吸烟与2型糖尿病血管并发症

血管并发症是2型糖尿病患者的严重慢性并发症之一.近年研究发现吸烟在糖尿病血管并发症(包括心、脑等大血管并发症和肾脏、视网膜等微血管并发症)的发生、发展中起着重要作用,其通过增加胰岛素抵抗,影响糖、脂代谢,损害血管内皮细胞及血小板功能,致低度炎性反应,诱导氧化应激等作用加速糖尿病血管并发症的出现和进展.研究吸烟与糖尿病血...     

Interaction between hydrogen peroxide and titanium: a possible role in the biocompatibility of titanium

Hydroxyl radicals formed from hydrogen peroxide during an inflammatory response are potent agents for cellular deterioration. The behaviour of implanted material in terms of its ability to sustain or stop free radical formation may be therefore very important. In vitro studies of titanium which is known to be biocompatible and osseointegrates into human bone were carried out. In our model studies, the production of free radicals from H2O2 at Ti and TiO2 surfaces was measured by spin trapping techniques. Our findings suggest that there is no sustained hydroxyl radical production at a titanium (oxide) surface. We propose that this is due to the quenching of the Fenton reaction through both trapping and oxidation of superoxide radicals in a TiOOH adduct.     

Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus

 Hyperglycemia is the major causal factor in the development of diabetic vascular complications and can mediate their adverse effects through multiple pathways. One of those mechanisms is the activation of protein kinase C (PKC) by hyperglycemia-induced increases in diacylglycerol (DAG) level, partly due to de novo synthesis. The activation of PKC regulates various vascular functions by modulating enzymatic activities such as cytosolic phospholipase A₂ and Na⁺,K⁺-ATPase, and gene expressions including extracellular matrix components and contractile proteins. Some of the resulting vascular abnormalities include changes in retinal and renal blood flow, contractility, permeability, proliferation, and basement membrane. Among the various isoforms of PKC predominantly the β isoforms are activated in cultured vascular cells exposed to high glucose and vascular tissues isolated from animal models of diabetes mellitus. Administration of vitamin E, which decreases DAG level possibly through the activation of DAG kinase, prevents hemodynamic changes in retina and renal glomeruli of diabetic rats. In addition, the inhibition of PKC β isoforms by a specific inhibitor (LY333531) can normalize the changes in gene expression of cytokines, caldesmon, and hemodynamics. These results provide supportive evidence that the activation of PKC, especially the β isoforms, is involved in the development of diabetic vascular complications, and that PKCβ inhibitors can be used in the treatment of diabetic vascular complications. Received: 1 January 1997 / Accepted: 29 May 1997     

On the association between amyloid fibrils and glycosaminoglycans; possible interactive role of Ca2+ and amyloid P-component.

We have previously reported the specific association of glycosaminoglycans (GAG) and proteoglycans (PG) with amyloid fibrils and characterized the polysaccharides directly extracted from amyloid-laden tissues. In the present study we further elucidate the association between purified amyloid fibrils and GAG/PG with special reference to those GAG/PG associated with amyloid P-component (AP) and the interactive role of Ca2+ ions. Amyloid fibrils were isolated from human hepatic AA amyloid employing water extraction with and without preceding removal of AP, an extrafibrillar protein component of all amyloids, using sodium citrate. GAG/PG co-isolated with the amyloid extracts, with and without AP, were isolated and characterized. Agarose-affinity chromatography of extracts containing AP was performed, and the GAG associated with this extrafibrillary protein were characterized as well. Several different GAG/PG populations were demonstrated in the various extracts. The abolition of calcium-dependent binding markedly influenced the amount of GAG/PG recovered in the fibril extracts, as well as the total amount of amyloid material obtained. Thus, it seems that calcium plays an important role in the association between the fibrils and the sugar moieties, and that a significant fraction of the GAG found in amyloid exhibits a Ca(2+)-dependent fibril-GAG interaction. No significant difference in the proportion between galactosaminoglycans and glucosamines was, however, disclosed when the two extraction protocols were compared, suggesting that no particular GAG species has a higher affinity for the fibrils themselves. Both dermatan/chondroitin sulphate and heparan sulphate identified in the present study exhibited a Ca(2+)-dependent interaction with AP, supporting previous findings. However, the amyloid-associated galactosaminoglycans found, especially the large PG appearing in small amounts, seemed to have a higher affinity for the extrafibrillar AP than the other GAG.     

Negative correlations between parenchymal amyloid and vascular amyloid in hippocampus.

Congo red was used to stain amyloid in 29 blocks of hippocampus from 17 unselected cases of Alzheimer's disease. Green birefringence under polarized light was used for evaluation of the average number of senile plaques and cross-sectional vessel profiles containing amyloid in five fields per slide, at a magnification of X100. Fields were selected that had large numbers of neurofibrillary tangles, also counted on the basis of green birefringence. The vascular involvement by amyloid was expressed as the ratio of amyloid positive to amyloid negative profiles. A negative correlation was found between Congophilic plaques or tangles on the one hand and vascular amyloid content on the other. In other words, cases with large numbers of Congophilic plaques had fewer Congophilic vessels, and vice versa: congophilic plaques = -3 (vessel amyloid) + 2.2, Spearman correlation coefficient, -0.61, P less than 0.01; tangles = -3.7 (vessel amyloid) + 15.6, Spearman correlation coefficient, -0.05, P greater than 0.05. When the slides were reexamined, using only fields with at least one Congophilic vessel, the negative correlation for plaque versus vessel amyloid remained highly significant, whereas that for tangles versus vessel amyloid became highly significant: Congophilic plaques = -1.2 (vessel amyloid) + 2.3, Spearman correlation coefficient, -0.48, P less than 0.01; tangles = -5 (vessel amyloid) + 19, Spearman correlation coefficient, -0.48, P less than 0.01. These data are most compatible with the hypothesis that amyloid is first produced in the parenchyma and is somehow cleared by the vessels. It is least compatible with the hypothesis that the amyloid precursor protein first enters the vessel wall to produce amyloid there, and then moves into the brain to produce amyloid in parenchymal sites.     

Association between serum amyloid A and obesity: a meta-analysis and systematic review

Background  

Emerging evidence indicates an association of the acute-phase protein serum amyloid A (SAA) with obesity. Here we review and summarize quantitatively the available data related to this association.     

A role for metallothionein in the pathogenesis of diabetes and its cardiovascular complications

It has been suspected for a long time that zinc has a role in various aspects of diabetes, but specific molecular targets of zinc remained largely elusive. Recent discoveries of associations between diabetes and polymorphisms in human genes now suggest that proteins that control the cellular availability of zinc ions are involved. One protein is the zinc transporter ZnT-8 that supplies pancreatic beta-cells with zinc. The other is metallothionein 1A, a member of a protein family that links zinc and redox metabolism. Changes in the availability of zinc ions modulate insulin signaling and redox processes. Both zinc and metallothionein protect cells against the redox stress that occurs in diabetes and contributes to its progression towards diabetic complications, including heart disease.     

A possible role for bacteria in the pathogenesis of insulin dependent diabetes mellitus

The hypothesis proposed is that insulin dependent diabetes mellitus (IDDM) is caused by an autoimmune response precipitated by common bacteria which have antigens in common with pancreatic beta cells. If the bacteria are enteric, but IDDM arises when first exposure occurs in the nasopharynx following a viral respiratory tract infection, then the various epidemiological features of IDDM can be explained. These include a latent interval between disease onset and clinical presentation, seasonal variation in presentation, an increased incidence in temperature climates and technologically advanced countries, and the lack of an effect of incidence on age distribution. The hypothesis points to new avenues of research and should be pursued.     

D-dimer identifies stages in the progression of diabetes mellitus from family history of diabetes to cardiovascular complications

AIM: The aim of the study was to ascertain whether there is variation in the fibrinolytic/coagulation component of diabetes associated with disease progression to macrovascular complications and whether D-dimer can discriminate such variation. METHODS: A total of 343 participants were selected based on clinical status and divided into 7 groups: control, family history of diabetes, pre-diabetes with/without CVD, diabetes with/without CVD and CVD only. Plasma D-dimer was tested. Statistical analysis was performed on log normalised data by ANOVA, Fisher's LSD post hoc test. After the initial analysis, data were classified and re-analysed by quartiles, interquartile range and 95(th) percentile. RESULTS: An overall significant difference between groups (p<0.002) and a steady rise in D-dimer levels that became increasingly higher than control as the disease progressed from pre-diabetes to cardiovascular complications was observed. A statistically significant difference was observed between control versus diabetes (p<0.0005). Analysis of data by quartiles and percentiles gave qualitatively similar results, but a greater significant difference between control versus pre-diabetes at 3rd quartile and interquartile range (p<0.014). CONCLUSION: We report changes in D-dimer levels that may indicate diabetes disease progression to macrovascular complications. Using D-dimer in conjunction with other biomarkers to identify stages of disease progression, commencing from pre-diabetes and continuing to development of asymptomatic and clinical cardiovascular disease in diabetes mellitus, is worthy of consideration.     

Rapid recycling of cholesterol: the joint biologic role of C-reactive protein and serum amyloid A

Proteins that are highly conserved throughout evolution are presumed to have critical roles in the survival of the species. The two major acute phase proteins, C-reactive protein (CRP) and serum amyloid A (SAA) increase up to 1000-fold during inflammation. Both proteins have been highly conserved phylogenetically for at least the last 500 million years. Thus far the physiologic role and the evolutionary significance of each remains uncertain and their potential interactions have been totally ignored despite a vast and accelerating scientific literature on the involvement of each in human disease. CRP is known to bind to phosphocholine in dead eukaryote and some live bacterial cell walls suggesting that CRP facilitates the phagocytosis of fragmented or intact dead cells and/or enhances host bacterial defenses. SAA has recently been shown to increase the rate of export of cholesterol of phagocytosed cell membranes from macrophages fourfold. We postulate that their combined physiological role is to facilitate the rapid endogenous recycling of cell membrane cholesterol and phospholipids during acute inflammation. CRP promotes efficient phagocytosis of dying cells by macrophages; SAA enhances the export of their free cholesterol/phospholipid for reuse in the membranes of the hundreds of billions of new cells required daily during acute inflammation and repair. The evolutionary conservation of these proteins in species from the horseshoe crab and echinoderms to humans suggests that the rapid endogenous recycling of cholesterol and phospholipids during the highly vulnerable period of acute inflammation is critical for their continual survival.     

Interaction between Chlamydia spp. and human polymorphonuclear leukocytes in vitro

Chlamydia psittaci and Chlamydia trachomatis elementary bodies (EB) incubated in the presence of complement or specific antibody or both caused chemotaxis of human polymorphonuclear leukocytes (PMN) in vitro. Reticulate bodies and culture supernatants had no effect on these cells. The ability of chlamydiae to enter and survive in PMN under nonopsonizing conditions was investigated by measuring the association of 3H-labeled EB and of inclusion-forming units with these phagocytes. Both assays indicated that C. psittaci as well as C. trachomatis EB are efficiently internalized. The mechanism by which this is accomplished is distinct from classical phagocytosis in that it is not dependent upon the presence of complement or antibody. Furthermore, uptake of at least C. psittaci appeared to be rapid, with no additional increase occurring after 15 min. The majority of cell-associated chlamydiae were rendered acid soluble or noninfectious within 1 h. Subsequently, there was a small but steady loss of infectivity for up to 10 h, which may have been due to the conversion of EB to the noninfectious reticulate-body form of the organism. However, even at 10 h after entry a small percentage of bacteria was still capable of infecting a second target cell. This is noteworthy in that PMN are relatively short-lived cells, and after lysis, intracellular organisms may be free to infect adjacent tissue. Electron microscopic observations were consistent with the data on uptake and persistence. The ability of a small percentage of infecting chlamydiae to maintain infectivity in PMN for at least several hours may enable these organisms subsequently to establish productive infection in permissive host cells.     

Increase in vascular permeability induced by leukotriene b4 and the role of polymorphonuclear leukocytes

Leukotriene B₄ (LTB₄), a metabolite of arachidonic acid, is known to be a potent chemotactic and chemokinetic substance. We have used the hamster cheek pouch microcirculation model to study the effect of LTB₄ on vascular permeability and the involvement of neutrophil granulocytes in this response. Intravascular fluorescein-labeled dextran (mol wt 150,000) was used as a tracer of macromolecular permeability. Topical application of LTB₄ (150 nM-5 M) to the hamster cheek pouch resulted in an immediate increase in adhering leukocytes in postcapillary venules and later larger venules. Leukocyte accumulation was reversible, but continued longer the higher the dose of LTB₄ used. Subsequently, a dose-dependent increase in vascular permeability was seen at postcapillary and larger venules, with a maximum 10–20 min after application; the maximum occurred later the higher the dose of LTB₄. Depletion of neutrophil granulocytes by pretreatment of the animals with antineutrophil serum obtained from immunized rabbits significantly decreased the permeability response to LTB₄, whereas the response to histamine was unaffected. These results suggest that neutrophil granulocytes play a role in LTB₄-mediated permeability increase. LTB₄ may be of importance both for the leukocyte accumulation and for the edema formation seen in inflammatory reactions.     

Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis

Imbalance oxidative stress and chemokines are considered as a universal factors involved in the development of various clinical features seen in the patients with SLE and arthritis. To evaluate the interaction between oxidative stress and chemokines and their relationship with disease activity in SLE and RA patients, oxidative/anti-oxidant profiles and chemokines were assessed. Oxidant and anti-oxidant enzymes were measured in the plasma and the levels of chemokines; MCP-1/CCL2, RANTES/CCL5, MIP-1β/CCL-4 and IP-10/CXCL-10 were evaluated in the serum by an enzyme-linked immunosorbent assay (ELISA). A significant increase in the level of lipid peroxidation was found in SLE and RA patients and positively associated with disease activity. The activities of anti-oxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and anti-oxidant molecule GSH were significantly reduced in both diseases. Strong positive associations were found between MDA with RANTES/CCL5 and MIP-1β/CCL4 than MCP-1/CCL-2 in SLE patients while a sturdy connotation was seen with MIP-1β/CCL4 and MCP-1/CCL-2 in RA patients. The anti-oxidant molecule GSH shows a negative association with serum levels of MCP-1/CCL-2, RANTES/CCL5 and IP-10/CXCL-10 in SLE patients and with MCP-1/CCL-2 and RANTES/CCL5 in RA patients. A low level of GSH and high level of RANTES/CCL5 were associated with lupus nephritis patients. These results indicates that excessive production of ROS disturbs redox status and can modulate the expression of inflammatory chemokines leading to inflammatory processes, exacerbating inflammation and affecting tissue damage in autoimmune diseases, as exemplified by their strong association with disease activity.     

Hypothesis: insulin is responsible for the vascular complications of diabetes

It is proposed that the systemic hyperinsulinemia and hepatic portal hypoinsulinemia that occurs with conventional injectable preparations of insulin currently used in the treatment of patients with diabetes mellitus is largely responsible for the morbidity associated with this disease. Epidemiological evidence and animal experimentation strongly support systemic hyperinsulinemia as a major factor in genesis of atherosclerosis in diabetic patients. In addition, in vitro studies demonstrate a direct effect of insulin on endothelial cell and arterial smooth muscle proliferation. On the other hand, inadequate hepatic delivery of insulin is associated with overproduction of renal vasoregulatory factors leading to glomerular hyperfiltration and ultimately to glomerulosclerosis and its clinical endpoint--end-stage renal disease. In the absence of widespread success of pancreatic and islet-cell transplantation as a means to deliver insulin physiologically into the hepatic portal circulation, methods must be devised and perfected to accomplish such delivery using approaches such as orally administering insulin in intestinal-enzyme protected capsules. Until such methods of delivery are available for safe and widespread use, one should abandon the illusory goal of rigid glucose control in favor of methods that reduce insulin requirement. Along these lines, dietary restriction and aerobic exercise should be the major life style changes advised for diabetic patients. Reduction of glomerular hyperfiltration in diabetic patients can be promoted with the use of low protein diets and/or angiotensin converting enzyme inhibitors.     

The role of polymorphonuclear leukocytes in rat chronic serum sickness-type nephritis

In order to investigate the role of polymorphonuclear leukocytes (PMN) in the distribution of antigen in various organs and in the development of nephritis, chronic serum sickness-type nephritis was induced in both anti-rat PMN rabbit serum (APS)-treated and normal rabbit serum (NRS)-treated rats by preimmunization with bovine serum albumin (BSA) and subsequent daily intravenous administration of BSA for 4 weeks. Kinetic studies using radiolabeled BSA showed that accumulation of BSA after the first intravenous administration was reduced by APS treatment in the liver, lungs and spleen and increased in the circulation, but was not affected in the kidneys and glomeruli. Histological studies supported the above findings. After 4 weeks of BSA administration, the BSA accumulation in the kidneys and glomeruli was significantly less in APS-treated rats than in NRS-treated ones, while amounts of BSA in the circulation and other organs were not different between the two groups. Furthermore, APS treatment reduced proteinuria, PMN infiltration and IC deposition in the glomeruli. These observations indicate that PMN play a partial role in IC deposition in the glomerular capillary walls and subsequent destruction of glomerular permeability in chronic serum sickness-type nephritis.