Detecting potential causal relationship between inflammatory bowel disease and rosacea using bi-directional Mendelian randomization.

The association between rosacea and inflammatory bowel disease (IBD) has been studied in previous observational studies. It is unclear, however, whether the association is causal or not. Independent genetic variants for IBD were chosen as instruments from published Genome-wide association studies (GWAS) studies involving 38,155 cases with an IBD diagnosis and 48,485 controls in order to investigate the causal effect of IBD on rosacea. Summarized data for rosacea were gathered from various GWAS studies that included 1195 cases and 211,139 controls without rosacea. Reverse-direction Mendelian randomization (MR) analysis was done to investigate the relationship between genetically proxied rosacea and IBD. With the use of the inverse variance-weighted (IVW), MR-Egger, and weighted median approaches, a 2-sample Mendelian randomization study was carried out. Analysis of heterogeneity and sensitivity was performed to examine the pleiotropy and robustness of effect estimates. The forward-direction of the MR study was to reveal that genetic predisposition to IBD including its two main subtypes: Crohn's disease (CD) and ulcerative colitis (UC) was associated with an increased risk of rosacea. The reverse-direction MR analyses did not demonstrate that a genetic predisposition to rosacea was associated with total IBD, UC and CD. Our findings provided evidence for a causal impact of IBD, UC, and CD on rosacea, but not vice versa. The elevated incidence of rosacea in patients with IBD should be recognized by doctors to make an early diagnosis and initiate specialized therapy.

PNU-282987 improves the hemodynamic parameters by alleviating vasopermeability and tissue edema in dogs subjected to a lethal burns shock.

Excessive inflammation and high vasopermeability can lead to blood volume loss and tissue edema, which can affect the resuscitation and prognosis for serious burn patients. In this experiment, we investigated the effect of PNU-282987, an α7 nicotine cholinergic receptor agonist on the hemodynamic parameters and survival rate by inhibiting vasopermeability and tissue edema during the fluid resuscitation for lethal burn shock. Forty Beagle dogs with intubation of the carotid artery and jugular vein 24 hours before the injury were subjected to 50% TBSA full-thickness burns, and were randomly divided into following four groups: no resuscitation group (group NR), venous fluid resuscitation group (group R), PNU-282987 treatment group (group P), and fluid resuscitation group plus PNU-282987 group (group RP), with 10 dogs in each group. Hemodynamic variables and biochemical parameters were determined with animals in a conscious and cooperative state. The plasma volume and the vasopermeability were determined by indocyanine green and fluorescein isothiocyanate-dextran, respectively. The level of tumor necrosis factor-α and interleukin-1ß in plasma, and the water content of different organs were also determined. The mean arterial pressure, cardiac output, and plasma volume of all dogs decreased significantly, and the lung extravascular water index and pulmonary vascular permeability index increased remarkably after burn. The hemodynamic parameters deteriorated continually in group N dogs, and then anuria, hyperlactacidemia, and multiple organ dysfunctions developed. The mean arterial pressure and cardiac output of dogs in group R and group RP returned to preinjury levels at 48 hours postburn. The lung extravascular water index and pulmonary vascular permeability in group R were higher than those before preinjury. The dogs in group RP were found to have a significant increase in plasma volume and urine output, and a remarkable decrease in the levels of tumor necrosis factor-α, interleukin-1α, lactic acid, and organ functions compared with those of group R (P <.05). The survival rate of RP group (100%; 10/10) was significantly higher than that of group N (0; 0/10), group P (20%; 2/10), and group R (60%; 6/10). PNU-282987 combined with intravenous fluid resuscitation significantly improved hemodynamics and the survival rate in the early period after this lethal burn shock. The mechanism may be attributable to the lowering of the level of proinflammatory mediators, amelioration of vasopermeability-induced visceral edema, less of blood volume loss, and protection of vital organs through activation of cholinergic anti-inflammatory pathway.

[Current status of studies on genome-wide gene-gene interactions].

Complex diseases have affected human's health throughout the world. Hundreds of studies show that complex diseases are caused by multiple loci. Currently, genome-wide association studies(GWAS) only focus on the single locus that contributes to the susceptibility of a certain disease. However, the interaction between genes could be one of the main factors that lead to complex traits. This fact has initiated scientists to propose some algorithms to detect these interactions, such as the penalized logistic regression model, multifactor dimensionality reduction method, set association analysis method, Bayesian networks analysis method and random forest. However, these algorithms are of high complexity, hypothesis-driven, causing over fitting of data, or not sensible of data at low dimensions. In this paper, we reviewed these algorithms, and then demonstrated a new algorithm based on GPU to provide a powerful strategy to analyze gene-gene interaction in genome-wide association datasets. This algorithm is of low computing complexity, free of hypothesis, not affected by single locus marginal effect, and also of high stability and speed.

Palmitate-induced inhibition of insulin gene expression in rat islet ß-cells involves the ceramide transport protein.

Endogenous ceramide plays an important role in the palmitate (Palm) impairment of proinsulin gene expression in pancreatic islet ß-cells. Changes in the liposoluble ceramide levels not only depend on metabolic enzymes but also on its transport to subcellular sites in response to Palm stimuli. In this study, we show that suppression of ceramide transport protein (CERT) mRNA with small interfering RNA contributed to intracellular ceramide accumulation in response to chronic Palm exposure and impairment of proinsulin gene expression, similar to the effect of inhibiting ceramide scavenging enzyme sphingomyelin synthase (SMS). High dose Palm treatment increased protein kinase D (PKD)-induced phosphorylation of CERT and its dysfunction. Intracellular accumulation of ceramide was associated with reduction of PDX-1 nuclear localization and MafA protein levels and stimulation of CCAAT/enhancer binding protein ß (C/EBP ß) expression. These conditions also corresponded with a reduction of PDX-1 and MafA and an increase of C/EBP ß binding to the insulin promoter. Furthermore, down-regulation of C/EBP ß could block ceramide impairment of proinsulin gene expression. The results reveal that Palm-mediated dysfunction of ceramide transport may contribute to intracellular ceramide accumulation and result in dysfunction of pancreatic beta cells by affecting binding of transcription factors to the insulin promoter.

Non-receptor tyrosine kinase Src is required for ischemia-stimulated neuronal cell proliferation via Raf/ERK/CREB activation in the dentate gyrus.

BACKGROUND: Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. However, Molecular mechanisms that regulate neuronal cell proliferation in the dentate gyrus (DG) following ischemic stroke insult are poorly understood. This study was designed to investigate the potential regulatory capacity of non-receptor tyrosine kinase Src on ischemia-stimulated cell proliferation in the adult DG and its underlying mechanism. RESULTS: Src kinase activated continuously in the DG 24 h and 72 h after transient global ischemia, while SU6656, the Src kinase inhibitor significantly decreased the number of bromodeoxyuridine (BrdU) labeling-positive cells of rats 7 days after cerebral ischemia in the DG, as well as down-regulated Raf phosphorylation at Tyr(340/341) site, and its down-stream signaling molecules ERK and CREB expression followed by 24 h and 72 h of reperfusion, suggesting a role of Src kinase as an enhancer on neuronal cell proliferation in the DG via modifying the Raf/ERK/CREB cascade. This hypothesis is supported by further findings that U0126, the ERK inhibitor, induced a reduction of adult hippocampal progenitor cells in DG after cerebral ischemia and down-regulated phospho-ERK and phospho-CREB expression, but no effect was detected on the activities of Src and Raf. CONCLUSION: Src kinase increase numbers of newborn neuronal cells in the DG via the activation of Raf/ERK/CREB signaling cascade after cerebral ischemia.