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.     

Prions and lymphoid organs: Solved and remaining mysteries

Prion colonization of secondary lymphoid organs (SLOs) is a critical step preceding neuroinvasion in prion pathogenesis. Follicular dendritic cells (FDCs), which depend on both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance, are thought to be the primary sites of prion accumulation in SLOs. However, prion titers in RML-infected TNFR1^−/− lymph nodes and rates of neuroinvasion in TNFR1^−/− mice remain high despite the absence of mature FDCs. Recently, we discovered that TNFR1-independent prion accumulation in lymph nodes relies on LTβR signaling. Loss of LTβR signaling in TNFR1^−/− lymph nodes coincided with the de-differentiation of high endothelial venules (HEVs)—the primary sites of lymphocyte entry into lymph nodes. These findings suggest that HEVs are the sites through which prions initially invade lymph nodes from the bloodstream. Identification of HEVs as entry portals for prions clarifies a number of previous observations concerning peripheral prion pathogenesis. However, a number of questions still remain: What is the mechanism by which prions are taken up by HEVs? Which cells are responsible for delivering prions to lymph nodes? Are HEVs the main entry site for prions into lymph nodes or do alternative routes also exist? These questions and others are considered in this article.     

Gas exchange studies in two Portuguese grapevine cultivars

Gas exchange characteristics of leaves of Vitis vinifera L. cvs Tinta Amarela and Periquita, two grapevine cultivars grown in distinct climatic regions of Portugal, were studied under natural and controlled conditions. Daily time courses of gas exchange were measured on both a hot, sunny day and a cooler, partly cloudy day. Responses of net photosynthesis to irradiance and internal partial pressure of CO₂, were also obtained. A strong correlation between net photosynthesis (P_N) and leaf conductance (g_s) was found during the diurnal time courses of gas exchange, as well as a relatively constant internal partial pressure of CO₂ (P_i), even under non-steady-state conditions. On the cloudless day, both P_N and g_s were lower in the afternoon than in the morning, despite similar conditions of leaf temperature, air to leaf water vapor deficit and irradiance. The response curves of net photosynthesis to internal CO₂ showed linearity up to p_i values of 50 Pa, possibly indicating a substantial excess of photosynthetic capacity. When measured at low partial pressures of O₂ (1 kPa), P_N became inhibited at high CO₂ levels. Inhibition of P_N at high CO₂ was absent under normal levels of O₂ (21 kPa). Significant differences in gas exchange characteristics were found between the two cultivars, with T. Amarela having higher rates under similar measurement conditions. In particular, the superior performance of T. Amarela at high temperatures may represent adaptation to the warmer conditions at its place of origin.     

Karyometry and histometry of renal-cell carcinoma

In an attempt to more objectively predict the outcome of renal cancers, karyometric and histometric studies were performed using an interactive computer-based system for the quantitative analysis of tissue sections. Analysis showed a significant relationship between patient survival and metastases and the histometric parameters of nuclear elongation, nuclear crowding and mitotic density, as well as tumor grade. Patients who died tended to have a high mitotic density, elongated and crowded nuclei and high-grade tumors. Ploidy showed no significant correlation with prognosis while nuclear elongation and crowding did. Differences in histologic grade were significantly associated with several histometric variables, including nuclear area, shape, crowding, elongation and mitotic density.     

Elutriation of human keratinocytes and melanocytes fromin vitro cultured epithelium

Summary Human epidermal keratinocytes grown in culture and at different stages of differentiation are shown to be viably separated by elutriation. A specific fraction enriched in melanocytes was obtained. Elutriation of cells obtained fromin vitro cultured epithlium could prove useful in studies concerning the biochemistry and molecular markers of cells isolated from normal epithelium and from different pathologies.     

Pathology of the human pulmonary paracoccidioidomycosis

Lungs of twelve patients with chronic paracoccidioidomycosis (Pb) were studied in an attempt to understand the pathogenesis of the pulmonary disease. Ribbons of the lung parenchyma including the hilar region and directed towards apical, basal and lateral regions were subdivided into sections from the hilar, intermediate and peripheral segments. The following histopathological reactions directly or indirectly related to P. brasiliensis were described and analysed in relation to the number of slides studied and the pulmonary region involved: (1) pneumonic reaction; (2) early granulomatous formation; (3) mature and healed granulomata; (4) mixed pattern (early and mature granuloma in the same pulmonary area visualized in the slide); (5) pulmonary fibrosis.It was concluded that chronic pulmonary Pb is a recurrent disease affecting equally both lungs. Fibrosis was connected mainly with the progressive evolution of the granulomata towards cicatrization and to a lesser degree probably to a direct induction by the fungi. Based chiefly on the tendency of the fibrosis to run around bronchi and to make up septa interconnecting bronchi and vessels it was hipothesized that these findings were the result of a previous chronic specific lymphangitis by the fungi. Hilar fibrosis would be the result of this lymphangitis and/or of the progression of the specific granulomatous reaction seen in the hilar lymph nodes.Non specific forms of arteritis and areas of destructive emphysema related to granulomatous inflammation and fibrosis were described. Three cases developed pulmonary hypertension.     

Polypeptide composition of rat sperm outer dense fibers. A simple procedure to isolate the fibrillar complex

Treatment of caput or cauda epididymal rat sperm with a low concentration (0.05%) of the cationic detergent cetyltrimethylammonium bromide and 30 mM 2-mercaptoethanol solubilized most of the sperm structures except for the sperm head and the outer dense fiber-connecting piece complex. The latter were purified, and about 10% of these complexes are formed by nine fibers attached to the connecting piece. Of these fibers, two are shorter than the other seven and presumably correspond to fibers 3 and 8 (Fawcett, D.W. (1975) Dev. Biol. 44, 394-436). Electron microscopy confirmed the purity of the isolated outer dense fibers and revealed their characteristic irregular cross-sectional shape. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate showed six major polypeptides (Mr = 87,000, 30,400, 26,000, 18,400, 13,000, and 11,500) with a high content of serine, aspartic and glutamic acids, proline, cysteine, leucine, and tyrosine. Furthermore, several lines of evidence indicate a close structural relationship between the components of 30,400 and 26,000 Da. The six major components of the fibers are phosphorylated at serine residues. These results indicate that the major components of rat sperm outer dense fibers are a unique family of phosphoproteins.