Diabetic foot ulcers are the most severe clinical manifestation of diabetes-related impaired wound healing. Current standard and experimental treatments for these ulcers are largely ineffective. Epicatechin gallate (ECG) is a nontoxic flavonoid previously shown to improve normal wound healing and scar formation. In this study, the neonatal streptozotocin-induced diabetes mellitus (nSTZ-DM) type 2 model in rats was used to investigate the effects of ECG on impaired wound healing and scar formation. Administration of 100 mg/kg STZ induced a significant (P < 0.05) state of mild hyperglycemia in nSTZ-DM type 2 rats, compared to nondiabetic controls. The effects of 0.8 mg/mL ECG on wound healing were then investigated using the full-thickness incisional wound-healing model. ECG significantly improves healing and reduces scar formation in nSTZ-DM type 2 rats (P < 0.05). Biochemical improvements were also found, including significantly increased total nitric oxide synthase activity ([NOS]; P < 0.001) and inducible NOS (iNOS) activity (P < 0.01). This work highlights ECG as a potential treatment for DM-impaired wound healing. .

The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.

The contribution of heme oxygenase (HO)-linked pathways to neurodegeneration following cerebral hypoxia-ischemia (HI) remains unclear. We investigated whether HO modulators affected HI-induced brain damage and explored potential mechanisms involved. HI was induced in 26-day-old male Wistar rats by left common carotid artery ligation, followed by exposure to a humidified atmosphere of 8% oxygen for 1 hr. Tin protoporphyrin (SnPP; an HO inhibitor), ferriprotoporphyrin (FePP; an HO inducer), or saline was administered intraperitoneally once daily from 1 day prior to HI until sacrifice at 3 days post-HI. SnPP reduced (P < 0.05) infarct volume compared with saline-treated animals, but FePP had no effect on brain injury. SnPP did not significantly inhibit HO activity at 3 days post-HI, but SnPP increased (P < 0.001) total nitric oxide synthase (NOS) activity compared with HI + saline. Both inducible NOS and cyclooxygenase activities were attenuated (P < 0.05) by SnPP, whereas mitochondrial complex I and V activities were augmented (P < 0.05) by SnPP. SnPP had no effect on NMDA receptor currents. Overall, like other HO inhibitors, SnPP produced many nonselective effects, such as attenuation of inflammatory enzymes and increased mitochondrial respiratory function, which were associated with a protective response 3 days post-HI.

The regional and cellular distribution of heme oxygenase (HO)-1 and -2 following cerebral ischemia has not been ascertained. Employing the transient middle cerebral artery occlusion (MCAO) and hypoxia–ischemia (HI) models of unilateral brain injury, the aim was to elucidate immunolocalization of HO-1 and HO-2. Animals were sacrificed 3 days post-ischemia and immunohistochemistry and Western blotting were utilized to determine HO-1 and HO-2 expression. In the ipsilateral hemisphere following HI, HO-1 immunoreactivity was significantly upregulated in many neuronal and glial populations (including the cortex, hippocampus and thalamus). HO-1 was also detected in macrophages/microglia within the infarct. In addition to widespread neuronal HO-2 labelling, HO-2 was also expressed in vascular endothelial cells. Inflammatory cells within the infarct of MCAO and HI animals were surprisingly immunoreactive for HO-2, but only HI animals had significantly elevated HO-2 protein expression in the ipsilateral hemisphere. This may be due to the presence of global hypoxia in the HI model which can upregulate vascular endothelial growth factor and subsequent proliferation of endothelial cells. This report of HO-2 protein expression upregulation following HI coupled with an increase in HO-1 immunoreactivity suggests that this response may be implicated in reducing cell death or repairing damage induced by cerebral ischemia.

The pineal gland hormone melatonin is known to have both anti-inflammatory and immunomodulatory effects. Given this, we propose that melatonin is an ideal candidate to enhance the process of wound healing. The present study assessed the effects of exogenously administered melatonin (1.2 mg/kg intra-dermal), on scar formation using a full-thickness incisional rat model of dermal wound healing. Melatonin treatment significantly improved the quality of scarring, both in terms of maturity and orientation of collagen fibres. An increase in nitric oxide synthase (NOS) activity and therefore nitric oxide production is detrimental during inflammation but is favourable during granulation tissue formation. Melatonin treatment significantly decreased inducible NOS (iNOS) activity during the acute inflammatory phase but significantly increased iNOS activity during the resolving phase. Cyclooxygenase-2, which has been shown to have anti-inflammatory effects, was elevated in the melatonin-treated rats following wounding. In addition, melatonin treatment also accelerated the angiogenic process, increasing the formation of new blood vessels and elevating the level of vascular endothelial growth factor protein expression during granulation tissue formation. Melatonin treatment increased arginase activity (which generates proline, a building block for collagen synthesis) from earlier time points. The protein profiles of hemoxygenase-1 (HO-1) and HO-2 isoforms, vital participants in the repair process, were also up-regulated upon melatonin treatment. This study has therefore demonstrated, for the first time, that melatonin can significantly improve the quality of wound healing and scar formation.

Until recently the cannabinoid CB2 receptor was believed to be absent from the central nervous system. In this study we have identified CB2 expressing cells that appear in the rat brain following stroke and hypoxic-ischemia. At 3 days following surgery CB2-positive macrophages, deriving from resident microglia and/or invading monocytes appear on the lesioned side of the brain. By day 7, a mixed population of CB2-positive cells is present. Microglia-derived macrophages are the key cells in the first stages of brain inflammation, and a pivotal step in the neurodegeneration that follows the acute stage of injury. Thus, CB2 may be important in the brain during injury, and in inflammatory neurodegenerative disorders. The presence of CB2-positive cells in the brain following stroke may provide a novel strategy for cannabinoid-mediated intervention into stroke induced neurodegeneration without the psychoactive effects of CB1 receptor stimulation.

Transfund New Zealand (Transfund) is developing an evidential based system for assessing the road engineering features that impact on the safety of roads. The purposes of RISA are to: 1. Provide Transfund with an objective measurement of Road Controlling Authorities� (RCAs�) performance with respect to road safety; and 2. Assist RCAs with a tool to improve road safety through engineering by identifying the features that make the greatest contribution to road safety. The paper will describe 1. Why RISA was needed; 2. The research that was commissioned to form the basis of RISA; 3. The development and trials of the method; 4. The early results of these trials and other comparisons; and 5. The uses that are foreseen for RISA, for both Transfund and RCAs. (a) For the covering entry of this conference, please see ITRD abstract no. E212706.

Skin is an essential protective organ for vertebrate animals. During skin injury, a plethora of cells and mediators occupy the wound site and, through a collective effort, perform repair of the tissue. This complex pathophysiological process is referred to as wound healing. The efficiency of wound repair is governed by the sequential influx of a variety of cell types to the wound site, upregulation/downregulation of many signaling molecules, and the interaction of various enzymatic pathways. Any dysregulation in this highly complex, but orderly, pathophysiological process results in impaired wound repair. A variety of metabolic enzymes are induced upon injury and are responsible for driving the key physiological processes within the wound milieu during the inflammatory and resolution phases of wound repair. This review will focus on the contribution of major enzymatic biosystems to the inflammatory, remodeling and resolution phases of normal wound healing, including the arachidonic acid metabolic pathway, L-arginine metabolism and the endogenous oxidant-antioxidant redox systems of the body. The major therapeutic targets within these processes will also be highlighted.

The purpose of this paper is to describe the background and development methodology of Road Infrastructure Safety Assessment (RISA) information. The paper also describes the ongoing development of the assessment methodology, the uses of the process and the proposed future development of RISA. Land Transport NZ will also be able to use this tool as a performance measurement and comparison of Road Controlling Authorities (RCAs). The assessment methodology also has opportunities for adaptation for review and assessment of road safety features for other purposes. Land Transport New Zealand (Land Transport NZ) is developing a tool to enable RCAs to understand and manage their road safety infrastructure provisions in a more effective way.

Wound healing is a multi-factorial physiological process. The complexity of this phenomenon makes it prone to several abnormalities. This review will focus on the most commonly observed wound healing abnormalities and factors which may play a vital role in the progression and regression of these abnormalities.

Catechins are dietary polyphenolic compounds associated with a wide variety of beneficial health effects in vitro, in vivo and clinically. These therapeutic properties have long been attributed to the catechins' antioxidant and free radical scavenging effects. Emerging evidence has shown that catechins and their metabolites have many additional mechanisms of action by affecting numerous sites, potentiating endogenous antioxidants and eliciting dual actions during oxidative stress, ischemia and inflammation. Catechins have proven to modulate apoptosis at various points in the sequence, including altering expression of anti- and proapoptotic genes. Their anti-inflammatory effects are activated through a variety of different mechanisms, including modulation of nitric oxide synthase isoforms. Catechins' actions of attenuating oxidative stress and the inflammatory response may, in part, account for their confirmed neuroprotective capabilities following cerebral ischemia. The versatility of the mechanisms of action of catechins increases their therapeutic potential as interventions for numerous clinical disorders. However, more epidemiological and clinical studies need to be undertaken for their efficacy to be fully elucidated.

Inflammation is the response of any tissue to injury or trauma. The inflammatory response forms the basis of several pathological and pathophysiological processes, including wound healing, rheumatoid arthritis and neurodegenerative disorders, including Alzheimer's disease and stroke. The response is mediated by various signaling molecules and enzymatic pathways, among which the cyclooxygenase (COX) pathway is one of the most predominant. COX catalyzes the formation of prostaglandins and thromboxanes from arachidonic acid (AA). In 1971, Sir John Vane demonstrated for the first time that the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is via inhibition of COX. Since the discovery of at least two isoforms of COX, inhibition of COX-2 has generally been considered the basis for the anti-inflammatory effects of NSAIDs. However, more recent studies of COX-2 have controversially postulated that the selective inhibition of COX-2 may not be beneficial, but rather can be detrimental. This is based on the observations that, during inflammation, not all AA-derived mediators are exclusively pro-inflammatory. This review will attempt to discuss the confusing and contradictory data relating to selective COX-2 inhibition and inflammation, particularly focusing on anti-inflammatory AA-derived mediators. We will also try to advance the perspective that inflammation is not just a single process, but is rather a dynamic and continuously changing event, not just in terms of time, mediators and cells, but also in the initiating stimuli, whether it be in the periphery or the central nervous system.