Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach.

A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.

Health benefits for women staying with their husbands during a long-term trip to a hot springs spa.

The authors collected saliva samples from 15 married couples and 13 women staying with a female companion (N = 43) during an 8-day stay at a spa resort in Nagano, Japan. To examine changes in endocrinological stress markers, the authors evaluated participants' levels of salivary cortisol and chromogranin A (CgA) by enzyme-linked immunosorbent assay. By the eighth day, women staying with their husbands had significantly increased levels of cortisol and CgA. During the protocol, the authors observed no significant variation in levels of cortisol or CgA for either the women who were staying with same-sex companions or the male spouses. These findings suggest that the effects of long-term stays in a spa resort are more beneficial for married women staying with their husbands than for either married men or women staying with female companions.

Effects of volatile constituents of rosemary extract on lung inflammation induced by diesel exhaust particles.

Epidemiological and experimental studies have implicated that diesel exhaust particles are involved in increases in morbidity and mortality from lung diseases. Recently, we have demonstrated that rosmarinic acid, a polyphenolic liquid component in perilla, inhibits lung inflammation induced by diesel exhaust particles in vivo, partly through its antioxidative property. We have also shown the antioxidative activities of volatile constituents of rosemary extract, the gaseous component in perilla, in vitro. The purpose of this study was to evaluate the effects of intratracheal administration of volatile rosemary extract on lung inflammation induced by diesel exhaust particles. ICR mice were treated with intratracheal administration of volatile rosemary extract before intratracheal exposure to diesel exhaust particles. Twenty-four hr later, diesel exhaust particles exposure elicited lung inflammation characterized by the infiltration of neutrophils and eosinophils, which was confirmed by cellular profile of bronchoalveolar lavage fluid and histological examination. Diesel exhaust particles enhanced the protein expressions of interleukin-1beta, macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractant in the lung. Pretreatment with rosemary extract significantly inhibited the diesel exhaust particles-induced lung inflammation. Rosemary extract treatment also suppressed the diesel exhaust particles-enhanced lung expression of macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractant. These results suggest that intratracheal administration of rosemary extract can prevent lung inflammation induced by diesel exhaust particles. The preventive effect is mediated, at least partly, through the inhibition of the enhanced lung expressions of macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractants.

Health effects of a long-term stay in a spa resort.

The authors examined periodic changes in endocrinological stress markers in saliva samples collected from 31 women who spent 8 days in a spa resort. Levels of salivary cortisol and chromogranin A (CgA) were evaluated by enzyme-linked immunosorbent assay. To evaluate health-related lifestyle factors, patterns of behavior, perceived stressors, and stress reactions of the subjects, the authors administered written questionnaires. Individuals who scored poorly on an index evaluating lifestyle health factors, or reported stressful life events, showed a significant increase in CgA levels during the stay. This suggests that, for these people, the long stay in the spa ameliorated stress. These findings are somewhat different from those of studies in which researchers have evaluated the effects of shorter-term leisure trips.

Effects of volatile constituents of a rosemary extract on allergic airway inflammation related to house dust mite allergen in mice.

Perilla leaf extract is known to have anti-inflammatory properties. Recently, we have demonstrated that rosmarinic acid, a polyphenolic liquid component in perilla, inhibits the allergic airway inflammation induced by house dust mites (HDMs) in vivo. The purpose of this study was to evaluate the effects of intratracheal (i.t.) exposure to volatile constituents of a rosemary extract (VR), gaseous components in perilla, on a murine model of allergic asthma induced by HDM. C3H/HeN mice were treated 7 times weekly with i.t. exposure. The HDM allergen challenge elicited a pulmonary eosinophilic inflammation accompanied by an increase in the lung expression of interleukin (IL)-5, IL-13, and eotaxin. VR inhibited increases in the number of eosinophils, neutrophils, and mononuclear cells around the airways and those in the bronchoalveolar lavage fluid. VR exposure also significantly suppressed the expression of IL-13 enhanced by HDM allergen. These results suggest that i.t. exposure to VR can, at least partially, prevent allergic airway inflammation induced by HDM. The preventive effect is associated with inhibition of the enhanced local expression of IL-13.

Medical assessment of the health effects of short leisure trips.

Using responses to questionnaires and results of saliva samples from 40 women, the authors assessed the effects on health of participation in a short leisure trip (2 nights, 3 d) to Kyushu Island in Japan. They addressed transportation, sightseeing, and group activities during the tour, which might differ from participants' usual activities. Levels of the salivary endocrinological stress markers cortisol and chromogranin A (CgA) were determined by enzyme-linked immunosorbent assay (ELISA). In each of the groups with characteristics considered healthy and related to lifestyle, patterns of behavior, perceived stressors, and stress reactions, a decrease in the cortisol levels and an increase in the CgA levels were apparent during the tour. The baseline for stress hormone changes was the levels on awakening on Day 1 (i.e., immediately before the tour). These findings suggest that even short periods of travel can bring about a reduction in di-stress and acquisition of eu-stress, experienced as feeling uplifted or fulfilled.