Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.
Anti-Inflammatory Agents, Non-Steroidal/pharmacology* ; Chromatography, Affinity ; Computer Simulation ; Enzyme Inhibitors/pharmacology ; Human ; Isoenzymes/isolation & purification ; Isoenzymes/antagonists & inhibitors ; Ketoprofen/pharmacology ; Leukocyte Elastase/isolation & purification ; Leukocyte Elastase/antagonists & inhibitors* ; Models, Molecular ; Naproxen/pharmacology ; Phenylbutazone/analogs & derivatives ; Salicylates/pharmacology ; Spectrum Analysis, Raman

The major defining pathological hallmarks of Alzheimer's disease (AD) are the accumulations of Abeta in senile plaques and hyperphosphorylated tau in neurofibrillary tangles and neuropil threads. Recent studies indicate that rather than these insoluble lesions, the soluble Abeta oligomers and hyperphosphorylated tau are the toxic agents of AD pathology. Such pathological protein species are accompanied by cytoskeletal changes, mitochondrial dysfunction, Ca2+ dysregulation, and oxidative stress. In this review, we discuss how the binding of Abeta to various integrins, defects in downstream focal adhesion signaling, and activation of cofilin can impact mitochondrial dysfunction, cytoskeletal changes, and tau pathology induced by Abeta oligomers. Such pathological consequences can also feedback to further activate cofilin to promote cofilin pathology. We also suggest that the mechanism of Abeta generation by the endocytosis of APP is mechanistically linked with perturbations in integrin-based focal adhesion signaling, as APP, LRP, and beta-integrins are physically associated with each other.
Alzheimer Disease ; Amyloid ; Cytoskeleton ; Endocytosis ; Focal Adhesions ; Integrins ; Mitochondria ; Neurofibrillary Tangles ; Neuropil Threads ; Oxidative Stress ; Plaque, Amyloid

PURPOSE: I-131 labeled (2'-deoxy-2-iodo-p-D-arabinofuranosyl) adenine (IAD) may be involved in DNA synthesis during active proliferation of tumor cells. We conducted this study to find out the biodistribution of IAD and its feasibility for scintigraphic tumor imaging. MATERIALS AND METHODS: Tosyl acetyl-adenosine was dissolved in acetonitrile, and I-131-NaI was added and heated to synthesize IAD. Female Fisher 344 rats innoculated with breast tumor cells were injected witb 0.27 MBq of IAD. Rats were sacrificed at 0.5, 1, 2, 4, 24h and the % of injected dose per gram of tissue (%ID/g) was determined. For scintigraphy, rats bearing breast cancer were administered with 1.11 MBq of IAD and imaging was perforrned after 2 and 24h. Then, rat body was fixed and rnicrotomized slice was placed on radiographic film for autoradiography, RESULTS: %ID/g of tumor wa.' 0.74 (0.5h), 0.73 (1h), 0.55 (2h), 0.38 (4h), and 0.05 (24h), respectively. At 1h after injection, %ID/g of tumor was higher than that of heart (0.34), liver (0.42), spleen (0.47), kidney (0,69), muscle (0.14), bone (0.33) and intestine (0.51). However, %1D/g of tumor was lower than blood (1.06), lung (0.77), and thyroid (177.71). At 4h, %ID/g of tumor in comparison with other tissue did not change. Tumor contrast expressed by tumor to blood ratio was 0.69 and tumor to muscle ratio was 5.11 at 1h. However, these ratios did not improve through 24h. On autoradiogram and scintigraphy at 2 and 24 hour, the tumor was well visualized. CONCLUSION: This results suggest that Ial) may have a potential for tumor scintigraphy. However, further work is needed to improve localization in tumor tissue.
Adenine ; Animals ; Autoradiography ; Breast Neoplasms* ; Breast* ; DNA ; Female ; Heart ; Hot Temperature ; Humans ; Intestines ; Kidney ; Liver ; Lung ; Radionuclide Imaging* ; Rats* ; Spleen ; Thyroid Gland ; X-Ray Film

OBJECTIVE: To investigate the prevalence and characteristics of musculoskeletal pain (MSK) pain in Korean farmers using initial survey data of Farmers' Cohort for Agricultural Work-Related MSK pain (FARM) study. METHODS: Farmers (534 females and 479 males; mean age 57.2±7.5 years) who owned or rented a farm and belonged to an agricultural cooperative unit were recruited. Presence of pain for each body part (neck, shoulder, arm/elbow, wrist/hand/finger, low back, leg/foot), and characteristics of MSK pain (prevalence, location, duration, severity, and frequency) during the last year was assessed. Additionally, demographic data such as farming duration, history of prior injury, and workload (low, moderate, somewhat hard, or hard) were collected using structured questionnaires. RESULTS: Almost all subjects (n=925; 91.3%) complained of pain in more than one body part. The frequency order was low back (63.8%), leg/foot (43.3%), shoulder (42.9%), wrist/hand/finger (26.6%), arm/elbow (25.3%), and neck (21.8%). Low back pain was more frequent in those with over 30 years of farming experience (odds ratio [OR], 1.40; 95% confidence interval, 1.08-1.81). MSK pain was related to history of prior injury (OR, 2.18-5.24; p<0.05) in all body parts except for leg/foot, and very hard workload was associated with low back, leg/foot, neck, shoulder, and wrist/hand/finger pain (OR, 2.88-10.83; p<0.05). CONCLUSION: Most Korean farmers experience MSK pain; furthermore, there is a significant association between pain, history of prior injury, and workload, suggestive of the necessity of coping and preventive strategies to reduce injury or workload.
Agriculture ; Cohort Studies ; Female ; Human Body ; Humans ; Low Back Pain ; Male ; Musculoskeletal Pain* ; Neck ; Prevalence* ; Shoulder