11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10⁻¹³ M cortisol, whereas 1 × 10⁻⁵ M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs.     

Chronic inflammation as a determinant of future aging phenotypes

Background:

The importance of chronic inflammation as a determinant of aging phenotypes may have been underestimated in previous studies that used a single measurement of inflammatory markers. We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.

Methods:

We obtained data for 3044 middle-aged adults (28.2% women) who were participating in the Whitehall II study and had no history of stroke, myocardial infarction or cancer at our study’s baseline (1997–1999). Interleukin-6 was measured at baseline and 5 years earlier. Cause-specific mortality, chronic disease and functioning were ascertained from hospital data, register linkage and clinical examinations. We used these data to create 4 aging phenotypes at the 10-year follow-up (2007–2009): successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning), incident fatal or nonfatal cardiovascular disease, death from noncardiovascular causes and normal aging (all other participants).

Results:

Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.38–0.74) and increased the risk of future cardiovascular events (OR 1.64, 95% CI 1.15–2.33) and noncardiovascular death (OR 2.43, 95% CI 1.58–3.80).

Interpretation:

Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice. Chronic inflammation has been implicated in the pathogenesis of age-related conditions, ¹ such as type 2 diabetes, ^{2 , 3} cardiovascular disease, ⁴ cognitive impairment ⁵ and brain atrophy. ⁶ Chronic inflammation may result from or be a cause of age-related disease processes (illustrated in Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.122072/-/DC1 ). For example, obesity increases inflammation, and chronic inflammation, in turn, contributes to the development of type 2 diabetes by inducing insulin resistance, ^{7 , 8} and to coronary artery disease by promoting atherogenesis. ⁹ Thus, raised levels of inflammation appear to be implicated in various pathological processes leading to diseases in older age. Of the various markers of systemic inflammation, interleukin-6 is particularly relevant to aging outcomes. There is increasing evidence that interleukin-6 is the pro-inflammatory cytokine that “drives” downstream inflammatory markers, such as C-reactive protein and fibrinogen. ^{10 , 11} Interleukin-6, in contrast to C-reactive protein and fibrinogen, is also likely to play a causal role in aging owing to its direct effects on the brain and skeletal muscles. ^{12 , 13} In addition, results of Mendelian randomization studies of interleukin-6 and studies of antagonists are consistent with a causal role for interleukin-6 in relation to coronary artery disease, again in contrast to C-reactive protein and fibrinogen. ¹⁴ However, current understanding of the link between chronic inflammation and aging phenotypes is hampered by the methodologic limitations of many existing studies. Most studies reported an assessment of inflammation based on a single measurement, precluding a distinction between the short-term (acute) and longer-term (chronic) impact of the inflammatory process on disease outcomes. ⁷ We conducted a study using 2 measurements of interleukin-6 obtained about 5 years apart to examine the association between chronic inflammation and aging phenotypes assessed 10 years later in a large population of men and women. Because inflammation characterizes a wide range of pathological processes, we considered several aging phenotypes, including cardiovascular disease (fatal and nonfatal), death from noncardiovascular causes and successful aging (optimal functioning across different physical, mental and cognitive domains).     

Refining the role of phenology in regulating gross ecosystem productivity across European peatlands

The role of plant phenology as a regulator for gross ecosystem productivity (GEP) in peatlands is empirically not well constrained. This is because proxies to track vegetation development with daily coverage at the ecosystem scale have only recently become available and the lack of such data has hampered the disentangling of biotic and abiotic effects. This study aimed at unraveling the mechanisms that regulate the seasonal variation in GEP across a network of eight European peatlands. Therefore, we described phenology with canopy greenness derived from digital repeat photography and disentangled the effects of radiation, temperature and phenology on GEP with commonality analysis and structural equation modeling. The resulting relational network could not only delineate direct effects but also accounted for possible effect combinations such as interdependencies (mediation) and interactions (moderation). We found that peatland GEP was controlled by the same mechanisms across all sites: phenology constituted a key predictor for the seasonal variation in GEP and further acted as a distinct mediator for temperature and radiation effects on GEP. In particular, the effect of air temperature on GEP was fully mediated through phenology, implying that direct temperature effects representing the thermoregulation of photosynthesis were negligible. The tight coupling between temperature, phenology and GEP applied especially to high latitude and high altitude peatlands and during phenological transition phases. Our study highlights the importance of phenological effects when evaluating the future response of peatland GEP to climate change. Climate change will affect peatland GEP especially through changing temperature patterns during plant phenologically sensitive phases in high latitude and high altitude regions.     

Identification of a novel homolog for a calmodulin-binding protein that is upregulated in alloplasmic wheat showing pistillody

Intracellular signaling pathways between the mitochondria and the nucleus are important in both normal and abnormal development in plants. The homeotic transformation of stamens into pistil-like structures (a phenomenon termed pistillody) in cytoplasmic substitution (alloplasmic) lines of bread wheat (Triticum aestivum) has been suggested to be induced by mitochondrial retrograde signaling, one of the forms of intracellular communication. We showed previously that the mitochondrial gene orf260 could alter the expression of nuclear class B MADS-box genes to induce pistillody. To elucidate the interactions between orf260 and nuclear homeotic genes, we performed a microarray analysis to compare gene expression patterns in the young spikes of a pistillody line and a normal line. We identified five genes that showed higher expression levels in the pistillody line. Quantitative expression analysis using real-time PCR indicated that among these five genes, Wheat Calmodulin-Binding Protein 1 (WCBP1) was significantly upregulated in young spikes of the pistillody line. The amino acid sequence of WCBP1 was predicted from the full-length cDNA sequence and found to encode a novel plant calmodulin-binding protein. RT-PCR analysis indicated that WCBP1 was preferentially expressed in young spikes at an early stage and decreased during spike maturation, indicating that it was associated with spikelet/floret development. Furthermore, in situ hybridization analysis suggested that WCBP1 was highly expressed in the pistil-like stamens at early to late developmental stages. These results indicate that WCBP1 plays a role in formation and development of pistil-like stamens induced by mitochondrial retrograde signaling.     

pfaB products determine the molecular species produced in bacterial polyunsaturated fatty acid biosynthesis

Insect blood (hemolymph) contains prophenoloxidase, a proenzyme that is activated to protective phenoloxidase when the insect is damaged or challenged with microorganisms. The Gram-negative bacterium Photorhabdus luminescens kills the lepidopteron insect Manduca sexta by using a variety of toxins. We screened P. luminescens and Photorhabdus asymbiotica cosmid libraries in an Escherichia coli host against previously activated M. sexta hemolymph phenoloxidase and identified three overlapping cosmid clones from P. luminescens and five from P. asymbiotica that suppressed the activity of the enzyme both in vitro and in vivo . Genome alignments of cosmid end sequences from both species confirmed that they contained orthologous loci. We examined one of the cosmids from P. luminescens in detail: it induced the formation of significantly fewer melanotic nodules, proliferated faster within the insect host and was significantly more virulent towards fifth-stage larvae than E. coli control bacteria. Insertional mutagenesis of this cosmid yielded 11 transposon mutants that were no longer inhibitory. All of these were insertions into a single 5.5-kb locus, which contained three ORFs and was homologous to the maltodextrin phosphorylase locus of E. coli . The implications of this novel inhibitory factor of insect phenoloxidase for Photorhabdus virulence are discussed.     

Docking and SAR studies of salacinol derivatives as α-glucosidase inhibitors

Salacinol is a potent α-glucosidase inhibitor isolated from Salacia reticulata, and a good lead compound for an antidiabetic drug. It is essential to clarify the binding state of salacinol to α-glucosidase for efficient optimization study using structure-based drug design. Redocking simulations of two inhibitors, acarbose and casuarine whose complex structures are known, were performed to assure the appropriate docking pose prediction. The simulation reproduced both experimental binding states with accuracy. Then, using the same simulation protocol, the binding mode of salacinol and its derivatives has been predicted. Salacinol bound to the protein with a similar binding mode as casuarine, and the predicted structures could explain most of the structure–activity relationships of salacinol derivatives.     

Comparison of Vegetation and CO2 Dynamics Between a Restored Cut‐Away Peatland and a Pristine Fen: Evaluation of the Restoration Success

We studied the restoration success of a cut‐away peatland 10 years after restoration by comparing the vegetation and CO₂ dynamics with those of a pristine peatland of similar nutrition level and climate. Vegetation and CO₂ dynamics were monitored during one growing season. We used DCA (detrended correspondence analysis) and diversity indices to study the vegetation composition within and between the sites, and non‐linear regression models to estimate the seasonal CO₂ fluxes and balances of the sites. Based on both DCA and diversity indices, the study plots in the restored site differed more in the vegetation composition than the study plots in the pristine site. The variation in the CO₂ fluxes and balance was greater in the restored than in the pristine site, resulting from the heterogeneous vegetation in the restored site. The seasonal net CO₂ balance was positive (sink) at both sites, the restored site binding on average 500 ± 410 g CO₂/m² and the pristine site 390 ± 265 g CO₂/m² (statistically not different, p = 0.575). The results indicate that the restoration of the vegetation composition is still incomplete but the vegetation coverage is sufficient for the restored site to function as a sink of atmospheric CO₂.     

Up to seven-fold inter-hospital differences in obstetric anal sphincter injury rates- A birth register-based study in Finland

Background

The occurrence of obstetric anal sphincter injuries (OASIS) - which may have serious, long-term effects on affected women, including faecal incontinence, despite primary repair - varies widely between countries and have been chosen one of the indicators for patient safety in Organisation for Economic Cooperation and Development (OECD) countries and in Nordic countries.

Findings

The aim of the study was to assess risks of OASIS among five university teaching hospitals and 14 non-university central hospitals with more than 1,000 deliveries annually during 1997-2007 in Finland. Women with singleton vaginal deliveries divided into two populations consisting of all 168,637 women from five university hospitals and all 255,660 women from non-university hospitals, respectively, derived from population-based register. Primiparous and multiparous women with OASIS (n = 2,448) were compared in terms of possible risk factors to primiparous and multiparous women without OASIS, respectively, using stepwise logistic regression analysis. The occurrences of OASIS varied from 0.7% to 2.1% in primiparous and from 0.1% to 0.3% in multiparous women among the university hospitals. Three-fold inter-hospital differences in OASIS rates did not significantly change after adjustment for patient mix or the use of interventions. In non-university hospitals OASIS rates varied from 0.2% to 1.4% in primiparous and from 0.02% to 0.4% in multiparous women, and the results remained virtually unchanged after adjustment for known risks.

Conclusions

Up to 3.2-fold inter-hospital differences in OASIS risk demonstrates significant differences in the quality of Finnish obstetric care.