Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice.

Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease

Prevention of preeclampsia in pregnant women with obesity

Reducing the occurrence of preeclampsia is one of the key tasks in modern obstetrics, especially in pregnant women with concomitant obesity, who are at high risk for preeclampsia, the leading pathogenetic segment of which is endothelial dysfunction. The purpose of this work is to evaluate the effectiveness of the integrated therapeutic and preventive complex (TPC) in order to prevent preeclampsia in pregnant women. These parameters were evaluated using such markers as the concentration of vascular endothelial growth factor (VEGF) in blood serum and the content of circulating endothelial microparticles (CEM) CD32+CD40+ in peripheral blood in pregnant women with obesity of varying severity over the course of treatment we proposed. 110 pregnant women were included in the study: women with physiological body weight (n=26); women with class I obesity (n=42), and women with class II-III obesity. The groups of pregnant women with concomitant obesity were divided into two equal subgroups; one of the subgroups received the TPC (acetylsalicylic acid, calcium supplements, L-arginine, diosmin). The findings obtained demonstrate a significant improvement of endothelial status over the course of the therapy that is manifested with an increase in the serum VEGF concentration and a decrease in the content of CD32+CD40+ CEM in the peripheral blood. Our clinical assessment of pregnancy course, childbirth and the postpartum period in women with obesity and physiological body weight has shown a decrease in the occurrence of complications due to taking the integrated TPC. We have registered a decrease in the incidence of preeclampsia, placental dysfunction, occurrence of miscarriage, operative delivery and postpartum complications.</p

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

An efficient solid-phase-supported peptide synthesis (SPPS) of morpholinoglycine oligonucleotide (MorGly) mimics has been developed. The proposed strategy includes a novel specially designed labile linker group containing the oxalyl residue and the 2-aminomethylmorpholino nucleoside analogues as first subunits

Investigation of the extraction dynamic of the biologically active substances of the raspberry (Rubus idaeus L.) shoots

The study has the intent of exploring the dynamics of biologically active substance (BAS) extractions from red raspberry (R. idaeus) shoots in order to determine the appropriate extraction frequency. A secondary objective is to assess the relationship between extract antioxidant activity and BAS content

A new mouse model of mild ornithine transcarbamylase deficiency (spf-j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation.

Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans

Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza.

AbstractIn response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection

Urea cycle perturbations in <i>Spf-J</i> males.

<p><i>Spf-J</i> (8 weeks) were maintained on a high protein chow diet (70% protein) and euthanized after 2 weeks (N = 6 / group). Blood was collected by retro-orbital bleeding with plasma separated and stored at −80°C until use. WT – wild-type, NP – normal protein, HP – high protein. A) Plasma ammonia and B) Plasma orotate for <i>spf-j</i> and WT. For immune challenge, 8-week-old <i>spf-J</i> (N = 6) and WT (N = 4) received an intraperitoneal injection of poly I:C (100 μg) once a day for 3 days. Tissues harvested and snap frozen and stored at −80°C until use. C) Plasma ammonia. D) Liver transaminases. Hatched bar indicates P < 0.05. WT – wild-type.</p