PubMed · 4576657
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H F Morrelli. 1973. Propranolol.. https://doi.org/10.7326/0003-4819-78-6-913
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The effective action of endothelium-derived nitric oxide (EDNO) is impaired in patients with atherosclerosis. This impairment has been attributed in part to increased vascular oxidative stress. EDNO action is improved by administration of ascorbic acid, a water-soluble antioxidant. Ascorbic acid is a potent free-radical scavenger in plasma, and also regulates intracellular redox state in part by sparing cellular glutathione. We specifically investigated the role of intracellular redox state in EDNO action by examining the effect of L-2-oxo-4-thiazolidine carboxylate (OTC) on EDNO-dependent, flow-mediated dilation in a randomized double-blind placebo-controlled study of patients with angiographically proven coronary artery disease. OTC augments intracellular glutathione by providing substrate cysteine for glutathione synthesis. Brachial artery flow-mediated dilation was examined with high-resolution ultrasound before and after oral administration of 4.5 g of OTC or placebo in 48 subjects with angiographically documented coronary artery disease. Placebo treatment produced no change in flow-mediated dilation (7.0+/-3.9% vs. 7.2+/-3.7%), whereas OTC treatment was associated with a significant improvement in flow-mediated dilation (6.6+/-4.4% vs. 11.0+/-6.3%; P = 0.005). OTC had no effect on arterial dilation to nitroglycerin, systemic blood pressure, heart rate, or reactive hyperemia. These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.
We previously demonstrated that recombinant plant virus particles containing a chimeric peptide representing two rabies virus epitopes stimulate virus neutralizing antibody synthesis in immunized mice. We show here that mice immunized intraperitoneally or orally (by gastric intubation or by feeding on virus-infected spinach leaves) with engineered plant virus particles containing rabies antigen mount a local and systemic immune response. After the third dose of antigen, given intraperitoneally, 40% of the mice were protected against challenge infection with a lethal dose of rabies virus. Oral administration of the antigen stimulated serum IgG and IgA synthesis and ameliorated the clinical signs caused by intranasal infection with an attenuated rabies virus strain.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune demyelinating disease of the central nervous system that serves as an animal model for multiple sclerosis. Antigen-specific tolerance regimens, including oral tolerance, have been used prophylactically to prevent development of acute EAE as well as a number of other autoimmune diseases. Two mechanisms have been proposed to explain the immunologic basis for disease inhibition: bystander immune suppression and clonal anergy/deletion. This report demonstrates a novel mechanism for monocyte chemotactic protein (MCP)-1 as a regulatory factor of oral tolerance. Oral administration of proteolipid protein peptide (PLP139-151) increased MCP-1 expression in the intestinal mucosa, Peyer's patch, and mesenteric lymph nodes. Increase in MCP-1 expression resulted in downregulation of mucosal interleukin (IL)-12 expression with concomitant increase in mucosal IL-4 expression. Functionally, MCP-1 upregulation was shown to regulate oral tolerance induction by the ability of antibodies to MCP-1 to inhibit tolerance induction. The anti-MCP-1 abrogation of oral tolerance induction also resulted in restoration of mucosal IL-12 expression as well as peripheral antigen-specific T helper cell 1 responses. These results demonstrate a novel and important role for MCP-1 in the regulation or oral tolerance for the prevention and treatment of autoimmune disease.