A new structural class of selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome

We describe the identification and in vitro characterization of a series of 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome. Our initial SAR data demonstrate that the 2-aminobenzylstatine core structure can effectively serve as the basis for designing potent, selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.     

Amphibians and reptiles from the Early Miocene of the Bardenas Reales of Navarre (Ebro Basin, Iberian Peninsula)

The Lower Miocene deposits of the Bardenas Reales of Navarre (NW Ebro Basin, northern Iberian Peninsula) have yielded a diverse vertebrate fauna, including remains of amphibians and reptiles. These remains occur in several localities in the Tudela Formation. The fossiliferous levels belong to the Biozones MN2b-3 (Biozones Z-A of the Ramblian, i.e., Late Aquitanian to Early Burdigalian in age). The amphibians and reptiles represent at least 13 out of 37 vertebrate species. Amphibians consist of a salamandrid urodele and two or three anurans. All the turtles are cryptodirans and consist of the chelydrid Chelydropsis apellanizi, the testudinids Ptychogaster (Temnoclemmys) bardenensis and Ptychogaster ronheimensis, and a Trionychinae indet. Squamates are represented by the anguid lizard Ophisaurus sp., a non-anguid lacertilian, an amphisbaenian, the erycine boid? Eryx sp., and indeterminate colubrids. Crocodilian remains are assigned to the basal alligatoroid Diplocynodon sp. The fossil associations of the Bardenas Reales of Navarre suggest that the vertebrates lived in the centre of an endoreic basin with stretches of water under intertropical to subtropical climatic conditions.     

Bone events and evolution of biologic markers in Gaucher disease before and during treatment

Introduction  

Known biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date.     

Cows' milk protein intolerance: a possible association with gastroenteritis,lactose intolerance,and IgA deficiency.

Twenty-five children with cows'' milk protein intolerance were studied. Twenty had presented with an illness clinically indistinguishable from infantile gastroenteritis; an enteropathogenic Escherichia coli was isolated from the stools in two children, and in six another member of the family simultaneously developed acute diarrhoea and vomiting. Twenty-three children had lactose intolerance secondary to cows'' milk protein intolerance. Eight out of 20 children were found to be partially IgA deficient. An acute attack of gastroenteritis, in damaging the small mucosa, may act as a triggering mechanism in cows'' milk protein intolerance, and a deficiency in IgA may be a predisposing factor in so far as it allows the patient to become sensitised to foreign protein.     

Striatal GABAergic Neuronal Activity Is Not Reduced in Parkinson''s Disease

The content of gamma-aminobutyric acid (GABA) and the activities of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) were measured in whole putamen obtained at autopsy from 13 patients dying with idiopathic Parkinson's disease and 13 appropriate control subjects. Mean GABA content was significantly elevated (by 28%) in the putamen of the Parkinson's disease patients. TH activity was markedly reduced, while there was no significant reduction of GAD activity in the putamen of these patients. GABA content was also measured in both sides of the striatum in rats which had received unilateral injections of 6-hydroxydopamine (6-OHDA) in the vicinity of the axons of the nigrostriatal projection. Mean GABA content was found significantly elevated (by 33%) in the ipsilateral striatum. Loss of dopaminergic nigrostriatal neurons, in both human Parkinson's disease and in the rat 6-OHDA model, is accompanied by increased striatal GABA content. The assumption that GABAergic neurotransmission is reduced in the striatum in Parkinson's disease may not be correct.     

Chemical modifications of heparin that diminish its anticoagulant but preserve its heparanase-inhibitory, angiostatic, anti-tumor and anti-metastatic properties

Structural features of heparin potentially important for heparanase-inhibitoryactivity were examined by measuring the ability of heparin derivativesto affect the degradation of [³H]acetylated heparan sulphateby tumor cell heparanases. IC₅₀ values were determined usingan assay which distinguished degraded from undegraded substrateby precipitation of the latter with cetylpyridinium chloride(CPC). Removal of heparin's 2-O-sulphate and 3-O-sul-phate groupsenhanced heparanase-inhibitory activity (50%). Removal of itscarboxyl groups slightly lowered the activity (18%), while combiningthe treatments abolished the activity. At least one negativecharge on the iduronic acid/idose moiety, therefore, is necessaryfor heparanase-inhibitory activity. Replacing heparin's N-sulphategroups with N-acetyl groups reduced its activity (37%). Comparingthis heparin derivative with 2,3-O-de-sulphated heparin, theplacement of sulphate groups appears important for activitysince the two structures have similar nominal linear chargedensity. In addition, unsubstituted uronic acids are nonessentialfor inhibition since their modification (periodate-oxidation/borohydride-reduction)enhanced rather than reduced heparanase-inhibitory activity.The most effective heparanase inhibitors (2,3-O-desulphatedheparin, and [periodate-oxidized, borohydride-reduced] heparin)were tested in the chick chorioallantoic membrane (CAM) bioassayfor anti-angiogenic activity and found to be at least as efficaciousas heparin. 2,3-O-desulphated heparin also significantly decreasedthe tumor growth of a subcutaneous human pancreatic (Ca-Pan-2)adenocarcinoma in nude mice and prolonged the survival timesof C57BL/6N mice in a B16-F10 melanoma experimental lung metastasisassay. angiogenesis chemically-modified heparins endoglycosidase hepara sulphate cancer