Annals of medicine
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Recent data demonstrate the fundamental role of endothelin in the pathogenesis of fibrosis, and the anti-fibrotic potential of dual endothelin receptor antagonists such as bosentan. Although transforming growth factor-beta, aldosterone and connective tissue growth factor, have already been established as contributors to the process of fibrosis, endothelin now emerges as a key player, which may have a role both in the initiation and in maintenance of fibrosis, and may mediate the pro-fibrotic effects of the other agents. ⋯ Bosentan even reverses existing fibrosis, possibly by its effect of stimulating matrix metalloproteinase type 1 (collagenase) expression. The anti-fibrotic effects of bosentan extend to fibrosis induced by mediators other than endothelin such as transforming growth factor-beta, angiotensin II and aldosterone, indicating a central role of endothelin and endothelin receptors in fibrotic processes.
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The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is thought to be important in its protection against cardiovascular disease. Anti-inflammatory properties of HDL have emerged as additional properties that may also be important. HDL appears to have evolved as part of the innate immune system functioning to inhibit inflammation in the absence of an acute phase response (APR) but functioning to increase inflammation in the presence of an APR. ⋯ Pro-inflammatory HDL was relatively weak in its ability to promote cholesterol efflux while anti-inflammatory HDL was better in promoting cholesterol efflux. In other studies, oxidative alterations of the major protein of HDL, apolipoprotein A-I (apoA-I), impaired the ability of the apoA-I to promote cholesterol efflux. Thus, HDL structure and function may be more important than HDL-cholesterol levels in predicting risk for cardiovascular disease.
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In the adult central nervous system (CNS) myelin and oligodendrocytes, Nogo-A exerts a growth inhibitory function leading to restricted axonal regeneration. After development of different anti-Nogo-A antibodies and other Nogo-A blocking reagents their application has recently been studied in various in vivo animal models of spinal cord injury and stroke. These studies show that intracerebral application of Nogo-A-inactivating reagents leads to enhanced regeneration and compensatory sprouting, structural reorganization or plasticity, and functional recovery as seen in different behavioural analyses.
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Bipolar disorder (BD) is a chronic, potentially disabling illness with a lifetime morbid risk of approximately 1%. There is substantial evidence for a significant genetic etiology, but gene-mapping efforts have been hampered by the complex mode of inheritance and the likelihood of multiple genes of small effect. In view of the complexity, it may be instructive to understand the biological bases for pathogenesis. ⋯ For example, it would be logical to investigate polymorphisms of genes encoding key proteins that mediate circadian rhythms. Association studies that analyzed circadian genes in BD have been initiated and are reviewed. Other avenues for research are also discussed.
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Twenty years ago Parkinson's disease (PD) was thought of as an environmentally determined neurodegenerative disease. It is now known that there are two autosomal dominant disease genes, alpha-synuclein and dardarin, and three genes responsible for autosomal recessive PD, parkin, DJ-1 and PINK-1. Although these gene mutations are not common, their identification has led to a new understanding of the pathogenesis of PD, and to a development in the understanding of the clinical and pathological definitions of PD and Lewy body disease. Ultimately, these advances may lead to the development of new disease-modifying therapies, but more immediately these discoveries have led to a more coherent view of the spectrum of PD and Lewy body diseases and to accurate genetic diagnosis and counselling for some families.