No abstract

Oral mucositis is a common, dose-limiting, acute toxicity of radiation therapy administered for the treatment of cancers of the head and neck. Accumulating data would suggest that the pathogenesis of mucositis is complex and involves the sequential interaction of all cell types of the oral mucosa, as well as a number of cytokines and elements of the oral environment. While a number of studies have reported on gene expression of particular cell types in response to radiation, the overall response of irradiated mucosa has only been evaluated in a limited way. The present study was undertaken to evaluate the expression of a target group of genes using RNA quantification assays and, more broadly, to assess patterns of mucosal gene expression using DNA microarray hybridization. Our results demonstrate the sequential upregulation of a series of genes that, when taken collectively, suggest an intricate functional interaction.

Mucositis is a common, dose-limiting toxicity associated with drug and radiation therapy for cancer. The ulcerative lesions of mucositis serve as systemic portals of entry for the micro-organisms that inhabit the mucosa of the gastrointestinal tract and the oral cavity, often leading to systemic infection. The pathogenesis of mucositis is complex, and consists of varying, sequential interactions between pro-inflammatory cytokines, transcription factors, and pro-apoptotic pathways of the mucosal epithelium and the cells and tissues within the submucosa. A possible mechanism for mucositis injury is the activation of caspases, a family of cysteine proteases. Caspase-11, one of 14 members of this enzymatic family, was studied to determine its role in the development of intestinal mucositis after exposure to melphalan in caspase-11 wild-type (+/+) and knockout (-/-) mice. Immunoblots demonstrated the activation of caspase-11 in duodenal and jejunal samples 24 and 48 h after melphalan administration. No significant differences in the level of intestinal cell death or macrophage infiltration, as measured by TUNEL staining and immunohistochemistry, were present between wildtype (+/+) and knockout (-/-) mice. These findings suggest that while caspase-11 activation occurs in response to melphalan, it does not have a primary role in the pathogenesis of intestinal mucositis.

Transdermal drug delivery (TDD) is gaining significance in the recent years due to its advantages over oral delivery and hypodermic needle injections. An insulin patch placed on the skin may be able to deliver sustained physiological levels of basal insulin; however, because insulin is a relatively large molecule, it does not penetrate the skin barrier easily. Using chemicals penetration enhancers (CPEs) is one of the promising ways to increase skin permeation. Previously, traditional chemical enhancers have had limited success in delivery of macromolecules and peptides such as insulin and vaccines. To resolve this challenge, we have reported on an effective methodology of predicting useful CPEs using genetic algorithms and neural networks for non-linear, quantitative structure-property relationship (QSPR) models based upon representative molecular properties. The predicted molecules were extensively tested for cytotoxicity and ex vivo transdermal delivery. The main objective of this study is to evaluate the in vivo efficacy of delivering insulin across the epidermal barrier with and without the newly designed CPEs in a streptozotocin (STZ)-induced diabetic rat model. These animals were randomly assigned to one of the following groups: (1) control (no CPE or insulin); (2) insulin alone (no CPE); (3) test CPE; (4) test CPE and insulin (at least n¼3 per group per CPE). Eight hours prior to application of the patch, all diabetic rats were transferred to individual metabolic cages and were fasted to normalize the glucose level. After application of the patch, blood glucose levels were monitored at different time points. After five days, we evaluated the overall body weight change, skin toxicity, and hepatotoxicity. Our findings through animal trials indicate proven safety and efficacy of the newly designed CPEs.

Psoriasis is a chronic inflammatory skin disease. Ginsenoside compound K (CK) is an active ingredient of ginseng which is reported to exert beneficial effects on inflammation. However, the biological role of ginsenoside CK in psoriasis is still unclear. Our aim was to investigate the effect of ginsenoside CK on the proliferation of keratinocytes and the expression of human regenerating islet-derived protein 3A (REG3A) and its mouse homolog RegIIIg as well as the inhibitory effect of ginsenoside CK on IMQ-induced psoriasis-like mice. The effect of ginsenoside CK on the proliferation of HaCaT cells and NHEK cells was measured by MTT. The apoptosis of HaCaT cells induced by ginsenoside CK was analyzed by flow cytometry. The inhibitory effect of ginsenoside CK on RAG3A induced by IL-36g in HaCaT cells was identified by WB and qRT-PCR. Psoriatic models in mice were induced by imiquimod cream. The thickness of mouse ear and skin epidermis was measured based on hematoxylin and eosin stain (HE) of tissues. The expression of RegIIIg protein in lesional skin of psoriatic mice was identified by WB and immunofluorescence. Ginsenoside CK could inhibit the proliferation of HaCaT cells and NHEK cells, but it could not induce the apoptosis of HaCaT cells. The expression of RAG3A protein stimulated by IL-36g is inhibited by ginsenoside CK in HaCaT cells. In the mouse model of psoriasis, the topical application of ginsenoside CK significantly decreased the epidermis thickness of lesional skin of psoriatic mice and the expression of RegIIIg protein. Ginsenoside CK inhibited the proliferation of HaCaT cells and NHEK cells as well as attenuated imiquimod-induced psoriasis-like pathology in mice by reducing the expression of RAG3A/RegIIIg protein. These results indicated that ginsenoside CK exhibited therapeutic effects in psoriasis.