Association of manganese superoxide dismutase gene polymorphism (V16A) with diabetic macular edema in Korean type 2 diabetic patients

This study was designed to investigate whether V16A polymorphism of the manganese superoxide dismutase (Mn-SOD) gene is associated with the development of type 2 diabetes mellitus and with progression of diabetic retinopathy (DR) and diabetic macular edema (DME). We simultaneously analyzed insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene in the 16th intron to avoid its confounding effect. A total of 192 nondiabetic subjects and 304 type 2 diabetic patients were included in the study. Diabetic retinopathy was classified as nonretinopathy, nonproliferative retinopathy, and proliferative retinopathy. Diabetic macular edema was defined as thickening of the retina and/or hard exudates within a 1-disk diameter of the center of the macula. Diabetic macular edema was further classified into focal, diffuse, and ischemic types. The A allele frequency of the Mn-SOD gene was not different between nondiabetic and type 2 diabetic subjects, between the normotensive and hypertensive groups, between the DR (-) and DR (+) groups, and among the stages of DR. In the DR (+) group, the DME (+) group had a lower A allele frequency than that of the DME (-) group. In the DME (+) group, focal, diffuse, and ischemic types were found in 8, 23, and 6 patients, respectively. The A allele frequency of each type was 0.188, 0.109, and 0.0. The D allele frequency of the angiotensin-converting enzyme gene did not differ in any of the comparisons. Clinical and laboratory parameters of the A allele carriers were not different from those of the noncarriers except for the prevalence of hypertension and DME. Hypertension, diabetic duration, and insulin therapy were related to DR. The A allele, hypertension, and insulin therapy were associated with DME. In conclusion, our results suggest that V16A polymorphism of the Mn-SOD gene is not related to the development of diabetes and progression of DR, but is associated with DME in Korean type 2 diabetic patients.     

Platelet-activating factor-acetylhydrolase can monodeacylate and inactivate lipoteichoic acid

Bacterial lipoteichoic acid (LTA) shares a structural motif with platelet-activating factor (PAF). Both molecules are strong inflammatory agents and have a glycerol backbone with two lipid chains at the sn-1 and sn-2 positions. PAF is normally inactivated by PAF-acetylhydrolase (PAF-AH), a phospholipase A2 (PLA2), which removes a short acyl group at the sn-2 position. To investigate whether PAF-AH can similarly degrade LTA, we studied the effects of porcine PLA2, bee venom PLA2, and recombinant human PAF-AH on pneumococcal LTA (PnLTA) and staphylococcal LTA (StLTA). After incubation with a porcine or bee venom PLA2, a large fraction of PnLTA lost 264 Da, which corresponds to the mass of the oleic acid group at the sn-2 position. After incubation with recombinant human PAF-AH, PnLTA lost 264 Da; the reduction did not occur when PAF-AH was exposed to Pefabloc SC, an irreversible inhibitor of the PAF-AH active site. Following PAF-AH treatment, PnLTA and StLTA were not able to stimulate mouse RAW 264.7 cells to produce tumor necrosis factor alpha but could stimulate CHO cells expressing human TLR2. This stimulation pattern has been observed with monoacyl PnLTA prepared by mild alkali hydrolysis (22). Taking these data together, we conclude that PAF-AH can remove one acyl chain at the sn-2 position of LTA and produce a monoacyl-LTA that is inactive against mouse cells.     

Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea

BACKGROUND/AIMS: The authors conducted a hospital-based case-control study to evaluate the role of Clonorchis sinensis infection as a risk factor for the development of cholangiocarcinoma (CC), including extrahepatic CC, in Korea. METHODS: Cases of 185 patients with CC (intrahepatic, 51; hilar, 53; and distal extrahepatic, 81) and matched controls underwent stool microscopy, pathological examinations, serologic test for C. sinensis using ELISA, skin test for C. sinensis, radiologic examinations, and interview concerning history of eating raw freshwater fish. RESULTS: Radiologic evidence of C. sinensis, history of eating raw freshwater fish, and positive serologic result for C. sinensis were found to be related to an increased risk of CC, with the odds ratios (OR)=8.615 (95% confidence interval [CI]=5.045-16.062), OR=2.385 (95% CI=1.527-3.832), and OR=2.272 (95% CI=1.147-4.811), respectively. The risk factors for distal extrahepatic CC were radiologic evidence of C. sinensis (OR=6.571; 95% CI=3.170-15.943) and history of eating raw freshwater fish (OR=2.6; 95% CI=1.294-5.66). CONCLUSIONS: Radiologic evidence of C. sinensis, history of eating raw freshwater fish and positive serologic result for C. sinensis were significantly associated with CC, including extrahepatic CC.     

Osteoarthritis susceptibility loci defined by genome scan meta-analysis

Genome scans for osteoarthritis (OA) have yielded inconsistent results. The absence of replication of linkage might be due to lack of power of individual studies. A meta-analysis of the published data was performed to assess evidence for linkage of OA across genome scan studies. Three OA whole-genome scans including 893 families with 3,000 affected individuals were used for genome scan meta-analysis (GSMA). A total of 5 bins lie above 95% confidence level (P = 0.05) and 1 bin is above 99% confidence level (P = 0.01) in OA GSMA; bins 7.6 (7q34–7q36.3, Psumrnk = 0.0035), 11.3 (11p12–11q13.4), 6.3 (6p21.1–6q15), 2.8 (2q31.1–2q34) and 15.3 (15q21.3–15q26.1). The highest summed rank was observed at bin 7.6. In conclusion, the OA GSMA has shown chromosome 7q34–7q36.3 with the highest summed rank and four additional loci with significant summed ranks across studies.     

Scleroderma associated with ANCA-associated vasculitis

We have recently reported on two cases of scleroderma patients with ANCA-associated vasculitis for the first time in Korea. In order to explore the nature of this disease combination, we pooled together all the previously known cases and statistically analyzed them. Out of the 50 selected cases, survival analysis was done for comparison of the scleroderma disease period and the clinical factors associated with ANCA-associated vasculitis (AAV). Kaplan-Meier analysis revealed that patients having anti-topoisomerase antibody (anti-Scl-70) and, probably, PR-3 ANCA are at a higher risk for developing AAV than patients without both anti-topoisomerase antibody and anti-centromere antibody (ACA), and patients with MPO-ANCA. Multivariate Cox regression analysis revealed having anti-topoisomerase antibody as a risk factor for developing AAV [OR 3.1 (95% CI 1.11–8.55), P=0.031]. We suggest that having anti-topoisomerase antibodies may play a role among scleroderma patients in developing AAV. The authors have declared that there is no conflict of interests or affiliation to any interest group, and no publication of this study has been done.     

Association of TNF-alpha –308 G/A polymorphism with responsiveness to TNF-α-blockers in rheumatoid arthritis: a meta-analysis

Tumor necrosis factor (TNF) antagonists are among the most effective therapies for rheumatoid arthritis (RA), yet not all patients show a response. Using meta-analysis, this present study was designed to investigate whether or not the TNF-α promoter –308 A/G polymorphism is associated with responsiveness to anti-TNF therapy in RA patients. We performed an exhaustive search for studies that examined the association of the TNF-α promoter –308 A/G polymorphism and responsiveness of anti-TNF therapy in RA using MEDLINE citations and manual review. Meta-analysis was performed for A allele carrier (genotypes A/A + A/G) between responders to anti-TNF therapy and a non-responder group in a random effects model. A total of 6 studies met the inclusion criteria. The number of patients in individual studies ranged from 33 to 123. There were 311 RA patients who were included in this meta-analysis. There was no heterogeneity between studies (I ² = 0%, P = 0.42). The overall OR for the A allele carrier status was significantly decreased in the responder group (OR = 0.33, 95% confidence interval = 0.17–0.63, P = 0.0008). The frequency of the A allele carrier was 53/240 (22.1%) in responders and 32/71 (45.1%) in non-responders. Patients not responding to anti-TNF therapy showed an increased frequency of the A allele. The meta-analysis of the available data shows a significant association between the TNF-α promoter –308 A/G polymorphism and responsiveness to anti-TNF therapy, suggesting that the individuals with RA who carry the A allele have a poorer response to anti-TNF therapy than those with the G allele.     

Phenolic compounds from <Emphasis Type="Italic">Pueraria lobata</Emphasis> protect PC12 cells against Aβ-induced toxicity

Bioassay-guided fractionation of the EtOAc-soluble extract of Pueraria lobata based on the inhibition of Aβ-induced toxicity in PC12 cells resulted in the isolation of four known active compounds, genistein (8), biochanin A (9), sissotrin (10), and puerol B (11). Of these, genistein (8) and biochanin A (9) exhibited potent neuroprotective effects with ED₅₀ values of 33.7 and 27.8 μM, respectively. In addition, a new coumestan, 2-(α,α-dimethylallyl)coumestrol (1) was isolated and characterized, but proved to be inactive, as were additional seven known compounds. The structure of new compound 1 was determined using spectroscopic techniques.     

Effects of a newly developed tricyclic PARP‐1 inhibitor,on ischemic stroke

Poly(ADP‐ribose) polymerase (PARP)‐1 plays an important role in the pathogenic mechanism of ischemic stroke. A number of studies have been undertaken to develop PARP‐1 inhibitors for clinical use. We report on the newly developed PARP‐1 inhibitors, among which 12a showed good activity (IC₅₀=7.8 nM in an enzyme‐based assay and=0.73 µM in a cell‐based assay) and pharmacokinetic profiles. Treatment of the middle cerebral artery (MCA) occluded rats with 3 mg/kg 12a reduced infarct volume suggesting that, may be a good candidate for the treatment of ischemic stroke. Drug Dev Res 71: 253–260, 2010. © 2010 Wiley‐Liss, Inc.