Interleukin-17E (IL-17E) belongs to a novel family of cytokines that possess significant homology to IL-17. IL-17E has potent inflammatory effects in vitro and in vivo. Overexpression of IL-17E in mice results in a T helper-2 (Th2)-type immune response, which includes the expansion of eosinophils through the production of IL-5, and elevated gene expression of IL-4 and IL-13 in multiple tissues. In this study, we show that IL-17E has antitumor activity in vivo, a previously unrecognized function of IL-17E. Antitumor efficacy of IL-17E was examined in a variety of human tumor xenograft models, including melanoma, breast, lung, colon, and pancreatic cancers. Injection of recombinant IL-17E every other day resulted in significant antitumor activity in these tumor models. In addition, the combination of IL-17E with chemotherapy or immunotherapy agents showed an enhanced antitumor efficacy in human tumor xenograft models in mice as compared to either agent alone. Antitumor activity was demonstrated using different routes of administration, including intraperitoneal, intravenous, and subcutaneous injection. Anticancer activity was shown for both mouse and human forms of IL-17E, which have a high degree of sequence identity. Tumor-bearing mice treated with IL-17E showed a significant increase in serum levels of IL-5 and increased numbers of eosinophils in peripheral blood compared to the control group. Spleens isolated from IL-17E-treated mice showed a significant increase in eosinophils that correlated with antitumor activity of IL-17E in a dose-response manner. Finally, we demonstrate that B cells are necessary for IL-17E-mediated antitumor activity and that IL-17E was found to activate signaling pathways in B cells in vitro. Taken together, these data demonstrate that IL-17E has antitumor activity in vivo, and support further investigation of the potential clinical use of IL-17E as an anticancer agent.

No abstract

Dehydrocorydaline (DHC) is an alkaloidal component isolated from Rhizoma corydalis. Previous studies have shown that DHC has anti-inflammatory and anti-tumor effects and that it can protect the cardiovascular system. However, there are few studies of the antinociceptive effects of DHC in vivo. This study explored the antinociceptive effects and possible mechanisms of DHC in mice using two inflammatory pain models: the acetic acid-induced writhing test and the formalin paw test. The intraperitoneal administration of DHC (3.6, 6 or 10 mg/kg) showed a dose-dependent antinociceptive effect in the acetic acid-induced writhing test and significantly attenuated the formalin-induced pain responses in mice. The antinociceptive effects of DHC were not associated with changes in the locomotor activity or motor responses of animals, and no obvious acute or chronic toxic effects were observed in the mice. Furthermore, the use of naloxone confirmed the involvement of the opioid receptor in the central antinociceptive effects of DHC. DHC reduced formalin-induced paw edema, which indicated that DHC may produce an anti-inflammatory effect in the periphery. In the formalin test, DHC decreased the expression of caspase 6 (CASP6), TNF-α, IL-1β and IL-6 proteins in the spinal cord. These findings confirm that DHC has antinociceptive effects in mice.

BackgroundExperimental and clinical studies showed that intraoperative infusionof remifentanil has been associated with postoperative hyperalgesia. Previous reports suggested that spinal N-methyl-D-aspartate (NMDA) receptors may contribute to the development and maintenance of opioid-induced hyperalgesia. In the present study, we used a rat model of postoperative pain to investigate the role of tyrosine phosphorylation of NMDA receptor 2B (NR2B) subunit in spinal cord in the postoperative hyperalgesia induced by remifentanil and the intervention of pretreatment with ketamine.ResultsIntraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by the plantar incision during the postoperative period (each lasting between 2 h and 48 h), which was attenuated by pretreatment with ketamine (10 mg/kg, subcutaneous). Correlated with the pain behavior changes, immunocytochemical and western blotting experiments in our study revealed that there was a marked increase in NR2B phosphorylation at Tyr1472 in the superficial dorsal horn after intraoperative infusion of remifentanil, which was attenuated by pretreatment with ketamine.ConclusionsThis study provides direct evidence that tyrosine phosphorylation of the NR2B at Tyr1472 in spinal dosal horn contributes to postoperative hyperalgesia induced by remifentanil and supports the potential therapeutic value of ketamine for improving postoperative hyperalgesia induced by remifentanil.

Cancer pain is one kind of the most common and severe kinds of chronic pain. No breakthrough regarding the mechanisms and therapeutics of cancer pains has yet been achieved. Based on the well established involvement of the NMDA (N-methyl-D-aspartate) receptor containing NR2B in inflammatory pain and neuropathic pain and the effective pain relief obtained with ketamine in cancer patients with intractable pain, we supposed that NR2B in the spinal cord was an important factor for cancer pain. In this study, we investigated the possible role of NR2B in the spinal cord using a murine model of bone cancer pain. C3H/HeJ mice were inoculated into the intramedullary space of the right femur with Osteosarcoma NCTC 2472 cells to induce ongoing bone cancer-related pain behaviors. At day 14 after operation, the expression of NR2B mRNA and NR2B protein in the spinal cord were higher in tumor-bearing mice compared to the sham mice. Intrathecal administration of 5 and 10 microg of NR2B subunit-specific NMDA receptor antagonist ifenprodil attenuated cancer-evoked spontaneous pain, thermal hyperalgesia and mechanical allodynia. These results suggest that NR2B in the spinal cord may participate in bone cancer pain in mice, and ifenprodil may be a useful alternative or adjunct therapy for bone cancer pain. The findings may lead to novel strategies for the treatment of bone cancer pain.

Background-Repair of muscular ventricular septal defects (MVSDs) has always been challenging to the surgeon.Long-term morbidity and mortality are significantly increased if the defects are closed via left ventriculotomy or if they are associated with other complex congenital anomalies. The purpose of this study was to close MVSDs with the Amplatz ventricular septal defect device. This device is constructed from 0.004-in nitinol wire mesh filled with polyester fibers. It is retrievable, repositionable, self-centering, and of low profile. Methods and Results-MVSDs were created with the help of a sharp punch in 10 dogs. The location of the defects was anterior muscular (nϭ3), midmuscular (nϭ3), apical (nϭ3), and inlet muscular (nϭ1). The diameter of the defects ranged from 6 to 14 mm. All defects were closed in the catheterization laboratory. The device was placed with the help of transesophageal echocardiography and fluoroscopy. A 7F sheath was used to deploy the device from the right ventricular side in 8 and the left ventricular side in 2 dogs. Placement was successful in all animals. The complete closure rate was 30% (3/10) immediately after placement and 100% at 1-week follow-up. Pathological examination of the heart revealed complete endothelialization of the device in dogs killed after 3 months. Conclusions-The Amplatz ventricular septal defect device appears highly efficacious in closing MVSDs. The advantages include a small delivery sheath, complete retrievability before release, and the fact that it is self-centering and self-expanding, thereby making it an attractive option in smaller children. (Circulation. 1999;100:320-328.)

De novo synthesis of contact female sex pheromone and hydrocarbons in Blattella germanica was examined using short in vivo incubations. Accumulation of pheromone on the epicuticular surface and the internal pheromone titer were related to age-specific changes in hydrocarbon synthesis and accumulation in normal and allatectomized females. The incorporation of radiolabel from [1-14C]propionate into the cuticular methyl ketone pheromone fraction was positively related to corpora allata activity during two gonotrophic cycles. During peak pheromone production the total internal lipid fraction contained greater titers of pheromone than the cuticular surface, and it too exhibited a cycle internally, preceding the rise in external pheromone. This suggests that synthesis and accumulation of pheromone internally are followed by transport of pheromone to the epicuticular surface where it accumulates. Radiolabel was incorporated efficiently into both cuticular and internal hydrocarbons after the imaginal molt and until the peak of pheromone synthesis, but it declined to lower levels before ovulation and throughout pregnancy. The internal hydrocarbon titer decreased 58% after oviposition, suggesting deposition in the egg case. It remained relatively unchanged during pregnancy and increased again during the second gonotrophic cycle. In allatectomized females, hydrocarbon synthesis was reduced relative to control females until oviposition in the latter. However, subsequent rates of hydrocarbon synthesis in allatectomized females (without oothecae) exceeded the rates in sham-operated females (with oothecae). In the absence of ovarian uptake of hydrocarbons, the internal titer increased without the decline found in control females at oviposition. As internal hydrocarbons increased, so did cuticular hydrocarbons and both internal and cuticular methyl ketone pheromones. These patterns corresponded well with feeding patterns in sham-operated and allatectomized females, suggesting that pheromone production is normally regulated by stage-specific feeding-induced hydrocarbon synthesis (precursor accumulation internally) and juvenile hormone-induced conversion of hydrocarbon to pheromone. They also suggest that both the cuticle and the ovaries might be target sites for hydrocarbon and possibly methyl ketone deposition.

Effective and permanent occlusion of secundum ASDs is feasible with a device that offers the advantages of easy placement, self-centering, and repositionability.