H12-(ADP)-liposomes for hemorrhagic shock in thrombocytopenia: Mesenteric artery injury model in rabbits.

BACKGROUND: Damage control resuscitation improves patient outcomes after severe hemorrhage and coagulopathy. However, effective hemostasis methods for these critical situations are lacking. OBJECTIVE: We evaluated the hemostatic efficacy of fibrinogen γ-chain (HHLGGAKQAGDV, H12)-coated, adenosine-diphosphate (ADP)-encapsulated liposomes (H12-[ADP]-liposomes) in thrombocytopenic rabbits with hemorrhagic shock. METHODS: Acute thrombocytopenia (80%) was induced in rabbits that also received mesenteric vessel injury, leading to hemorrhagic shock. Five minutes after injury, subjects received intravenous bolus injection with H12-(ADP)-liposomes (20 mg/kg), followed by isovolemic transfusion with stored red blood cells (RBCs)/platelet poor plasma (PPP) (RBC:PPP = 1:1 [vol/vol]), or lactated Ringer solution every 5 min to compensate blood loss. One group received H12-(phosphate buffered saline [PBS]) liposomes followed by RBC/PPP. Additional groups were received isovolemic transfusion with RBC/platelet rich plasma (PRP) (RBC:PRP = 1:1 [vol/vol]), RBC/PPP, PPP alone, or lactated Ringer solution. RESULTS: Treatment with H12-(ADP)-liposomes followed by RBC/PPP transfusion and RBC/PRP transfusion effectively stopped bleeding in all thrombocytopenic rabbits. In contrast, three of 10 rabbits treated with RBC/PPP failed hemostasis, and no rabbits receiving lactated Ringer solution stopped bleeding or survived. Twenty-four hours after hemorrhage, 80% of rabbits receiving H12-(ADP)-liposome followed by RBC/PPP transfusion survived and 70% of rabbits receiving RBC/PRP transfusion also survived, although RBC/PPP-transfused rabbits showed 40% survival. Rabbits receiving H12-(ADP)-liposomes followed by lactated Ringer solution showed a transient hemostatic potential but failed to survive. H12-(PBS)-liposomes showed no beneficial effect on hemostasis. Neither the PPP group nor the lactated Ringer group survived. CONCLUSION: H12-(ADP)-liposome treatment followed by RBC/PPP may be effective in lethal hemorrhage after mesenteric vessel injury in coagulopathic rabbits.

A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid ß-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid ß-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Biosynthesis of (2-nitroethyl)benzene and (Z)- and (E)-(2-nitroethenyl)benzenes from (Z)- and (E)-phenylacetaldoximes and phenylacetonitrile; defense allomone of Eutrichodesmus elegans and Eutrichodesmus armatus (Polydesmida: Haplodesmidae).

The defense allomones of two haplodesmid millipedes, Eutrichodesmus elegans and E. armatus (Polydesmida: Haplodesmidae), are known as a mixture of the following three nitro compounds: (2-nitroethyl)benzene and (Z)- and (E)-(2-nitroethenyl)benzenes. Administrations of a mixture of 2H-labeled (Z)- and (E)-phenylacetaldoximes and of 2H-labeled phenylacetonitrile as precursors resulted in the same production of three 2H-labeled nitro compounds, [2'-nitroethyl][2,3,4,5,6-2H5]benzene and [(Z)- and (E)-2'-nitroethenyl][2,3,4,5,6-2H5]benzenes, in both species. Oxime administration at an appropriate dose resulted in the production of three nitro compounds with similar natural ratios more effectively than nitrile administration. Conversion from oximes to nitrile and vice versa was evidenced during administration. Occurrences of three precursors (Z- and E-oximes and nitrile) were detected sporadically in millipede extracts by selected ion chromatography.

(2-Nitroethyl)benzene: a major flower scent from the Japanese loquat Eriobotrya japonica [Rosales: Rosaceae].

(2-Nitroethyl)benzene was identified as a major component of the flower scent of the Japanese loquat Eriobotrya japonica [Rosales: Rosaceae], together with p-methoxybenzaldehyde and methyl p-methoxybenzoate. The corresponding volatiles from chopped leaves did not contain these three compounds. This is the first time that 1-nitro-2-phenyl-ethane has been demonstrated to be a natural product among Japanese plants, although two Japanese millipedes are known to possess the same aromatics.

Hyper-activation of the target of rapamycin (Tor) kinase 1 decreases intracellular glutathione content in Saccharomyces cerevisiae as revealed by LC-MS/MS analysis.

The targets of rapamycin (Tor) kinases play central roles in the integrated regulation of cellular activities. Although the molecular mechanisms of Tor-mediated signaling pathways have been studied extensively in yeast, the relationship between kinase activity and the redox maintenance system remains obscure. In this study, we established a quantitative extraction and determination method for glutathione-related compounds in Saccharomyces cerevisiae utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found decreases in the levels of glutathione and its precursors resulting from the introduction of a Tor1 hyper-active mutation. In line with this finding, the mutant was more sensitive to several heavy metal ions, indicating a physiological defect arising from a failure to regulate the kinase activity.