Multi-Targeting Tacrine Conjugates with Cholinesterase and Amyloid-Beta Inhibitory Activities: New Anti-Alzheimer's Agents

Alzheimer's disease (AD) is a severe age dependent and chronic problem with no cure so far. The available treatments are temporary, acting over short period of time. The main pathological hallmark of the disease includes cholinergic dysfunction, oxidative stress, accumulation of Aβ fibrils and tau tangles. In context with the multi-factorial nature of this disease, two different series of molecules were developed to hit the multifactorial disease targets. Mainly, the molecules were designed to inhibit the AChE and aggregation of Aβ, and also oxidative damage. Two novel series of TAC-fenbufen/menbutone conjugated molecules were designed, synthesized and bio-assayed. All compounds showed inhibition capacity towards AChE, Aβ aggregation and moderate to good radical scavenging capacity. Particularly, five TAC-menbutone molecules showed improved AChE and Aβ aggregation inhibition capacity compared to TAC-fenbufen conjugated molecules. Overall, these novel series of molecules may be potential drug lead molecules in the treatment of AD.     

Comparative 16S rRNA oligonucleotide analyses and murein types of round-spore-forming bacilli and non-spore-forming relatives

The phylogenetic incoherency of the genus Bacillus as presently described is demonstrated by analysis of both published and new data from comparative 16S rRNA cataloguing of nine Bacillus species and a number of related non-Bacillus taxa, i.e. Caryophanon latum, Filibacter limicola and Planococcus citreus. While the ellipsoidal-spore-forming bacilli, e.g. B. subtilis and allied species, formed a coherent cluster, the round-spore-forming bacilli showed a higher degree of relationship to the non-spore-forming organisms than these bacilli show among each other. Thus B. sphaericus clustered with C. latum, B. globisporus grouped with F. limicola, B. pasteurii with Sporosarcina ureae, and 'B. aminovorans' with P. citreus, respectively. These organisms formed two related subclusters which, in their phylogenetic depth, are comparable to that of the B. subtilis subline. With the exception of 'B. aminovorans', the 16S rRNA phylogeny was entirely consistent with the distribution of murein types. Even more distantly related to and grouping outside the main Bacillus cluster was B. stearothermophilus, which displayed a moderate relationship to Thermoactinomyces vulgaris. Taxonomic problems arising from the new insights into the intrageneric relationships of Bacillus are discussed.     

New details on the morphology of fossil onagraceous pollen grains

Fossil onagraceous pollen grains from two Upper Miocene localities in E. Austria were investigated by LM and EM. Exine structure and sculpture as well as viscin threads suggest affinities with the extant genusCircea.     

Isoelectric and mass characterization of human platelet thromboxane A2/prostaglandin H2 receptors

To further characterize the human thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor, preparative isoelectric focusing (IEF) was performed on solubilized platelet membranes. TXA2/PGH2 receptors, assayed by specific binding of the TXA2/PGH2 antagonist [125I]PTA-OH, were electrofocused at pH 5.6. Scatchard analysis of IEF fraction pH 5.6 revealed a 180-fold concentration of TXA2/PGH2 receptors (Bmax = 3650 +/- 228 pM/mg focused, 19 +/- 4 pM/mg unfocused) with no change in binding affinity (Kd = 47 +/- 7 nM focused, 36 +/- 14 nM unfocused). SDS-polyacrylamide gel electrophoresis of photoaffinity-labelled electrofocused receptors revealed concentration of specifically labelled proteins having molecular masses of 49,000 and 27,000 Daltons. These results suggest that the human platelet TXA2/PGH2 receptor has a pI of 5.6, molecular mass of 49,000 Daltons, and may exist as a dimer. Preparative IEF should prove useful in the eventual purification of this receptor.     

Studies on protein kinases involved in regulation of nucleocytoplasmic mRNA transport.

The rate of energy-dependent nucleoside triphosphatase (NTPase)-mediated nucleocytoplasmic translocation of poly(A)-containing mRNA [poly(A)+mRNA] across the nuclear envelope is thought to be regulated by poly(A)-sensitive phosphorylation and dephosphorylation of nuclear-envelope protein. Studying the phosphorylation-related inhibition of the NTPase, we found that phosphorylation of one polypeptide of rat liver envelopes by endogenous NI- and NII-like protein kinase was particularly sensitive to poly(A). This polypeptide (106 kDa) was also phosphorylated by nuclear-envelope-bound Ca2+-activated and phospholipid-dependent protein kinase (protein kinase C). Activation of kinase C by tumour-promoting phorbol esters resulted in inhibition of nuclear-envelope NTPase activity and in a concomitant decrease of mRNA (actin) efflux rate from isolated rat liver nuclei. Protein kinase C, but not nuclear envelope NI-like or NII-like protein kinase, was found to be solubilized from the envelope by Triton X-100, whereas the presumable poly(A)-binding site [the 106 kDa polypeptide, representing the putative carrier for poly(A)+mRNA transport] remained bound to this structure. RNA efflux from detergent-treated nuclei lost its susceptibility to phorbol esters. Addition of purified protein kinase C to these nuclei restored the effect of the tumour promoters. Protein kinase C was found to bind also to isolated rat liver nuclear matrices in the absence but not in the presence of ATP. The NII-like nuclear-envelope protein kinase co-purified together with the 106 kDa polypeptide which specifically binds to poly(A) in an ATP-labile linkage.     

Die endokrinen drüsen im embryo von Oncopeltus fasciatus Dallas (Insecta,Heteroptera)

The differentiation of the endocrine glands in the embryo of Oncopeltus fasciatus is described. The function of these glands can be correlated with the embryonic moults. The nuclei of some tissues already become polyploid in the embryo. It is discussed whether the endomitotic growth is dependent upon the function of the endocrine glands.

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Abkürzungen in den Abbildungen A Ca Anlage des Corpus allatum - A Cc Anlage des Corpus cardiacum - A Maxd Anlage der Maxillendrüse - A Meth Anhang des Mesothorax - A Mth Anhang des Metathorax - A Pl Anlage des-Pleuropodiums - A Prd Anlage der Prothoraxdriise - A Pth Anhang des Prothorax - A Spd Anlage der Speicheldrüse - Am Amnion - Ant Antenne - Ao Aorta - Blz Blutzelle - Ca Corpus allatum - Cc Corpus cardiacum - Cul Cuticulinschicht - Cut Cuticula - Des Desmosom - dl denselayer - Do Dotter - Ent Entoderm - Ep Epidermis - Epk Epidermiskern - Fk Fettkörper - fl Do verflüssigter Dotter - Hyp Hypocerebralganglion - Hz Herzschlauch - Kl Kopflappen - La Labrum - Lab Labium - M Mitteldarm mit verschiedenen Abschnitten (I, II, III und IV) - Mal Malpighisches GefäB - Max Maxille - Md Mandibel - Mes Mesoderm - Mik Mikrovilli - Ms Muskel - Mst Mittelstrang - Nbl Neuroblast - NZ Neurosekretorische Zellen - Oen Oenocyt - Oes Oesophagus - Ogl Oberschlundganglion - p Cut Procuticula - Pcz Pericardialzelle - Pi Pleuropodium - Prd Prothoraxdrüse - Pyl Pylorus - Re Rectum - Rk Riesenkern - S Schlüpfakt - Sal Salivarium - Ser Serosa - Sg Segmentgrenze - Spd Speicholdrüse (I = vorderer Lappen, II = scitlicher Lappen, III = hinterer Lappen, IV = akzessorische Drüse und V = Hylus) - Spdg Speicheldrüsengang - St Stechborste - Std Stinkdrüse - Sti Stigma - Stom Stomodaeum - Stt Stechborstentasche - tb E tubuläre Einstülpung des Prothorax - Ugl Unterschlundganglion - V Vakuole Mit Unterstutzung der Deutschen Forschüngsgemcinschaft.     

Isolation and characterization of a 3-chlorobenzoate degrading pseudomonad

A pseudomonad has been isolated from sewage, which can utilize 3-chlorobenzoic acid as a sole carbon source. In cells grown on benzoate the enzymes of the -ketoadipic acid pathway are present. Considerable enzymic activities for chlorinated substrates were found in benzoate grown cells only for the oxygenation of 3-chlorobenzoate and the dehydrogenation of 3- and 5-chloro-3,5-cyclohexadiene-1,2-diol-1-carboxylic acid. 3-Chlorobenzoate grown cells show additional high activities for the turnover of 3- and 4-chlorocatechols and chloromuconic acids.Abbreviations Used DHB (-)-3,5-cyclohexadiene-1,2-diol-1-carboxylic acid (derived from the trivial name, dihydrodihydroxybenzoate) - 3- and 5-Cl-DHB correspondingly 3- and 5-chloro-3,5-cyclohexadiene-1,2-diol-1-carboxylic acid     

The Epidemiology of Cancer in Animals

The principles of epidemiology are applicable to the study of the distribution and determinants of cancer in both human and animal populations. There are many examples of epidemiologic factors (host, environment, agent and time) related to cancer in animals. Certain host characteristics such as age, sex and breed are related to risk of developing cancer. Some environmental influences are illustrated by differences in the geographical distribution of certain types of animal cancer.Aggregations of cancer cases have been reported in herds, families and households. However, the usual distribution of cases in a population does not resemble epidemics typical of infectious diseases. Several factors (radiological, chemical, dietary, parasitic, mechanical, genetic and viral) have been identified as influences that affect the development of animal tumors.Animal species that have been domesticated live longer and consequently malignant disease develops in more of them. Cancer incidence rates now available from data compiled by an animal neoplasm registry in Alameda and Contra Costa counties, California, indicate that some of the frequent sites of cancer in man (skin, breast and the hemic and lymphatic systems) are among the most frequent sites in dogs and cats, man''s closest animal associates.     

Cell-free transfer of sterols from dictyosome-like structures to plasma membrane vesicles of guinea pig testes

Summary Transfer of radiolabeled lipids from dictyosome-like structures (DLS) from testis tubules of the guinea pig as donor to unlabeled plasma membrane from testis tubules immobilized on nitrocellulose as acceptor was studied in a completely cell-free system. As a general label for lipids of the donor DLS, isolated testis tubules were incubated with [¹⁴C]acetate. Time- and temperature-dependent transfer of [¹⁴C]acetate labeled constituents was observed in the cellfree system. However, despite the fact that phospholipids and other constituents were highly labeled in the donor fraction, primarily radioactive sterols were transferred to the plasma membrane acceptor vesicles. Transfer at 37°C represented 0.4 to 0.7% of the total radiolabeled cholesterol at 37°C but little or no transfer occurred at 4°C. The sterols transferred exhibited Chromatographic mobilities corresponding to those of cholesterol and lanosterol. Similar results were obtained with [¹⁴C]mevalonic acid. In subsequent experiments, cholesterol transfer from DLS to plasma membrane was demonstrated by incubation of DLS with [³H]squalene which was converted into sterol or with [¹⁴C]cholesterol. Transfer of sterols required ATP, but not cytosol, and was both time- and temperature-dependent. DLS were more effective than either endoplasmic reticulum or plasma membrane as the donor fraction. The results from the cell-free analysis suggest a possible functional role of the DLS in sterol biogenesis and transfer to the plasma membrane during spermatid development.Abbreviations DLS dictyosome-like structure(s) - PBS phosphatebuffered saline - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - BSA bovine serum albumin