Drug discovery today. Disease mechanisms最新文献

Cancer-associated thrombosis is a common complication seen in oncology patients, and its incidence is rising. Thromboembolism is the second most common cause of death in cancer patients. Cancer-associated venous thromboembolism (VTE) is associated with high rate of recurrence, increased risk of bleeding, and a requirement for long-term anticoagulation. The hypercoagulable state in cancer involves several complex interdependent mechanisms including emerging roles for tumor-derived tissue factor and platelets. Identifying patients at risk for VTE and utilizing available anticoagulant agents for primary or secondary prophylaxis is crucial to reduce morbidity, enhance quality of life, and improve survival.

Dengue has established itself as one of the world's most common mosquito-borne viral diseases. Although it prevails in tropical areas, sustained transmission of dengue has recently occurred in Florida. Dengue viruses can induce a spectrum of symptoms and, in severe cases, mortality in approximately 1–5% of infected individuals. A hallmark of dengue infection is thrombocytopenia that associates with abnormal platelet function, which is the focus of this review.

Platelet transfusion has long been practiced with rudimentary knowledge about optimal storage conditions and their implications for efficacy and, particularly, safety. Recent concerns have been raised about platelet transfusion complications such as inflammation, thrombosis and altered recipient immunity. This review will discuss recent important findings that have raised these issues about platelet transfusion associated morbidity, mortality and the possible role of platelet storage in these associations.

Antiphospholipid syndrome is an autoimmune disease characterized by the presence of circulating antiphospholipid antibodies (aPL) that promote thrombosis, pregnancy complications and cardiovascular diseases. Alterations in the function of vascular cells induced by aPL underlie these outcomes. This review will discuss recent findings that indicate a novel mechanism by which aPL antagonize endothelial cell production of nitric oxide and thereby promote thrombosis.

Platelets and microparticles might have a crucial role in the pathogenesis of cerebral malaria by assisting in the binding of infected erythrocytes to the cerebral vasculature and mediating numerous inflammatory and immune processes. The present review compiles a selection of the recent findings on their interactions with microvascular endothelium, infected erythrocytes and immune cells that may influence the development of cerebral malaria.

The incidence of obesity and related metabolic disorders is currently increasing at an alarming rate in modern society. Therefore, the development of effective antiobesity therapies represents a high priority area for the research-based pharmaceutical industry. The search for lipid mediators that control metabolism is now one of the major goals of obesity research. The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that play multiple roles in living organisms, including plants and vertebrates. The present review focuses on the naturally occurring FAE oleoylethanolamide (OEA), a mediator of satiety that exerts anorectic effects mainly through peripheral mechanisms. This property is essential to avoid central effects and minimize the risk of adverse reactions that may limit its use. In mammals, OEA has been described as a mediator of lipid metabolism, insulin secretion, energy expenditure and gastrointestinal motility based upon its mechanism of action and its main target receptors: the peroxisome proliferator activated-receptor alpha (PPAR-α) and the orphan receptor GPR119. Additional anti-inflammatory and neuroprotective actions of OEA have been suggested. In the present article, we review the roles of OEA and drugs developed from this acylethanolamide using a structure–activity relationship approach.

Clinical and epidemiological studies suggest that patients who are overweight or obese are at greater risk to develop glucose intolerance and insulin resistance leading to type II diabetes and cardiovascular disease. Despite many hypotheses, it has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipid-derived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune/inflammatory systems to provide a dual strategy to combat metabolic disease, especially insulin resistance and type II diabetes.

Persistent inflammation in adipose tissue is a key feature in the pathophysiology of obesity-related comorbidities. Increasing evidence supports the view that the presence of a chronic ‘low-grade’ inflammatory state in adipose tissue during obesity is the likely consequence of a ‘resolution deficit’ that prevents the return to tissue homeostasis. This article describes state-of-the-art knowledge and novel insight into the role of the recently described omega-3-PUFA-derived lipid autacoids termed resolvins and protectins. These lipid mediators display potent anti-inflammatory and pro-resolving properties and may work as endogenous ‘stop signals’ associated with the resolution of adipose tissue inflammation.