The effect of the typical peptidases (proteases) inhibitors on the degradation of Glp6 (125I) Tyr8SP6-11 hexapeptide in the nuclear and synaptosomal fraction of the cortex and hippocampus of rat brain.

The main peptidase PN/cutting Tyr8-Gly9 or Gly9-Leu10 bond (of sequence Glp6-Phe7-Tyr8-Gly9-Leu10-MetNH2) seems to be, at least in part, cysteine type enzyme. Cutting of Phe7-Tyr8 bond with PC enzyme is apparently negligible. Further degradation of labelled PN products seems to be accomplished with PI, being serine enzyme at least in part. Metalloenzymes, including "enkephalinase", seem to be of minor importance in hexapeptide degradation, at least in its very low concentration. Some typical inhibitors enhance the degradation what might be explained assuming that products of action of one peptidase strongly inhibit the other peptidase's action. Namely, products of PN and PI seem to inhibit PC except the hippocampal synaptosomes where the opposite is true.     

Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1)

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.     

Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity

A novel series of non-imidazole bicyclic and tricyclic histamine H₃ receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.     

Surfactant metabolism and anti-oxidative capacity in hyperoxic neonatal rat lungs: effects of keratinocyte growth factor on gene expression in vivo

Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl-PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85 % O₂ for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development.     

Differentially Expressed miRNAs Influence Metabolic Processes in Pituitary Oncocytoma

Neurochemical Research - Spindle cell oncocytomas (SCO) of the pituitary are rare tumors accounting for 0.1–0.4% of all sellar tumors. Due to their rarity, little information is available...     

Novel,X-ray supported kinetic imaging of hidden-lifestyle arthropods

Dear Editor,There are several arthropods,which live and develop covertly in plant tissues.The plant tissues surrounding them provide them with shelter during their vulnerable developing stage or ensure overwintering as well as they can supply them with essential food for their ontogenetic development(McNaughton,1983).