norvir, was developed as a protease inhibitor and used to target hiv infection. however, it has been shown to inhibit proteasomes as well as free proteases; to be specific, the chymotrypsin-like activity of the proteasome is inhibited by ritonavir, while the trypsin-like activity is somewhat enhanced. studies in animal models suggest that ritonavir may have inhibitory effects on the growth of glioma cells. proteasome inhibitors have also shown promise in treating autoimmune diseases in animal models. for example, studies in mice bearing human skin grafts found a reduction in the size of lesions from psoriasis after treatment with a proteasome inhibitor. inhibitors also show positive effects in rodent models of asthma. labeling and inhibition of the proteasome is also of interest in laboratory settings for both in vitro and in vivo study of proteasomal activity in cells. the most commonly used laboratory inhibitors are lactacystin and the peptide aldehyde mg132 initially developed by goldberg lab. fluorescent inhibitors have also been developed to specifically label the active sites of the assembled proteasome. clinical significance the proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. more recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. an improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future. the proteasomes form a pivotal component for the ubiquitin–proteasome system (ups) and corresponding cellular protein quality control (pqc). protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. proteasome defects lead to reduced proteolytic activity and the accumulation of damaged or misfolded proteins, which may contribute to neurodegenerative disease, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic dna damage responses leading to malignancies. research has implicated ups defects in the pathogenesis of neurodegenerative and myodegenerative disorders, including alzheimer's disease, parkinson's disease and pick's disease, amyotrophic lateral sclerosis (als), huntington's disease, creutzfeldt–jakob disease, and motor neuron diseases, polyglutamine (polyq) diseases, muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. as part of the ubiquitin–proteasome system (ups), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury, ventricular hypertrophy and heart failure. additionally, evidence is accumulating that the ups plays an essential role in malignant transformation. ups proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. accordingly, gene expression by degradation of transcription factors, such as p53, c-jun, c-fos, nf-κb, c-myc, hif-1α, matα2, stat3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the ups and thus involved in the development of various malignancies. moreover, the ups regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (apc) in colorectal cancer, retinoblastoma (rb). and von hippel–lindau tumor suppressor (vhl), as well as a number of proto-oncogenes (raf, myc, myb, rel, src, mos, abl). the ups is also involved in the regulation of inflammatory responses. this activity is usually attributed to the role of proteasomes in the activation of nf-κb which further regulates the expression of pro inflammatory cytokines such as tnf-α, il-β, il-8, adhesion molecules (icam-1, vcam-1, p-selectin) and prostaglandins and nitric oxide (no). additionally, the ups also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of cdk inhibitors. lastly, autoimmune disease patients with sle, sjögren syndrome and rheumatoid arthritis (ra) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.