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Purpose Repeated administration of anti–vascular endothelial growth factor drugs to treat age-related macular degeneration leads to resistance. To overcome this drawback, we developed the novel recombinant dual-targeting antibody fragment IDB0062, which is comprised of the anti–vascular endothelial growth factor A Fab and neuropilin 1-targeting peptide, and we assessed its properties. Methods We compared the in vitro activity of IDB0062 and conventional drugs using cell proliferation, wound healing, and Transwell assays. The in vivo efficacy of IDB0062 was determined using mouse choroidal neovascularization and oxygen-induced retinopathy models. To evaluate the ocular distribution of IDB0062, we intravitreally administered IDB0062 and ranibizumab to cynomolgus monkeys and measured the retinal drug levels. Results IDB0062 effectively inhibited not only vascular endothelial growth factor A in vitro but also placenta growth factor 2, vascular endothelial growth factor B, and platelet-derived growth factor BB, which induce vascular endothelial growth factor A–independent angiogenesis. In addition, IDB0062 showed non-inferior efficacy compared with aflibercept in vivo despite the low selectivity for mouse vascular endothelial growth factor A. In the monkey intravitreal pharmacokinetic study, IDB0062 improved drug distribution in the retina compared with ranibizumab, confirming the accelerated onset of pharmacological action when IDB0062 is injected in the vitreous humor. Conclusions Through neuropilin 1 binding, IDB0062 can improve the efficacy and accelerate the onset of pharmacological action in the posterior segment, which is targeted for macular degeneration, thereby improving drug responsiveness in drug-resistant patients. Translational Relevance Considering its novel mechanism of action, IDB0062 may help in controlling resistance to conventional anti–vascular endothelial growth factor drugs in clinical settings.

The rhizome of Polygonatum sibiricum Redoute (Liliaceae) has long been used to treat diabetes-associated complications. However, the pharmacological mechanism of P. sibiricum on metabolic disorders is not clear.This study investigates the effect of an ethanol extract of P. sibiricum rhizomes (designated ID1216) on obesity conditions including weight loss in high-fat (HF) diet-fed mice and explores the potential underlying mechanisms.To identify the metabolic impact of the P. sibiricum rhizome extract, HF diet-fed mice were administered ID1216 orally at doses of 250 and 1000 mg/kg/d for 10 weeks, and various factors related to metabolic syndrome were analyzed. We also examined the effects of ID1216 on the expression of genes involved in adipogenesis and lipolysis in 3T3-L1 cells, as well as genes associated with energy homeostasis in C2C12 myocytes.ID1216 administration led to significant decreases in body weight gain (37.5%), lipid accumulation in adipose tissues (52.8%), and the levels of plasma triglycerides (26.4%) and free fatty acids (28.1%) at a dose of 250 mg/kg/d, compared with the vehicle-treated group, as well as improved insulin resistance. In addition, ID1216 was found to regulate the expression of genes related to adipogenesis and fatty acid oxidation in 3T3-L1 cells and enhance the expression of genes that modulate energy homeostasis in C2C12 myocytes.ID1216 may be a promising therapeutic agent for improving obesity conditions through the sirtuin-1 and peroxisome proliferator-activated receptor γ coactivator-1α pathway.

The silkworm (Bombyx mori L.) droppings were extracted with 80% aqueous MeOH, and the concentrated extract was partitioned in succession with EtOAc, n-BuOH, and H(2)O. From the EtOAc fraction, five megastigmane sesquiterpenes were isolated through repeated silica gel and ODS column chromatography. According to the results of spectroscopic data, such as NMR, MS, and IR, the chemical structures of the isolated compounds were determined as (3S,5R,8R)-3,5-dihydroxymegastigma-6,7-dien-9-one (1), (S)-dehydrovomifoliol (2), (6R,7E,9R) -9-hydroxy-4,7-megastigmadien-3-one (3), (3S,5R,6S,7E)-3,5,6-trihydroxy-7-megastigmen-9-one (4), (6R,9R)-9-hydroxy-4-megastigmen-3-one (5). Compounds 2 through 5 were isolated for the first time from silkworm droppings. GC/MS analysis indicated silkworm powder contained compound 3, and mulberry leaves contained compound 4. Compounds 1 and 5 increased the expression of heme oxygenase-1 and SIRT1 in HepG2 and HEK239 cells, respectively. Heme oxygenase-1 is considered to be an antioxidant enzyme that catabolizes heme to carbon monoxide, free iron and biliverdin, while SIRT1 is the mammalian homologue of the yeast silent information regulator (Sir)-2, which are involved in the suppression of inflammatory mediators or factors that may be used to improve atopy-related symptoms.

A series of 5-arylamino-6-chloro-1H-indazole-4,7-diones were synthesized and evaluated for their inhibitory activity on protein kinase B/Akt. The compounds exhibited a potent Akt1 inhibitory activity. Further mechanistic study revealed that they might have dual inhibitory effects on both activity and phosphorylation of Akt1 in PC-3 tumor cell line.

Recent advances in childhood cancer treatment have increased survival rates to 80%. Two out of three survivors experience late effects (LEs). From a group of 241 survivors previously described, 193 were followed at the long-term follow-up clinic (LTFC) of Severance Hospital in Korea; the presence of LEs was confirmed by oncologists. We reported the change in LEs during 3 yr of follow-up. The median follow-up from diagnosis was 10.4 yr (5.1-26.2 yr). Among 193 survivors, the percentage of patients with at least one LE increased from 63.2% at the initial visit to 75.1% at the most recent visit (P = 0.011). The proportion of patients having multiple LEs and grade 2 or higher LEs increased from the initial visit (P = 0.001 respectively). Forty-eight non-responders to the LTFC were older and had less frequent and severe LEs than responders at initial visit (all P < 0.05). In multivariate analysis, younger age at diagnosis, older age at initial visit, a diagnosis of a brain tumor or lymphoma, and use of radiotherapy were significant risk factors for LEs (all P < 0.05). Adverse changes in LEs were seen among the survivors, regardless of most clinical risk factors. They need to receive comprehensive, long-term follow up.

Invasive fungal infections are a major cause of morbidity and mortality for childhood patients who underwent stem cell transplantations. Patients who underwent SCT have varying degree of gastrointestinal complications. In this study, invasive fungal infection prophylaxis with intravenous itraconazole (ITR) administration to pediatric patients with SCT was performed in order to evaluate effectiveness and safety. Prospective examination was performed between jan. 2006 and Feb. 2007. Total 30 patients were enrolled. Patient group was divided into autologous and allogenic transplantation due to cyclosporin-A (CsA) use in allogenic transplantation courses. ITR (2.5mg/kg/dose) was administered twice daily from D+1 to D+2. After D+2, once daily administration of ITR (2.5mg/kg/dose) was performed until D+16. Each group constitutes with 15 patients. Sampling was performed after 48 hours after initial administration of ITR. Sampling times were as follows: D+3 (0hr), D+4 (8hr, 19hr, 21hr, 24hr) after infusion of ITR administration for drug level change monitoring, and trough level monitoring for ITR at D+6, D+8, D+11, D+15, D+16. Blood plasma ITR and hydroxyl-itraconazole (OH-ITR) were measured by HPLC technique. CsA level also measured concomittantly. Any evidences for fungal infection, liver and kidney dysfunction were monitored. Mean trough concentrations of ITR were greater than prophylactic level (250 ng/mL), except 1st time (D+3, 0hr) level as 243.39 ± 172.19 in allogenic transplant group (figure). ITR and OH-ITR level were highter in autologous than allogenic group at D+4, 8hr (figure). Trough levels of ITR and OH-ITR for both allogenic and autologous group were not different statistically (figure). Trough level of CsA was 189.9 ± 43.9 ng/mL. Average reduction rate of CsA was 69% (30%–100%, no case for increasing dose) from starting dose. Figure. Itraconazole (A) and hydroxy-itraconazole (B) plasma levels in pediatric stem cell transplantation recipients. Figure One case of mortality due to sepsis (not due to fungal infection) was reported in allogenic transplantation group. No case of proven fungal infection during study period. There are no renal toxicities greater than grade I. Five patients of autologous transplantation group had liver toxicity more than grade I but no more than grade III. Allogenic transplantation group patients showed only 2 patients with liver toxicity of grade I. Prophylactic intravenous ITR for childhood stem cell transplant recipients showed stable trough levels for both autologous and allogenic transplantation conditions with acceptable toxicities. After achievement of trough level, drug level change showed that 8 hour level after infusion of ITR (maintain once daily dose) revealed most high level. CsA level showed stable, but dose should reduce to 69% of original amount. CsA level should be carefully monotored in case of concomittant use of ITR. Figure . / One case of mortality due to sepsis (not due to fungal infection) was reported in allogenic transplantation group. No case of proven fungal infection during study period. There are no renal toxicities greater than grade I. Five patients of autologous transplantation group had liver toxicity more than grade I but no more than grade III. Allogenic transplantation group patients showed only 2 patients with liver toxicity of grade I. Prophylactic intravenous ITR for childhood stem cell transplant recipients showed stable trough levels for both autologous and allogenic transplantation conditions with acceptable toxicities. After achievement of trough level, drug level change showed that 8 hour level after infusion of ITR (maintain once daily dose) revealed most high level. CsA level showed stable, but dose should reduce to 69% of original amount. CsA level should be carefully monotored in case of concomittant use of ITR.