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Although bevacizumab (Avastin&reg, ) has been approved as an antiangiogenic agent against some cancers, the efficacy is transient and unsatisfactory in other cancers most likely owing to the presence of alternative proangiogenic factors. Therefore, simultaneous blocking of several proangiogenic factors may be a promising strategy for antiangiogenic cancer therapeutics. Accordingly, neuropilin-1 (NRP1) is an attractive target because it serves as a multifunctional receptor for the vascular endothelial growth factor (VEGF) family. Here, we aimed to generate and test an anti-VEGFA and anti-NRP1 dual-targeting bispecific antibody (named as IDB0076) by genetic fusion of an NRP1-targeting peptide to the C-terminus of the bevacizumab heavy chain. Similar to the parental antibody (bevacizumab), IDB0076 suppressed VEGFA-induced migration of human endothelial cells. In contrast, IDB0076 inhibited endothelial-cell migration induced by other angiogenesis growth factors and manifested a more potent antitumor activity than that of bevacizumab in a murine tumor xenograft model. When toxicity was preliminarily evaluated in cynomolgus monkeys, IDB0076 showed no substantial adverse effects, e.g., the absence of noticeable nephrotoxicity, which has previously been documented for the combination therapy of bevacizumab and an anti-NRP1 antibody. Thus, VEGFA-and-NRP1 dual-targeting bispecific antibody IDB0076 may be a potent and safe anticancer agent worthy of further preclinical and clinical studies.

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.

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.