Similar physiological and biochemical responses are induced by a variety of invasive stimuli including bacterial, viral, protozoan and metazoan infection, and some tumors. These include fever, leukocytosis, and elevated concentrations of specific serum proteins such as fibrinogen, haptoglobin (1, 2), and serum amyloid A protein (SAA) 1 (3, 4). Recently, we noted that an additional biochemical response, a hypertriglyceridemia, characteristically occurs in rabbits infected with the protozoan parasite, T~ypanosoma brucei (5). This hypertriglyceridemia, representing an accumulation of very low density lipoprotein in plasma, was found to result from decreased removal due to a deficiency of lipoprotein lipase, the key enzyme of triglyceride metabolism (6) in the peripheral tissue. A similar biochemical derangement was observed in rabbits carrying the V-2 carcinoma (C. A. Rouzer and A. Cerami, unpublished observations). Hyperlipidemia has also been associated with several bacterial (7,8) and viral infections (9, 10) and with endotoxemia (11-13). The generalized occurence of this phenomenon stimulated us to investigate the biochemical mechanism(s) responsible for the lipoprotein lipase deficiency.The hypertriglyceridemia associated with the administration of bacterial endotoxin was chosen as an experimental model because it is simpler and more quantifiable than experimental infection. Furthermore, endotoxin is a well-characterized material. The endotoxin model has the significant additional advantage of having two genetically similar strains of mice, one of which is sensitive to and one of which is resistant to this material (14). Using these endotoxin-sensitive and -resistant mice, previous workers (15, 16) have demonstrated that several biological actions of endotoxin are mediated by exudate cells. These include granulocytosis, changes in plasma iron and fibrinogen concentration, and production of SAA. It appears that endotoxin interacts with these exudate ceils, causing the release of a humoral mediator factor that is responsible for the effect observed. In the present communication we report that the endotoxin-induced decrease in lipoprotein lipase activity proceeds by a similar mechanism. Exudate cells, in response to stimulation by endotoxin, release a mediator substance that causes a lowering of lipoprotein lipase activity in adipose tissue. Materials and Methods Endotoxin.Endotoxin (lipopolysaccharide) from Escherichia coli 0127:B8 isolated by the method of Westphal (17) was purchased from Difeo Laboratories, Detroit, Mich.
Natural polyamines, spermine, spermidine, and putrescine, play a pivotal role in the regulation of gene expression; therefore, the age-dependent decreases and the disease-dependent increases in polyamine synthesis suggest a possible contribution of polyamines to the age-related and disease-associated changes in cellular function. In this study, we examined the effects of polyamines on the cellular function and the expression of adhesion molecules on human PBMCs from healthy volunteers. Flow cytometry revealed that PBMCs cultured with spermine decreased mean fluorescent intensities (MFIs) of CD11a and CD18 in the lymphocyte light-scattered region, but not in the monocyte region. This suppression was observed in a dose- and time-dependent manner and found nonspecifically on all cell subsets we tested (CD3+, CD4+, CD8+, CD19+, CD45RA+, CD45RO+, CD4+CD45RA+, CD4+CD45RO+, CD8+CD45RA+, CD8+CD45RO+). The decreases of CD11a and CD18 MFIs were accompanied by the decrease in adherent capacity of PBMCs to HUVECs. Spermine did not hinder cell activities or cell viability. Among 42 healthy volunteers (mean, 49.5 years old; from 26 to 69), blood spermine levels inversely correlated with the CD11a MFIs of cells in the lymphocyte region (r = −0.48; p = 0.001), but not with those in the monocyte region. The effects of spermidine seemed weaker than those of spermine, and blood spermidine levels had no correlation with CD11a MFIs of the lymphocyte region. Putrescine had no effect on the expressions of membrane molecules. Polyamines, especially spermine, decrease LFA-1 (CD11a/CD18) expression on human lymphocyte and adhesion capacity of PBMCs to HUVECs.
In pancreatic b-cells, closure of the ATP-sensitive K + (K ATP ) channel is an initial process triggering glucosestimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K ATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose-and incretinactivated NSCC (TRPM2) works in concert with closure of the K ATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in b-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.It has been long proposed that glucose-stimulated insulin secretion in pancreatic b-cells is initiated by closure of the ATP-sensitive K + (K ATP ) channel, followed by membrane depolarization (1). In theory, closure of the K ATP channel is an important process but is not sufficient to induce the shift of the membrane potential toward a threshold level, as membrane potential is determined by the overall balance of outward and inward currents. Modest constitutive opening of background inward current through nonselective cation channels (NSCCs) is crucial to facilitate depolarization after K ATP channel closure (2). This idea suggests that further regulated opening of a class of NSCCs may bring about greater depolarization. However, whether glucose metabolism regulates NSCC activity remains unclear.The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), potentiate insulin secretion in association with increased intracellular Ca 2+ concentrations at insulin-secreting glucose concentrations (3-5). GLP-1 fails to increase insulin secretion from the islets of mice deficient in transmembrane receptor potential (TRP) melastatin 2 (TRPM2) (6,7), a type of NSCC, suggesting that the TRPM2 channel is essential for GLP-1-induced potentiation of glucose-stimulated insulin secretion (8). GLP-1 depolarizes the plasma membrane by the opening of NSCC in b-cells (2). Several types of NSCC (TRPs) are expressed in insulin-secreting cells (9). The aims of the current study were to determine 1) the type of NSCC activation (through TRPM2 or other TRPs) that is crucial for signaling after stimulation of the incretin receptor, 2) whether the NSCC is modulated by glucose
The present study investigates whether lower-limb dominant exercise training in patients with chronic heart failure (CHF) improves endothelial function primarily in the trained lower extremities or equally in the upper and lower extremities. Twenty-eight patients with CHF were randomized to the exercise or control group. The exercise group underwent cycle ergometer training for 3 months while controls continued an inactive sedentary lifestyle. Exercise capacity (6-min walk test) and flow-mediated vasodilation in the brachial and posterior tibial arteries were evaluated. After 3 months, walking performance increased only in the exercise group (488+/-16 to 501+/-14 m [control]; 497+/-23 to 567+/-39 m [exercise, p<0.05]). The flow-mediated vasodilation in the brachial arteries did not change in either group (4.2+/-0.5 to 4.5+/-0.4% [control]; 4.3+/-0.5 to 4.6+/-0.4% [exercise]), but that in the posterior tibial arteries increased only in the exercise group (4.1+/-0.5 to 4.1+/-0.3% [control]; 3.6+/-0.3 to 6.4+/-0.6% [exercise, p<0.01]). Cycle ergometer training improved flow-mediated vasodilation in the trained lower limbs, but not in the untrained upper limbs. Exercise training appears to correct endothelial dysfunction predominantly by a local effect in the trained extremities.
Tumor necrosis factor (TNF) has been reported to be identical to "cachectin," a monokine which we have previously proposed as a mediator of the enhanced catabolism observed in patients or animals responding to various invasive stimuli such as infections. Detailed quantitative studies were conducted on the effects of TNF on fatty acid metabolism in 3T3-L1 cells in order to explore the extent of the catabolic effects exerted by TNF compared with those by the crude cachectin. 3T3-L1 adipocytes responded to recombinant human TNF, showing a decrease in LPL activity and an increase in intracellular lipolysis. When TNF in the crude cachectin preparation was completely neutralized with anti-TNF antibody, about 75% of LPL suppression activity in the crude cachectin was absorbed, indicating that most of the mediator responsible for LPL suppression in the crude preparation is TNF. In contrast to the above effect on LPL, TNF markedly increased the lipolysis of stored fat in the cells. The effect on LPL was observed as early as 2 h after the addition of TNF, but enhancement of lipolysis required a time lag of at least 3 h before any increase of glycerol release became apparent. The effective concentrations of TNF for the stimulation of lipolysis were much higher (2.5 to 49 nM) than those for LPL suppression (50 pM to 50 nM), but both were in the same range as the concentration required for tumoricidal effect. These results demonstrate that cachectin is synonymous with TNF and that it plays an important role in the pathophysiology of deranged lipid metabolism through both suppression of LPL and enhancement of lipolysis in patients coping with invasive conditions such as infections.
Abstract-Acute aortic dissection (AAD) is associated with an inflammatory reaction, as evidenced by elevated inflammatory markers, including C-reactive protein (CRP). The association between the peak CRP level and long-term outcomes in type B AAD has not been systematically investigated. The purpose of this study was to investigate whether the peak CRP level during admission predicts long-term outcomes in type B AAD. We conducted a clinical follow-up study of type B AAD. We divided the study population into 4 groups according to the tertiles of peak CRP levels (T1: 0.60 to 9.37 mg/dL; T2: 9.61 to 14.87 mg/dL; T3: 14.90 to 32.60 mg/dL; and unavailable peak CRP group). Multivariate Cox regression analysis was applied to investigate whether the tertiles of peak CRP predict adverse events even after adjusting for other variables. A total of 232 type B AAD patients were included in this analysis. The median follow-up period was 50 months. CRP reached its peak on day 4.5Ϯ1.7. Mean peak CRP values in T1, T2, and T3 were 6.4Ϯ2.
Background and Purpose-We sought to establish the relation between the pulsatile components of pressure and flow waveforms in the carotid artery and their change with age. Methods-Distention (pressure) and axial flow velocity waveforms were recorded noninvasively and simultaneously from the common carotid artery of 56 healthy subjects aged 20 to 72 years. Results-There was a close relation between the time intervals of pressure and flow waves: from foot to first shoulder or peak, to second shoulder or peak, and to incisura (rϭ0.97, PϽ0.0001 for each), which approximated the line of identity.The peak and nadir of flow velocity decreased with age, but late systolic flow augmentation increased substantially (1.6 times in the older group); this can be attributed to earlier wave reflection from the lower body. Pressure augmentation index (PAI) and flow augmentation index (FAI) increased similarly with age (PAI (%)ϭ0.84ϫageϪ26.6; FAI (%)ϭ0.75ϫageϩ11.9; both PϽ0.0001). Conclusions-Arterial
Conditioned medium from cultures of mouse peritoneal exudate cells incubated with endotoxin contains a mediator that markedly suppresses (>90%) lipoprotein lipase (triacylglycero-protein acylhydrolase, EC 3.1.1.34) activity in differentiating 3T3-L1 mouse preadipocytes. The effect is dependent upon the amount ofmediator and is evident as early as 30 min after the addition of the mediator-containing medium-to 3T3-L1 cell cultures. Neither endotoxin nor conditioned medium from cultures ofexudate cells not exposed to endotoxin shows the presence of the mediator. Lysates of the exudate cells are also unable to suppress the lipase activity. Increasing the amount of insulin does not reverse this suppression, even at 1000 times the concentration used for standard experiments. The lipoprotein lipase suppression mediator present in the conditioned medium of endotoxin-treated exudate cells is heat labile and has an apparent molecular weight of at least 12,000. The mediator does not inhibit lipoprotein lipase activity directly nor does it affect the half-life of enzyme activity released in the medium. The present study demonstrates that endotoxin promotes the release of a mediator from exudate cells that suppresses the activity, of lipoprotein lipase in 3T3-L1 preadipocytes.
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