Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.
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PMID:TNF blockade: an inflammatory issue. 1633 57

Monocytes have been isolated from patient's blood and directly radiolabelled in vitro using a variety of radiopharmaceuticals such as 99mTc-HMPAO, 111In-oxine, 99mTc-colloids and 18F-FDG. Overall, the best labeling results were obtained using 99mTc-HMPAO. The wide availability of 99mTc and of the ligand HMPAO in kit-formulation makes it the most versatile procedure for imaging localized inflammation using in-vitro labeling. Injection of 99mTc-HMPAO labeled monocytes in adult patients has proven safe with an effective dose of 0.011 mSv/Mbq, equivalent to that of 99mTc-HMPAO labeled mixed white blood cells. Furthermore, in a proof of concept studies, in-vitro labeled monocytes were shown to specifically accumulate in the bowels of patients suffering from inflammatory bowel disease as well as in inflamed joints of rheumatoid arthritis patients. Inversely, the decrease in disease activity of inflamed joints of rheumatoid arthritis patients treated by Adalimumab could not be substantiated using 99mTc-HMPAO labelled monocytes suggesting this type of treatment does not reduce monocyte influx. In spite of their wide availability, in-vitro labeling procedures are cumbersome and time-consuming. Furthermore, cell activation may occur during the labeling process and it cannot be excluded that the radiopharmaceuticals used for labelling interfere with ongoing cellular processes. As such, various authors turned towards the development of radiopharmaceuticals for in-vivo labeling of both monocytes and more importantly macrophages, many of which were subsequently validated in animal models. Targets studied in this regard include amongst others the folate receptor, the mannose receptor, the peripheral benzodiazepine receptor as well as more general characteristics of macrophages such as phagocytosis. Various of these novel molecules appear promising and clinical studies using these radiopharmaceuticals are awaited in the near future. Some of these radiopharmaceuticals also reached the clinical stage, respectively the translocating protein targeting radiopharmaceutical 11C-PK11195 and the folate receptor targeting radiopharmaceutical 99mTc-EC20. Uptake of 11C-PK11195 in inflamed joints and sites of atherosclerosis in patients proved to be directly related to the number of peripheral benzodiazepine binding receptors available as well as to the severity of ongoing inflammation. Comparable results were obtained using 99mTc-EC20 in rheumatoid arthritis patients. In spite of these promising results, additional studies are warranted demonstrating that in vivo, quantitative visualization of monocyte trafficking and accumulation of M1 or M2 macrophage subtypes in sites of ongoing inflammation by means of SPECT and PET will contribute to a better understanding of human inflammatory diseases as well as to diagnosis, treatment planning and the development of targeted treatment strategies.
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PMID:Targeting monocytes and macrophages by means of SPECT and PET. 2484 56