Anti-Inflammatory Activity of (Polyphenolic)-Sulfonates and Their Sodium Salts in Rodents

A series of polyphenolic-sulfonated compounds were observed to have potent anti-inflammatory activity and were protective against induced endotoxic shock in mice at 8 and 16 mg/kg, I.P. These agents proved to be potent elastase inhibitors in human leukocytes and J774-AI and IC-21 mouse macrophages as well as prostaglandin cyclo-oxygenase inhibitors in J774-AI macrophages. The compounds from 5 to 50 μM inhibited TNFα release from IC-21 macrophages and IL-1 release from mouse P388D1 macrophages induced by LPS. The binding of these cytokines to high affinity receptors on target cells, e.g. L929 fibroblasts and IL-2 in HuT78 T lymphoma cells, were also suppressed by the agents. These compounds blocked the adhesion of leukocytes and macrophages to the plasma membranes of L929 fibroblasts

The Effects of Amine-Carboxyborane Related Derivatives on UMR-106 Bone Metabolism

The amine-carboxyboranes and related derivatives have been shown to be potent anti-inflammatory and anti-osteoporosis agents. Their action in part appears to be mediated by the modulation of cytokines, e.g. TNFα or IL-1. Previous studies have demonstrated that LPS induced macrophages release of TNFα maximally at 60 to 90 min. and IL-1 from 5 to 8 hr. The amine-carboxyboranes reduced significantly the release of these cytokines but also blocked TNFα high affinity binding to UMR-106 receptor at 90 min. at 10 μM, and IL-1 high affinity binding at 5 hr. at 12.5 μM. In addition, the agents suppressed IL-8 binding to CHO K1 high affinity receptor at 24 hr. at 50 μM and IL-2 binding to HuT-8 receptors at 25 μM at 90 min. and 5 hr. Correlation of metabolic events associated with osteoporosis showed that at 90 min., when TNFα receptor binding was reduced by the agents, calcium uptake into UMR-106 cells was reduced at 10 μM as well as the acid and alkaline phosphatases, and the prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D3 binding was reduced by the agents as was acid and alkaline phosphatase, and 5′-lipoxygenase activities and white blood cell adhesion. At this time calcium uptake and proline incorporation was increased significantly by the agents. At later times e.g. 18-48 hr. calcium uptake was still increased, and NAG activity was inhibited in the presence of the agents. These effects may be related more to the inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of the observed metabolic effects of amine-carboxyboranes as antiosteoporosis agents can be correlated with their inhibition of cytokine high affinity binding to target cell receptors

Transepithelial Transport and Metabolism of Boronated Dipeptides Across Caco-2 and HCT-8 Cell Monolayers

Oral delivery of proteins and peptides as therapeutic agents is problematic due to their low bioavailability. This study examined the effect of boronation on the transepithelial transport and metabolism of three glycine-phenylalanine dipeptides in Caco-2 and HCT-8 cell monolayers. The three dipeptides exhibited passive transport characteristics in the monolayer systems. However, metabolism of the boronated dipeptides did occur, but to a lesser extent than the non-boronated glycine-phenylalanine dipeptide. The same metabolic scheme was seen in both cell monolayer system, but greater metabolism was seen in the HCT-8 cell monolayers

Large Scale Comparison of Innate Responses to Viral and Bacterial Pathogens in Mouse and Macaque

Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens

Incidental retrieval of prior emotion mimicry.

When observing emotional expressions, similar sensorimotor states are activated in the observer, often resulting in physical mimicry. For example, when observing a smile, the zygomaticus muscles associated with smiling are activated in the observer, and when observing a frown, the corrugator brow muscles. We show that the consistency of an individual's facial emotion, whether they always frown or smile, can be encoded into memory. When the individuals are viewed at a later time expressing no emotion, muscle mimicry of the prior state can be detected, even when the emotion itself is task irrelevant. The results support simulation accounts of memory, where prior embodiments of other's states during encoding are reactivated when re-encountering a person

Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9.

Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVS-infected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium