Regulation of Human Formyl Peptide Receptor 1 Synthesis: Role of Single Nucleotide Polymorphisms, Transcription Factors, and Inflammatory Mediators

The gene encoding the human formyl peptide receptor 1 (FPR1) is heterogeneous, containing numerous single nucleotide polymorphisms (SNPs). Here, we examine the effect of these SNPs on gene transcription and protein translation. We also identify gene promoter sequences and putative FPR1 transcription factors. To test the effect of codon bias and codon pair bias on FPR1 expression, four FPR1 genetic variants were expressed in human myeloid U937 cells fused to a reporter gene encoding firefly luciferase. No significant differences in luciferase activity were detected, suggesting that the translational regulation and protein stability of FPR1 are modulated by factors other than the SNP codon bias and the variant amino acid properties. Deletion and mutagenesis analysis of the FPR1 promoter showed that a CCAAT box is not required for gene transcription. A −88/41 promoter construct resulted in the strongest transcriptional activity, whereas a −72/41 construct showed large reduction in activity. The region between −88 and −72 contains a consensus binding site for the transcription factor PU.1. Mutagenesis of this site caused significant reduction in reporter gene expression. The PU.1 binding was confirmed in vivo by chromatin immunoprecipitation, and the binding to nucleotides −84 to −76 (TTCCTATTT) was confirmed in vitro by an electrophoretic mobility shift assay. Thus, similar to many other myeloid genes, FPR1 promoter activity requires PU.1. Two single nucleotide polymorphisms at −56 and −54 did not significantly affect FPR1 gene expression, despite differences in binding of transcription factor IRF1 in vitro. Inflammatory mediators such as interferon-γ, tumor necrosis factor-α, and lipopolysaccharide did not increase FPR1 promoter activity in myeloid cells, whereas differentiation induced by DMSO and retinoic acid enhanced the activity. This implies that the expression of FPR1 in myeloid cells is developmentally regulated, and that the differentiated cells are equipped for immediate response to microbial infections

Comparing high- and low-lethality factors regarding attempted suicide-associated risk factors [Factores de riesgo, asociados a intento de suicidio, comparando factores de alta y baja letalidad]

This study was aimed at identifying the most common risk factors associated with suicide attempts to determine differences between risk factors present in patients regarding their low-lethality and high-fatality suicide attempts. 106 patients from both sexes who had been hospitalised in a psychiatric unit following their attempts at suicide were interviewed; they were divided into two groups: low-lethality and high-lethality suicide attempt patients. Results 58.5% of the 106 patients were placed in the low-lethality group and 41.5% in the high-lethality group. The highest rates occurred in the high-lethality group but only two factors had significant statistical difference: "living alone" and "prior alcohol poisoning". 77.4% of the sample were aged under 39, 7% were female and 31% male. Having a family background of alcoholism, previously attempted suicide, generalised anxiety and dysthymia had the highest percentages as risk factors associated with attempted suicide in both groups. The risk factors having the highest percentages were consistent with those reported in the literature. The fact of living alone and having previously suffered alcohol poisoning had statistically significant differences in this study. No significant differences were found in the rest of the factors studied here

Glycophosphopeptical as adjuvant treatment of diabetic foot injury: A pilot study [Glycophosphopeptical como adyuvante en el tratamiento de lesiones del pie diab�tico: estudio piloto]

Background: Due to the complexity of the diabetic foot, its high frequency of amputations and accompanying immunosuppression, treatment is difficult. We tested the usefulness of glycophosphopetical immunoregulator as adjuvant herapy for diabetic foot injury. Methods: We carried out a prospective double-blind randomized controlled study with 19 patients per group with diabetic foot injury III and IV (Wagner injury classification). The study group was treated orally with glycophosphopeptical (1 g/every 8 h for 4 weeks). Control group was treated with placebo. Both groups received conventional treatment: wound debridement, antibiotic therapy and metabolic control. Area and depth of injury was measured at the beginning of the study and after 2 months. Patients who were healed or showed improvement were quantified as well with serum levels of TNF-?, interferonand IL-1?, 15 days after treatment initiation. Results: The study group was comprised of 13 males and six females (mean age 61.6 � 14.9 years) and the control group was comprised of five females and 14 males (mean age 56.7 � 14.6 years). At the end of the study, the area and depth of the lesions were significantly lower in the study group (p <0.05). There were 13 amputations in the study group vs. 17 in the control group. In the group treated with glycophosphopeptical, there were 15 patient who were healed or improved and four failures vs. seven patients in the control group who were healed or improved and 12 failures. There were only four failures in the study group vs. seven in the control group with 12 failures (p = 0.03). TNF-? was lower in the study group than in the control group (p <0.02). Conclusion: Glycophosphopeptical is useful as adjuvant therapy in diabetic foot injuries

Neutrophil Formylpeptide Receptor Single Nucleotide Polymorphism 348T > C In Aggressive Periodontitis

Background: Neutrophil formylpeptide receptors (FPRs) play an important role in bacterial recognition and chemotaxis. Defective FPR1 expression and impaired polymorphonuclear leukocyte chemotaxis toward bacterial formylpeptides are associated with aggressive periodontitis (AgP). The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in FPR1 are associated with AgP. Methods: Genomic DNA was isolated from blood samples obtained from African Americans (30 subjects with AgP and 33 healthy controls) and Turks (75 subjects with AgP and 63 healthy controls). A highly polymorphic fragment of the FPR1 gene was amplified by polymerase chain reaction and sequenced for analysis of SNPs. Results: Five previously identified SNPs were detected in African Americans, whereas six were detected in Turkish subjects. The frequency of synonymous SNP c.348T>C was significantly higher in African Americans with AgP than in controls (P=0.029). The 348T allele was significantly associated with AgP (P= 0.010). Seven of the subjects with AgP, but none of the controls, were homozygous for 348T. FPR1 haplotypes 348T.568A, 348T.576T, and 348T.568A.576T were significantly increased in African Americans with AgP (P C is associated with AgP in African Americans. Individuals who are homozygous for 348T may have an increased risk for developing this disorder. J Periodontol 2009;80:492-498.Wo