admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1600-079X.2003.00092.x

Regulation of antioxidant enzymes: a significant role for melatonin.

The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

Lipid peroxidation in cell death.

The critical role of inflammatory processes in health and disease has long been recognized,1 yet the detailed molecular mechanisms and biological events that regulate the progression and resolution of inflammation remain of interest. A number of recent investigations have provided strong evidence that the resolution of inflammation is not a passive process, as believed earlier.2–4 Instead, resolution is a biosynthetically active process, regulated by biochemical mediators and receptor-signaling pathways, and driven by specialized pro-resolving mediators (SPM). In particular, following a number of findings by Serhan and his group, the authors and their collaborators introduced and systematically investigated a number of SPM derived from polyunsaturated fatty acids (PUFA), including lipoxins, E-series resolvins, D-series resolvins, protectins/neuroprotectins, and, most recently, maresins. This review summarizes efforts on the resolvins and protectins with an emphasis on the corresponding biochemical pathways. Additional reviews covering different aspects of these anti-inflammatory and pro-resolving lipid mediators,5 including immunology,6,7 pathology,8 biochemistry,9 pharmacology10 and chemistry11 are also available.6–9,12

1.1 The Inflammatory Response and the Resolution of Inflammation
Localized acute inflammation is part of the host’s normal protective response to tissue injury and infection by invading microbial pathogens.1 Although this inflammatory response to a range of harmful stimuli is protective to the host, if kept uncontrolled it can result in a wide range of acute, chronic and systemic inflammatory disorders. Indeed, some of the most common and difficult to treat diseases are linked to excessive, uncontrollable, or chronic inflammation, including: cardiovascular disease, rheumatoid arthritis, periodontal disease, asthma, diabetes, inflammatory bowel disease (IBD), as well as neurological disorders such as Alzheimer’s disease and age-related macular degeneration (AMD).1,13,14 Although the involvement of inflammatory pathways in the initiation of all of these diseases is well established, the specific role by which inflammation contributes to their pathogenesis is not fully understood. The recent findings that the resolution of inflammation is an active process2–4,15 have provided new insights and created new paradigms for understanding and treating these conditions.

The key role of a number of lipid mediators in the initiation of the inflammatory response and the subsequent progression towards resolution is illustrated in Fig. 1. Among the first signaling events following microbial infection or tissue injury, is the release of pro-inflammatory lipid mediators, such as leukotrienes (LTs) and prostaglandins (PGs) that launch a series of signaling cascades with the ultimate goal of destroying the invading pathogens and repairing the damaged tissue.16–18 Thus, the biosynthesis and release of the potent chemotactic agent leukotriene B4 (LTB4) promotes the recruitment of neutrophils (PMNs) to the inflamed tissue, while the formation of prostaglandins E2 and D2 (PGE2 and PGD2)15 further accelerates the inflammatory process, ultimately resulting in a condition of acute inflammation. Despite its critical host-protective function, acute inflammation is not sustainable over a prolonged period of time, giving rise to disruptive conditions of chronic inflammation that may be responsible for the pathogenesis of a wide range of diseases, that can be attributed to a failure of resolution.19 Typically, the therapeutic treatment of such conditions involves the inhibition of pro-inflammatory mediators, but in many cases such approaches are often not very effective.



Figure 1

From initiation of acute inflammation to resolution: The inflammatory response to microbial infection and tissue injury, and the role of selected cell types and specialized pro-resolving lipid mediators.



The recognition of the proactive nature of the resolution of inflammation has revealed alternative therapeutic paradigms based on resolving acute inflammation and preventing the onset of chronic inflammation.19 Indeed, a number of endogenous lipid mediators identified are able to act in this manner, suggesting a lipid mediator class switching3 from the initial actions of pro-inflammatory lipid mediators, i.e. leukotriene and prostaglandins, to the anti-inflammatory and pro-resolving actions of lipoxins, resolvins, protectins and maresins, which are discussed in this review. Each family of these pro-resolving mediators exert specialized actions, including blocking neutrophil recruitment, promoting the recruitment and activation of monocytes, as well as mediating the nonphlogistic phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages. Eventually, through the combined actions of these mediators, the resolution of inflammation is completed and homeostasis is reached. In this regard, it was important to introduce precise definitions for resolution mechanisms and indices19–21 that also permitted the first information that certain agents can be resolution-toxic.22–24

/pdf/resolvins-and-protectins-in-inflammation-resolution-5kmutz61le.pdf

Resolvins and Protectins in Inflammation-Resolution

5-Lipoxygenase: regulation of expression and enzyme activity

5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease.

The Nuclear Receptor for Melatonin Represses 5-Lipoxygenase Gene Expression in Human B Lymphocytes

Therapeutic options for 5-lipoxygenase inhibitors.

Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.

/pdf/vitamin-d-in-inflammatory-diseases-1nhkch4qo0.pdf

Dieter Steinhilber

Papers

5-Lipoxygenase: regulation of expression and enzyme activity

5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease.

The Nuclear Receptor for Melatonin Represses 5-Lipoxygenase Gene Expression in Human B Lymphocytes

Therapeutic options for 5-lipoxygenase inhibitors.

Vitamin D in inflammatory diseases