BackgroundInflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα).Methodology/Principal FindingsExpression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE−/−) and TNFα deficient (TNFα−/−, ApoE−/−/TNFα−/−) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE−/− than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE−/− mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides.Conclusions/SignificanceHyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE−/− mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.
In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA. (Palapattu et al, 2005;Sun et al, 2005). Moreover, population studies have revealed an increased relative risk for development of prostate cancer in men with a prior history of sexually transmitted infections (Dennis and Dawson, 2002). These findings support the hypothesis that an infectious agent can be a potential cofactor in prostate cancer development. Human papilloma virus (HPV), Epstein -Barr virus (EBV) and the polyoma viruses JCV and BKV represent viruses with proven linkage to different human cancers and have been traced in prostate cancer tissues (Grinstein et al, 2002;Zambrano et al, 2002). To further evaluate if a viral infection could contribute to prostate cancer development, we conducted a case -control study of 402 patients with benign prostate hyperplasia (BPH), of which 201 later progressed to prostate cancer. We examined whether the presence of genetic traces of EBV, herpes simplex virus (HSV) 1 and 2, cytomegalovirus (CMV), adenovirus, HPV, polyoma viruses BKV and JCV and Candida albicans in the prostate correlate with histological inflammation and subsequent prostate cancer diagnosis. MATERIALS AND METHODSA case -control study of 402 archival prostate tissue samples obtained during transurethral resection of the prostate (TURP) collected at the Department of Pathology at the University Hospital of Northern Sweden, Umeå was conducted as described previously Bergh et al, 2006). Briefly, tissues were obtained from men with BPH (median age 64, range 51 -71), fixed in formalin, paraffin-embedded and stored at room temperature until tested. A total of 201 men developed prostate cancer at least 6 months after the TURP. For each case, a control was randomly selected from a cohort of patients that did not develop prostate cancer. The case -control pairs were matched for year of birth, residence and year of TURP. Histological inflammation was graded as mild or severe as described . DNA from prostate tissue was purified and checked for integrity as described . Nested PCR assays were used for all the assays except HPV and C. albicans PCRs. Primers and PCR protocols for adenovirus (Allard et al, 2001), CMV (Brytting et al, 1991), EBV (Meyohas et al, 1996), HSV1 and 2 (Aurelius et al, 1991) and HPV (de Roda Husman et al, 1995) were used with minor modifications. Primers for the polyoma viruses JCV and BKV and C. albicans were designed according to published sequence information (Table 1). To verify the positive PCR findings, PCR products were purified with QIAquick Purification Kit protocol (Qiagen s , Hilden, Germany) and directly sequenced in the ABI PRISM 3700 DNA ANALYSER (AME Bioscience, Toroed, Norway) using the Big Dyet Terminator Cycle Sequencing kit 1.1 (Applied Biosystems, Forster City, CA, US...
ABSTRACT.Purpose: To assess and correlate the levels of inflammatory mediators in the eyes from non-diabetic and diabetic subjects without retinopathy (NDR), with non-proliferative diabetic retinopathy (NPDR) or with proliferative diabetic retinopathy (PDR) to corresponding erum levels. Methods: The levels of interleukin 1b, interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a) were analysed by an ELISA-mimicking technique in the vitreous from 26 diabetic subjects with active PDR and 27 non-diabetic subjects, or by a multiplex bead assay in the aqueous humour from 35 diabetic subjects with NDR ⁄ NPDR and 40 non-diabetic subjects. Intraocular protein production was estimated in vitreous specimens by calculating a vitreous ⁄ serum ratio. Results: In the vitreous, IL-6 was higher in diabetic [157.5 (25.0-1401.0) pg ⁄ ml; median (min-max)] than in non-diabetic subjects [44.0 (5.0-4425) pg ⁄ ml; p = 0.021]. The vitreous ⁄ serum ratio was high (55.5:1 and 16:1, respectively), suggesting intraocular production. TNF-a was lower in diabetic [18.0 (8.0-46.0) pg ⁄ ml] than in non-diabetic subjects [22.0 (13.0-47.0) pg ⁄ ml; p = 0.034], but the vitreous ⁄ serum ratio was elevated in both groups (2:1 and 3.4:1, respectively). TNF-a levels were higher in serum from diabetic subjects [9.0 (5.0-53.0) pg ⁄ ml versus 6.7 (3.0-11.0) pg ⁄ ml; p < 0.001]. Aqueous levels of inflammatory mediators did not differ between diabetic subjects with NDR ⁄ NPDR and non-diabetic subjects despite elevated TNF-a in serum [27.8 (6.8-153.7) pg ⁄ ml versus 16.4 (4.1-42.4) pg ⁄ ml; p = 0.021]. Conclusion: Intraocular inflammation seems to be involved in PDR but does not seem to be prominent in early retinopathy stages, i.e. NDR or NPDR. Diabetic subjects have an overall increased inflammatory activity compared to non-diabetic subjects, as demonstrated by increased serum levels of TNF-a.
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