharmacological targeting of these signaling molecules may reduce the pathological changes associated with aging in the kidney.

Post-exposure Prophylaxis against Varicella Zoster Virus in Hospitalized Children after Inadvertent Exposure

PURPOSE: This study described the post-exposure prophylaxis (PEP) and secondary varicella infection in children inadvertently exposed to varicella zoster virus (VZV) in the hospital. METHODS: We retrospectively analyzed data from patients with VZV infection who were initially not properly isolated, as well as children exposed to VZV at the Seoul National University Children's Hospital between January 2010 and December 2015. The PEP measures were determined by the presence of immunity to VZV and immunocompromising conditions. Patient clinical information was reviewed via medical records. RESULTS: Among 147 children hospitalized between 2010 and 2015, 13 inadvertent exposures were notified due to VZV infection. Five index children had a history of VZV vaccination. Eighty-six children were exposed in multi-occupancy rooms and 62.8% (54/86) were immune to VZV. The PEP measures administered to 27 exposed patients included varicella zoster immunoglobulin and VZV vaccination. Four children developed secondary varicella, which was linked to a single index patient, including one child who did not receive PEP and three of the 27 children who received PEP. The rates of secondary varicella and prophylaxis failure were 4.7% (4/85) and 11.1% (3/27), respectively. The secondary varicella rates were 1.9% (1/54) and 9.7% (3/31) among immunocompetent and immunocompromised children, respectively. CONCLUSIONS: Delayed diagnosis of VZV infection can lead to unexpected exposure and place susceptible children and immunocompromised patients at risk for developing varicella. The appropriateness of the current PEP strategy based on VZV immunity may require re-evaluation.

Regulator of Calcineurin 1 Isoform 4 (RCAN1.4) Is Overexpressed in the Glomeruli of Diabetic Mice

Calcineurin (CaN) is activated in diabetes and plays a role in glomerular hypertrophy and extracellular matrix (ECM) accumulation. Here, kidneys from diabetic model mice were investigated for the expression of the regulator of CaN 1 (RCAN1) isoform 4 (RCAN1.4) which had been shown to be transcriptionally upregulated by CaN activation. We found the increased immunoreactivity for RCAN1 in the glomerular cells of db/db mice and streptozotocin-induced diabetic mice. In concordance, the expression of RCAN1 protein and RCAN1.4 mRNA were elevated in the whole kidney sample from db/db mice. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and glycated albumin (AGE-BSA) were identified as inducers of RCAN1.4 in mesangial cells. Pretreatment of cyclosporine A blocked the increases of RCAN1.4 stimulated by IL-1beta or AGE-BSA, suggesting that activation of CaN is required for the RCAN1.4 induction. Stable transfection of RCAN1.4 in Mes-13 mesangial cells upregulated several factors relevant to ECM production and degradation. These results suggested that RCAN1.4 might act as a link between CaN activation and ECM turnover in diabetic nephropathy.