Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 9, Issue 4, 2009

I was able to compile this work due to an enthusiastic response from experts in the field. It encompasses the pathophysiology of inflammation relevant to physiological states, infections, autoimmune and metabolic diseases. This supplement demonstrates the increasing importance of redox-sensitive mechanisms during physiological function, inflammatory pathology, sepsis and carcinogenesis. The relevance of anti-oxidant defences and therapeutic applications, including current and future potential for nanotechnology is highlighted. It could play a strategic role in the adjunctive therapy of protracted chronic diseases by avoiding side effects of prescriptive medication. There are several advances in therapeutic utilisation of antioxidants produced by the host in response to pathophysiological states and those of dietary origin for their effective management. The diverse conditions addressed project the importance of oxidative stress during inflammation and effective methods of intervention which could benefit co-existing diseases with a similar progression. The ubiquitous nature of inflammation as a component of diverse acute and chronic pathological states underscores the importance of effective therapeutic targeting; often made difficult by complex interactions between receptors, therapeutic agents and host derived products. Streamlined application of these concepts for effective therapeutic targeting and focused delivery is a challenge for the future.

Sepsis and septic shock are the major causes of death in intensive care units. The prevalent hypothesis regarding the mechanisms of sepsis and septic shock indicates that this syndrome is caused by an excessive defensive and inflammatory response characterised by massive increases in reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. The consequences of these syndromes are systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, glutathione depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O2 consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves in a range of conditions, including sepsis. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria currently under development. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in antioxidants that target the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for sepsis.

Cancer is one of the leading causes of death in Europe and United States. New blood vessel formation penetrating into solid tumors seems to be required for their growth and metastasis. Several protein growth factors can induce endothelial cell proliferation and angiogenesis, through signal transduction cascades that result in the production of several inflammatory mediators and lipid second messengers such as prostaglandins and Platelet Activating Factor (PAF). PAF is a potent mediator of inflammation that is implicated in several inflammatory pathological conditions such as atherosclerosis, cardiovascular and renal diseases, allergy, AIDS, cancer etc. It exerts its biological activities through Gprotein- coupled receptors. The presence of PAF in the microenvironment of tumors may be due to its synthesis from circulating and / or cancer cells. Moreover, cancer cells and activated endothelial cells expose PAF-receptor on their membrane surface. PAF binding on its receptor induces several pathways that result in the onset and development of tumor induced angiogenesis and metastasis. PAF-receptor antagonists have exhibited promising results in vitro and in vivo as anti-angiogenic molecules in several cancer cells and tumors. A dietary profile reach in antioxidants and PAF-inhibitors (such as the Mediterranean Diet) may provide beneficial preventive and protective effects against development, growth and metastatic manifestations of cancer cells, through either their inhibition of PAF activity and / or its biosynthesis. The clarification of factors that may down regulate pathologically increased PAF-levels in a tumor microenvironment may also contribute to the planning of a potent nontoxic preventive and therapeutic approach against cancer.

Diet and nutrition have played an important role in maintaining physiological homeostasis. Recent literature emphasizes potential therapeutic effects of micronutrients found in natural products, indicating positive applications for controlling the pathogenesis of chronic diseases driven by an inflammatory nidus. Nutritional compounds which display anti-inflammatory and antioxidant effects have specific applications in preventing oxidative stress induced injury which characterizes their pathogenesis. Patient control over diet and disease has been demonstrated in diabetes mellitus, cardiovascular disease, rheumatology, carcinogenesis and other diseases. Polyphenolic compounds are ubiquitous dietary components, mainly flavonoids and tannins. Specific polyphenols are effective in scavenging reactive oxygen and reactive nitrogen species. They are able to modulate genes associated with metabolism, stress defence, drug metabolizing enzymes, detoxification and transporter proteins. Their overall effect is protective in overcoming damaging effects of chronic diseases and in delaying the degenerative effects of ageing. The mechanisms involved in radical scavenging activity are complex, determined by the structure of the compound, redox status of the environment and interactions with other agents. Atherogenic dyslipidaemia associated with a pro-inflammatory pro-thrombotic state in metabolic syndrome and related risk of fatty liver, arthritis, neurodegenerative disorders and certain types of cancers are ideal therapeutic targets for bioactive phytochemicals which can combat oxidative stress induced damage at a sub-cellular level. It is relevant that purified micronutrients isolated from natural products may be less effective than a combination seen in the natural product due to synergistic effects of interacting agents. Some of these mechanisms and potential therapeutic targets are discussed.

The aetiopathogenesis of periodontal diseases is initiated by microbial biofilm which could lead to a hyperinflammatory status in aggressive forms of the disease; and cause an imbalance in the redox status, resulting in oxidative stress-induced damage. There is increasing documentation of the link between periodontal and other inflammatory diseases driven by a pro-oxidant profile. This could impose a significant systemic loading of reactive oxygen species relevant to metabolic, arthritic, age related and neoplastic diseases. They demonstrate similar markers of risk / oxidative stress induced injury during disease progression which abate in response to treatment. In certain aggressive forms of periodontal diseases resulting in a substantial systemic pro-oxidant profile, the co-existence of systemic diseases with a similar inflammatory pathogenesis could lead to progressive tissue / organ damage fuelled by the same process. Some of the common mechanisms involved are discussed, relevant to periodontal, metabolic and rheumatoid diseases, pregnancy and the foetus, age related changes and certain neoplasias which have been recently linked to periodontal disease progression. In view of a distinct pro-oxidant profile in severe cases there may a role for selective use of antioxidant adjuncts with suitable therapeutic targeting. It is relevant that periodontal diseases are associated with the above diseases and a small but significant overall cancer risk which persists in non-smokers. Periodontal disease may be a useful marker of a susceptible immune system, or directly affect the progression of systemic diseases due to inflammatory loading. Formulation of therapeutic agents shown to have efficacy in this context, with accurate targeting is a challenge.

Skeletal muscle contraction, growth, differentiation and adaptation are governed by complicated biological mechanisms still being studied intensively. Generation of reactive oxygen and nitrogen species (RS) is one of the most prominent events during contractile activity that could influence muscle function and health. While RS generation is known to cause oxidative stress, activate certain pathogenic pathways and aging, they also serve as useful signaling molecules to regulate gene expression of proteins and enzymes that play a vital role in the normal muscle function and defense against detrimental effects of RS. The purpose of the present review is two-fold: first, to provide an overview of cell signaling controlled by a redox sensitive mechanism and its impact on skeletal muscle health and function; and second, to review the various muscular diseases and disorders that have an etiological origin of RS overproduction and/or inadequate antioxidant defense. Given the physiological role of skeletal muscle we will emphasize the importance of physical exercise in promoting cellular antioxidant defense and its benefits in the maintenance of muscle health.

The new ground being broken by the field of nanotechnology provides us with numerous prospects for treatment and prevention of infectious diseases. Recent reports have demonstrated that several types of nanoparticles act as potent free radical scavengers and antioxidants. Specific nanoconstructs are also reported to have anti-inflammatory activities. Given these properties, the potential application of antioxidant nanoparticles for controlling infectious diseases are discussed in this review. Numerous pathogenic agents establish their virulence and pathogenicity by virtue of their ability to produce free radicals and damage the cells of the immune system. For example, Pseudomonas aeruginosa is a bacterium that produces the toxin pyocyanin, which induces cell damage and compromises the immune system through production of reactive oxygen species (ROS). Nanoparticle antioxidants may provide unique opportunities to counteract the pathogenicity of these types of microorganisms and their formation of biofilms, which are also related to oxygen levels and ROS production. The use of nanoparticles may also play a role in controlling conditions such as ventilation associated pneumonia, where high levels of oxygen induces oxidative stress and inhibits respiratory tract immunity. In contrast, nanoparticle antioxidants, by virtue of their anti-inflammatory activity, may blunt a host's normal immune defenses to certain microorganisms. This review will address this emerging double-edged sword for nanomedicine and its potential role in controlling infectious disease and will address future directions for research in this emerging frontier.

Melatonin is a neurohormone that has attracted a great deal of attention, being frequently investigated in recent years. Due to its wide-spectrum of properties, melatonin has been suggested to be effective with respect to the etiology and treatment of several diseases. Its action on the immune system and antioxidant features has brought interest to this hormone's role in chronic inflammatory diseases. Furthermore, the detection of a correlation between the circadian release of melatonin and the rhythmic symptoms and signs of rheumatoid patients has led scientists to address its involvement in rheumatic diseases. Studies with suitable methodologies and broad perspectives are required in order to determine the functions of this neurohormone, whose effects are dependent on its physiological and pharmacological doses.