|α1-Antitrypsin inhibits ischemia reperfusion-induced lung injury by reducing inflammatory response and cell death.|
Gao, W; Zhao, J; Kim, H; Xu, S; Chen, M; Bai, X; Toba, H; Cho, HR; Zhang, H; Keshavjeel, S; Liu, M
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Pulmonary ischemia-reperfusion (IR)-induced lung injury is a severe complication that increases the likelihood of primary graft dysfunction and early death after lung transplantation. Inflammatory cytokine release and cell death play a critical role in the development of IR-induced lung injury. α1-Antitrypsin (A1AT) is a protease inhibitor clinically used for the treatment of A1AT-deficiency emphysema. On the basis of a literature review, we hypothesize that A1AT may have the potential to reduce IR-induced lung injury through its anti-inflammatory and anti-apoptotic effects.A human pulmonary cell culture model was used to simulate IR processes in lung transplantation. Effects of A1AT on cell death and cytokine production were examined. A rat pulmonary IR model, in which the left pulmonary hilum was clamped for 90 minutes, followed by reperfusion for 2 hours, was used to determine the effects of A1AT on acute lung injury, function, cell death, and inflammatory response.A1AT significantly inhibited cell death and inflammatory cytokine release dose-dependently in vitro and significantly improved lung oxygenation and lung mechanics and reduced pulmonary edema in vivo. Moreover, A1AT inhibited neutrophil infiltration in the lung and reduced cell death and significantly reduced IR-induced inflammatory mediators in plasma, including interleukin (IL)-1α, IL-4, IL-12p70, monocyte chemotactic protein 1, and tumor necrosis factor-α.Considering its current clinical use, our findings indicate that administration of A1AT may be an effective and safe therapy for the treatment of IR injury in human lung transplantation.
|The preclinical efficacy, selectivity and pharmacologic profile of MK-5932, an insulin-sparing selective glucocorticoid receptor modulator.|
Brandish, PE; Anderson, K; Baltus, GA; Bai, C; Bungard, CJ; Bunting, P; Byford, A; Chiu, CS; Cicmil, M; Corcoran, H; Euler, D; Fisher, JE; Gambone, C; Hasbun-Manning, M; Kuklin, N; Landis, E; Lifsted, TQ; McElwee-Witmer, S; McIntosh, IS; Meissner, RS; Miao, J; Mitchell, HJ; Musselman, A; Schmidt, A; Shin, J; Szczerba, P; Thompson, CD; Tribouley, C; Vogel, RL; Warrier, S; Hershey, JC
European journal of pharmacology
Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.
|Ginsenoside Rd maintains adult neural stem cell proliferation during lead-impaired neurogenesis.|
Wang, B; Feng, G; Tang, C; Wang, L; Cheng, H; Zhang, Y; Ma, J; Shi, M; Zhao, G
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Lead exposure attracts a great deal of public attention due to its harmful effects on human health. Even low-level lead (Pb) exposure reduces the capacity for neurogenesis. It is well known that microglia-mediated neurotoxicity can impair neurogenesis. Despite this, few in vivo studies have been conducted to understand the relationship between acute Pb exposure and microglial activation. We investigated whether the acute Pb exposure altered the expression of a marker of activated microglial cells (Iba-1), and markers of neurogenesis (BrdU and doublecortin) in aging rats. As compared to controls, Pb exposure significantly enhanced the expression of Iba-1 immunoreactivity; increased the expression levels of IL-1β, IL-6, and TNF-α and decreased the numbers of BrdU(+) and doublecortin(+) cells. Our prior work demonstrated that ginsenoside Rd (Rd), one of the major active ingredients in Panax ginseng, was neuroprotective in a variety of paradigms involving anti-inflammatory mechanisms. Thus, we further examined whether Rd could attenuate Pb-induced phenotypes. Compared with the Pb exposure group, Rd pretreatment indeed attenuated the effects of Pb exposure. These results suggest that Rd may be neuroprotective in old rats following acute Pb exposure, which involves limitation of microglial activation and maintenance of NSC proliferation.
|Implications of time-series gene expression profiles of replicative senescence.|
Kim, YM; Byun, HO; Jee, BA; Cho, H; Seo, YH; Kim, YS; Park, MH; Chung, HY; Woo, HG; Yoon, G
Although senescence has long been implicated in aging-associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain-of-senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence-associated β-galactosidase activity (SA-β-gal), and high levels of SA-β-gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence-associated secretory phenotype-related genes also displayed a stage-specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins. We validated these phenomena at the protein level using human diploid fibroblasts and aging Sprague-Dawley rat skin tissues. Finally, disease-association analysis of the modular genes also revealed stage-specific patterns. Taken together, our results reflect a detailed process of cellular senescence and provide diverse genome-wide information of cellular backgrounds for senescence.