IntroductionWe show that treatment of adult mice with recombinant human insulin-like growth factor 1 (rhIGF-1) induces striking modifications in lymphocyte number and function. 9-mo-old male mice received rhIGF-1 (4 mg/kg per d) or its excipient by subcutaneous infusion from osmotic minipumps for 7 or 14 d. Mice were weighed daily and bled at sacrifice; the spleen and thymus were harvested and single cell suspensions were made for analysis of cell phenotype and cell number. The responses of splenocytes to mitogens (concanavalin A, lipopolysaccharide, and pokeweed mitogen), alloantigens and dinitrophenyl ovalbumin were measured. After either 7 or 14 d of treatment, rhIGF-1 had an overall whole-body anabolic effect, resulting in increased body and organ weights with prominent increases in the weight of the spleen and thymus. Furthermore, the rhIGF-1 treated mice were normoglycemic but had reduced blood urea nitrogens, again reflecting the anabolic activity of rhIGF-1. The increased spleen and thymus weights were associated with a large increase in the number of lymphocytes in both organs. In addition to an increase in T cells, specifically CD4 + T cells, a dramatic increase in splenic B cells was also observed. This increase was accompanied by an enhanced responsiveness to dinitrophenyl ovalbumin resulting in increased immunoglobulin production. However, despite the increases in cellularity, there was a decrease in the in vitro responses of spleen cells to mitogens after 7 d of rhIGF-1 treatment. In contrast, treatment with rhIGF-1 for 14 d increased both the cell number and mitogenic responses of splenocytes suggesting that some time is required for the cells populating the peripheral organs to gain mitogenic responsiveness. It is clear from these data that rhIGF-1, at doses that have whole-body anabolic activity, can expand cell number in lymphoid tissue in a normal adult mouse. These dual effects of rhIGF-1, of increasing lymphocyte number and activity, indicate that, in a normal adult animal, rhIGF-1 can cause major changes in lymphoid tissues that are of potential benefit to the functioning of the immune system. (J.
Abstract-Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator-response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPAR␣ activators and are used in the treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin ™ ), like gemfibrozil, can activate the PPAR␣/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and acyl-CoA oxidase RNA are induced and the combination of LGD1069 and gemfibrozil leads to a greater induction. Importantly, in hypertriglyceridemic db/db mice treated with RXR or PPAR␣ agonists, triglyceride levels are lowered, and the combination again has significantly greater efficacy. RXR agonists also raise HDL cholesterol levels without changing apoA-I RNA expression. This observation suggests the use of RXR-selective agonists, "rexinoids," either alone or in combination with a fibrate as a new therapeutic approach to treating patients with high triglyceride and low HDL cholesterol levels. 10 -12 In fibrate-treated animals, there is a rapid increase in the expression of genes that encode enzymes for the -oxidation of fatty acids such as AOX and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme).13 PPREs have been identified in the promoters of these genes, suggesting that activation of the peroxisomal fatty acid -oxidation pathway contributes to the lipid lowering observed with fibrates.We have recently shown that the RXR/PPAR␥ heterodimer is activated by RXR agonists. 4 This finding emphasizes the permissive nature of the RXR/PPAR heterodimer, whereby either partner can bind ligand and activate gene expression. RXR agonists have similar effects as thiazolidinediones; they induce adipocyte differentiation, 14 lower elevated glucose and insulin levels, and improve insulin resistance in ob/ob and db/db mice. 15 We refer to these RXRselective ligands as "rexinoids" because their pharmacology is clearly distinct from "retinoids," which are retinoic acid receptor activators that mimic the action of retinoic acid. 16 We hypothesized that rexinoids would mimic the effects of fibrates via activation of the RXR side of the RXR/PPAR␣ heterodimer. Here we demonstrate for the first time that rexinoids elicit similar responses as PPAR␣ activators in vivo. In particular, expression of the bifunctional enzyme and AOX gene is induced in rat livers by gemfibrozil or an RXRselective agonist LGD1069 (Targretin ™ ) treatment. 17 The combination of LGD1069 and gemfibrozil gives a much stronger induction. Further, in db/db mice, RXR activators like LGD1069 17 and LG100268 18 lower triglyceride levels. HDL-C levels are also raised in rexinoid-treated...
ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.Historically, variola virus, the etiologic agent of smallpox, has been estimated to have killed, crippled, or disfigured nearly 10% of the human population prior to eradication (5). Smallpox is highly communicable and carries exceptionally high morbidity. Secondary attack rates among unvaccinated members of households in which someone had smallpox have been reported to range from 30% to 80%. Mortality rates range from 1% for variola minor to 30% for variola major. With
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.