Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2.

Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic beta-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/- mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/- mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/- islets. These results suggest that ASC-2 regulates insulin secretion and beta-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

Effect of epidermal growth factor against radiotherapy-induced oral mucositis in rats.

PURPOSE: We tested the efficacy of oral recombinant human epidermal growth factor (rhEGF) against radiation-induced oral mucositis in a rat model. METHODS AND MATERIALS: Each of 35 Sprague-Dawley rats, 7 to 8 weeks of age and weighing 178 +/- 5 grams, was irradiated once in the head region with 25 Gy, using a 4-MV therapeutic linear accelerator at a rate of 2 Gy/min. The irradiated rats were randomly divided into four groups: those receiving no treatment (Group 1), those treated with vehicle only three times per day (Group 2), and those treated with 50 microg/mL (Group 3), or 100 microg/mL (Group 4) rhEGF three times per day. RESULTS: Rats were monitored for survival rate and daily activity, including hair loss, sensitivity, and anorexia. We found that survival rate and oral intake were significantly increased and histologic changes were significantly decreased in the rhEGF-treated rats. There was no difference, however, between rats treated with 50 microg/mL or 100 microg/mL rhEGF. CONCLUSION: These findings suggest that orally administered rhEGF decreased radiation-induced oral mucositis in rats.

Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers.

This paper studies the healing effect of recombinant human epidermal growth factor (EGF) on chronic diabetic foot ulcers. A total of 89 patients (65 male and 24 female) aged from 36 to 82 years (average of 54) enrolled for the prospective, open-label trial, crossover study. Predetermined criteria were used for diagnosis and classification of ulcer. The average duration of ulcer was 6 months (range from 3 to 27 months) prior to study. Upon study, the ulcers were debrided and treated with hydrocolloid or composite dressing depending on the condition of the wound. If treatment effect was minimal using advanced dressing for 3 weeks, patients were crossed over to twice-a-day treatment with 0.005% EGF and advanced dressing. Among the patients, 21 patients showed improvement using hydrocolloid or composite dressing alone and 68 patients were crossed over to treatment with EGF and advanced dressing. In the EGF-treated patients, complete healing was noted in 52 patients within an average of 46 days (range from 2 to 14 weeks). Recurrence was not noted during the 6-month observation. But 5 patients showed new lesions different from the prior site. Sixteen patients required further interventions. This paper suggests that topical treatment with EGF combined with advanced dressing may have positive effects in promoting healing of chronic diabetic foot wounds.

The effect of various concentrations of human recombinant epidermal growth factor on split-thickness skin wounds.

Epidermal growth factor (EGF) is a potent stimulant of epithelialisation. However, topical application of EGF to achieve facilitated re-epithelialisation in partial thickness wounds has been controversial. A total of 10 pigs, each with eight 4 x 4 cm partial thickness wounds, were treated twice a day for 10 days to observe the effect of human recombinant EGF in concentrations of 0.1, 1, 5, 10, 25 ug/g, vehicle only and two controls. The control and the vehicle-only wounds each demonstrated 100% healing time (HT100) of 9.31 +/- 1.34 and 8.5 +/- 1.12 while the wounds treated with EGF ointment with concentrations of 0.1 (HT100 = 6.4 +/- 0.71), 1 (HT100 = 5.2 +/- 0.63), 5 (HT100 = 5.8 +/- 0.85), 10 (HT100 = 7.1 +/- 1.45) and 25 ug/g (HT100 = 7.4 + 0.57) demonstrated significant reduction in time to achieve re-epithelialisation. Among the EGF-treated wounds, the wounds treated with EGF concentrations of 1 and 5 ug/g achieved the fastest re-epithelialisation with evidence of substantial increase in basal keratinocyte activity observed through Ki-67 activity. In conclusion, this article demonstrates the efficacy of human recombinant EGF in facilitating re-epithelialisation of partial thickness wounds with the most efficient healing found in EGF concentrations of 1 and 5 ug/g.

MR imaging of in vivo recruitment of iron oxide-labeled macrophages in experimentally induced soft-tissue infection in mice.

PURPOSE: To evaluate the feasibility of magnetic resonance (MR) imaging in depicting in vivo recruitment of iron oxide-labeled macrophages in experimentally induced soft-tissue infection. MATERIALS AND METHODS: The study was performed according to the guidelines of the U.S. National Institutes of Health and recommendations of the committee on animal research. The protocol was approved by the local institutional review committee on animal care. Experimental soft-tissue infection in 12 mice was induced by inoculation with a 5 x 10(7) colony-forming units of Staphylococcus aureus into the left calf. Peritoneal macrophages were harvested from thioglycollate-treated mice, cultured, and labeled with iron oxide in vitro. The iron oxide-labeled macrophage (macrophage group, n = 6) or iron oxide solution (control group, n = 6) was administered through the tail vein. The left calf of the mice was imaged on days 2 and 3 with a 4.7-T MR unit. Changes in relative signal intensity (SI) and pattern of contrast material enhancement (macrophage distribution) were analyzed and compared with histopathologic findings. Statistical analysis was performed with the Wilcoxon matched-pairs signed rank test. RESULTS: On MR images obtained 24 hours after administration of macrophage labeled with iron oxide, a band-shaped lower SI zone was noted in the abscess wall, which corresponded to the distribution of the iron oxide-labeled macrophages at histopathologic examination. The relative SI of the abscess wall significantly decreased after injection of iron oxide-labeled macrophages (median, 0.42) compared with that before injection (median, 1.23) (P = .031). In the control group, the SI change after administration of iron oxide solution was not significant (P = .688). CONCLUSION: Homing of intravenously administered iron oxide-labeled macrophages can be monitored with MR imaging and may provide a tool to investigate interactions between macrophages and the invading pathogens.