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Bergantini  L  Cameli  P  d’Alessandro  M  Vagaggini  C  Refini  RM  Landi  C  Pieroni  MG  Spalletti  M  Sestini  P  Bargagli  E 《Clinical and experimental medicine》2019,19(4):487-494
Clinical and Experimental Medicine - Background The pathogenetic and regulatory roles of natural killer (NK) and natural killer T-like cells in interstitial lung diseases (ILDs), fibrotic and...  相似文献   
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Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ9-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3–4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [3H]CP55,940 displacement and its effect on [35S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [35S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.The CB2 cannabinoid receptor functions as an endogenous protective entity (1). Thus, it is an important regulator of bone mass and inflammation. It represents a therapeutic target that avoids the undesired psychotropic effects caused by CB1 receptor activation. CB2 is expressed in osteoblasts, the bone-forming cells, and in osteoclasts, the bone-resorbing cells (2). Monocytes/macrophages, B cells, certain T-cell subtypes, and mast cells also express CB2 (37). In the skeleton, activation of CB2 favors bone formation over resorption, thus protecting the skeleton against age-related bone loss. Inflammatory responses are restrained by CB2 agonists in several instances such as hepatic ischemia-reperfusion injury (8), uveitis (9), and contact dermatitis (10). With their terpene and resorcinol-derived moieties, some synthetic CB2 agonists, such as HU-308 (10), JWH-133 (11), and HU-910 (12), structurally resemble the phytocannabinoids Δ9-tetrahydrocannabinol and cannabidiol. Other, non-phytocannabinoid-type agonists have been also reported (13). HU-308 was one of the first fully characterized, highly selective, and highly efficacious cannabinoid type-2 agonist (10). It has three chiral centers, namely, at carbon atoms in positions 3, 4, and 6 (Scheme 1). HU-308 has a 3R, 4S, 6S configuration; that of its enantiomer (HU-433) is 3S, 4R, 6R.Open in a separate windowScheme 1.Structures of HU-433 and -308.In most experiments, the optimal HU-308 mitogenic activity in osteoblasts, as well as its antiosteoclastogenic effect, was obtained by using concentrations in the nanomolar range (2, 14). Surprisingly, testing a new HU-308 batch, we noticed a 3- to 4-magnitude decrease in the dose that triggers optimal proliferative response in osteoblasts, reasoning that this preparation contained a significant amount of the HU-308 enantiomer, presumably responsible for the enhanced activity. We report here that this enantiomer, designated HU-433, was synthesized and compared with HU-308, and indeed showed markedly enhanced bone-anabolic and antiinflammatory activities, but inferior CB2 receptor binding affinity. Although both enantiomers seem to target the same binding pocket, two different orientations relative to the binding site are possible, leading to different behavior of the two enantiomers due to their different occupancy of these orientations. This observation appears to reflect a situation in which relatively small differences in possible binding conformations of the ligands within the receptor—referred to as poses—lead to significant diminution of receptor-binding properties and a marked increase in biological activity.  相似文献   
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In order to better understand the epidemiology of fusariosis in Europe, a survey collecting information on the clinical characteristics of the patients infected by Fusarium as well as on the infecting isolates was launched. A total of 76 cases of invasive fusariosis occurring from January 2007 to June 2012 were collected and Fusarium isolates were identified by sequencing the translation elongation factor 1α (TEF) gene. Also, antifungal susceptibility was tested by broth microdilution according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Etest. Disseminated disease was considered proven in 46 cases and probable in 17 cases. Localised infection was seen in 13 cases. Gibberella fujikuroi species complex (SC), including Fusarium verticillioides and F. proliferatum, and F. solani SC were the most frequent aetiology of disseminated and localised infections, respectively. The crude mortality rate was 46 %, the highest associated with F. solani SC (67 %) and F. proliferatum (62.5 %). A wide range of antifungal susceptibilities was observed. Amphotericin B was the most potent antifungal in vitro, and itraconazole the least effective. The azoles exhibited lower minimum inhibitory concentrations (MICs) against F. verticillioides strains, with posaconazole having a slightly better performance, while F. solani SC isolates were resistant to all three azoles tested. The essential agreement between the Etest and the EUCAST method was 100 % for itraconazole and voriconazole, and 96 % for amphotericin B and posaconazole. In conclusion, we confirm that fusariosis is a rare but severe event in Europe, that G. fujikuroi SC is the predominant cause of deep infections and that different species have different antifungal in vitro susceptibility patterns.  相似文献   
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The purpose of this study was to examine the relationship between bullying victimization, post-traumatic stress symptoms, and alexithymia. Self-report measures concerning bullying victimization, alexithymia, and post-traumatic stress symptoms were administered to 488 adolescents (52 % boys, 48 % girls) ages 16 to 17 attending high schools. Results show that the experience of being bullied is associated with post-traumatic stress symptoms. Moreover, alexithymia mediated the impact of bullying victimization on post-traumatic stress symptoms. Findings thus show that difficulties identifying and describing feelings combined with an externally oriented thinking, the core symptoms of alexithymia, can play a crucial role in linking bullying victimization with the onset of post-traumatic stress disorder among adolescents.  相似文献   
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Background

The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on human health.

Objective

We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization.

Methods

We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES).

Results

An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (β = 2.17 mg/dL; 95% CI: –0.24, 4.59), and the association appeared to be limited to women (β = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with β = 0.14 mg/dL; 95% CI: –3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 8.36; 95% CI: –0.15, 16.9 and β = 5.98; 95% CI: –3.96, 15.9, for TEZ 5 and 6, respectively).

Conclusion

Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C.

Citation

Ward-Caviness CK, Kraus WE, Blach C, Haynes CS, Dowdy E, Miranda ML, Devlin RB, Diaz-Sanchez D, Cascio WE, Mukerjee S, Stallings C, Smith LA, Gregory SG, Shah SH, Hauser ER, Neas LM. 2015. Association of roadway proximity with fasting plasma glucose and metabolic risk factors for cardiovascular disease in a cross-sectional study of cardiac catheterization patients. Environ Health Perspect 123:1007–1014; http://dx.doi.org/10.1289/ehp.1306980  相似文献   
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