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Wound healing is a dynamic process that ultimately leads to restoration of tissue integrity and function. The pineal gland hormone melatonin is known for its anti-oncotic, anti- inflammatory and immuno-modulatory effects. However, its role in wound healing has not been established. Since melatonin is synthesised endogenously, we primarily sought to investigate whether the melatonin receptors played a role in the wound healing process. Using immunohistochemical methods and Western blot analysis we observed that MT₁ was normally absent in the rat skin but was strongly expressed on day 1 to day 3 post wounding in the epidermis adjacent to the wound edge. MT₁ expression was restricted to the stratum granulosum and stratum spinosum layers of the epidermis in the rat wounds. MT₁ expression declined thereafter and became nonexistent by day 21 when the wound had completely healed. In contrast, MT₂ was constitutively expressed in all the layers of the normal rat epidermis. MT₂ expression gradually decreased at the injury site following wounding but returned to the normal profile by day 21. Aged rat epidermis showed similar MT₁ and MT₂ expression as adult rats. The profile of tissue distribution of MT₁ and MT₂ in the human epidermis was comparable to the rat epidermis. In the CVUs MT₁ and MT₂ localisation profiles resembled that of a healing wound, akin to a day 1 or day 3 rat dermal wound, during the inflammatory phase. Surprisingly, in contrast to all the tissues investigated, MT₁ was also localised in the stratum basale layer of the keloid epidermis. MT₂ localisation in the same keloid tissues however resembled normal human skin profiles. Secondly, we determined the effects of exogenously administered melatonin, on scarring and wound healing, using a full thickness incisional model of wound healing in rats. Melatonin treatment significantly improved the quality of scarring by day 21. However, our findings would have been strengthened by a more explicit wound closure analysis, measurement of granulation tissue weight, tensile strength, hydroxyl proline content and immunohistochemical assessments of neutrophil infiltration, macrophages, fibroblasts, myofibroblasts and reepithelialization. The treatment also accelerated the angiogenic process and enhanced the VEGF protein profile. Arginase generates proline, the building block for collagen synthesis. Melatonin treatment increased arginase activity and consequently would increase collagen synthesis from day 1. An increase in NOS activity and therefore NO production is known to be detrimental during inflammation. However, various studies have also shown that the NO is essential for granulation tissue formation. Melatonin treatment significantly decreased iNOS activity during the acute inflammatory phase in this study, but significantly increased iNOS activity during the resolving phase. Other markers of inflammatory response and repair were also examined in this study. COX-2 has been shown to play an anti-inflammatory role and melatonin increased COX-2 activity and protein following wounding. SOD (the antioxidant enzyme) activity was also significantly increased during the chronic inflammatory phase on melatonin administration. HO-1 and HO-2 isoforms have also been previously demonstrated to participate in the repair process. Melatonin treatment increased up-regulation of both HO-1 and HO-2 protein expression in the wounded skin. A significant decrease in all the mitochondrial enzyme activities (except complex-II-III), was observed post wounding. Melatonin treatment restored the complex activities to near normal levels. Melatonin also protected mitochondrial membrane integrity and reduced oxidative stress as evidenced by the maintained level of aconitase and citrate synthase activities at near normal levels. In vitro experiments using macrophage and fibroblast cell lines illustrated that melatonin may decrease NOS activity and protein profiles indirectly by stimulating arginase activity and thereby depleting the availability of arginine. This study is the first to fully demonstrate the distribution of melatonin receptors in normal and abnormal wounds. Improvement in the quality of scarring in a rat model of wound healing on melatonin administration is promising but much more quantitative work and preclinical studies are required before melatonin advances into clinical assessment.

ix, 237 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1979) from the Dept. of Obstetrics and Gynaecology, University of Adelaide

[20] 172 [45] leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1974) from the Dept. of Medicine, University of Adelaide

Includes bibliographical references (leaves 165-225) / xx, 298 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biological Sciences, Discipline of Physiology, 2004

Graduation date: 1968

Sialic acids are involved in many cellular interactions. They can serve as an adhesion ligand or act as an inhibitor to cellular adhesion by charge repulsion or by masking potential ligands. Although sialic acids are implicated in the process of blastocyst implantation, their expression and regulation in uterine epithelium of mice have not been studied. The lectin, Sambucus nigra (SNA) specifically recognizes ��2,6-linked sialic acids, which are involved in cell recognition phenomena. It was used to probe frozen uterine sections from mice during days one through six of pregnancy. SNA staining was most intense at the apical surface of uterine epithelial cells on day one of pregnancy, decreased gradually through day four, and was undetectable by day five. The role of the steroid hormones, estrogen and progesterone, in regulating the expression of ��2,6-linked sialic acids was studied in uterine sections from mice during the estrous cycle and in ovariectomized mice given hormone replacement using SNA. SNA staining of these sections during the estrous cycle showed that the expression of ��2,6-linked sialic acids was stage dependent. Staining was most intense in uterine sections from mice in estrus, and was not detected in sections from mice in diestrus. In ovariectomized mice, staining was most intense in mice injected with estradiol alone, and no staining was evident in mice injected with progesterone alone. These results suggest that the expression of ��2,6-linked sialic acids decreases during the time of implantation and that estrogen stimulates and progesterone inhibits its expression. ��-Galactoside ��2,6-Sialyltransferase (��2,6-ST) is the enzyme that links sialic acids to Gal��1-4GlcNAc termini of N-linked oligosaccharides. In order to investigate the mechanism behind the hormonal regulation of ��2,6-linked sialic acids, the expression of ��2,6-ST was followed in uterine sections from mice during early pregnancy, during the estrous cycle, and in ovariectomized mice given hormone replacement. In-situ hybridization was performed using digoxigenin labeled RNA probes to characterize ��2,6-ST mRNA levels in uterine sections. Expression of ��2,6-ST protein was also measured in uterine sections with a polyclonal antibody against ��2,6-ST. The expression of ��2,6-ST mRNA and protein correlated well with the timing of the appearance of ��2,6-linked sialic acids. These results show that the expression of ��2,6-linked sialic acids on the surface of mouse uterine epithelium decreases at the time of implantation and furthermore, that this decrease is due to the regulation of ��2,6-ST by the steroid hormones. ��2,6-linked sialic acids may serve to inhibit cellular adhesion by creating a charge repulsion, or by masking potential binding sites. Removal of this inhibition may permit blastocyst implantation. / Graduation date: 2001

Numerous properties of Yucca schidigera and Quillaja saponaria have been studied with respect to the saponins in the plant. These saponins are present in the extract as well and have been utilized commercially in the food and cosmetic industry for various products. Saponins have detergent-like properties in the presence of water. The detergent-like behavior of saponins plays a major role in their membranolytic properties. In addition, emulsification effects on fat which are characteristic of surfactant-type substances, may occur as well. Three studies were conducted using adult roosters, growing broiler chicks, and growing Japanese quail. Various effects of supplementing Yucca schidigera in the diets of these birds were studied such as: growth performance, overall health, and nutrient availability. An additional experiment was conducted comparing effects of Quillaja saponaria and Yucca schidigera extracts on body weight and fat digestibility in adult roosters. Addition of Yucca schidigera extract to high fat diets (tallow-based) increased lipid excretion in roosters, broilers, and quail. In roosters, dose of yucca extract affected excretion of lipid but no dose effects were seen in broilers or quail. Fat digestibility was not significantly affected by addition of saponins to the diet of adult roosters. However, fat digestibility was reduced in broilers and quail consuming a high fat diet. In general, level of dietary fat seemed to play a role in the effects of Yucca schidigera supplementation in growing birds. Addition of Yucca schidigera to high fat diets resulted in decreased plasma levels of vitamin A and E in broiler chicks. / Graduation date: 2000