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91.
92.
Sterling J Herzig Y Goren T Finkelstein N Lerner D Goldenberg W Miskolczi I Molnar S Rantal F Tamas T Toth G Zagyva A Zekany A Finberg J Lavian G Gross A Friedman R Razin M Huang W Krais B Chorev M Youdim MB Weinstock M 《Journal of medicinal chemistry》2002,45(24):5260-5279
Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere. 相似文献
93.
Pola R Gaetani E Flex A Aprahamian T Proia AS Bosch-Marcé M Smith RC Pola P 《Experimental neurology》2003,184(1):264-273
Apolipoprotein E-knockout (apoE KO) mice have peripheral sensory nerve defects, reduced and delayed response to noxious thermal stimuli, abnormal morphology of unmyelinated fibers, and impaired blood-nerve and blood-brain barriers. In this study, we show that, compared to wild-type mice, peripheral nerves of apoE KO mice have impaired ability to respond to ischemia, as demonstrated by measurement of motor and sensory conduction velocity. In addition, mice lacking apoE exhibit a deficit of reinnervation of ischemic epidermis, evaluated by immunofluorescent staining for the pan-neuronal marker PGP 9.5. Also regional nerve blood flow, measured by laser Doppler, and intraneural angiogenesis after ischemia are significantly compromised in apoE-deficient mice. Finally, upregulation of the angiogenic cytokine vascular endothelial growth factor (VEGF), which physiologically occurs after ischemia in the peripheral nerve of wild-type mice, is severely impaired in apoE KO mice. Among the several neural defects that have already been described in mice lacking apoE, this is the first demonstration that functional recovery to ischemia is impaired in the peripheral nerves of these animals. This deficit is mirrored by the inability of upregulating VEGF and mounting an appropriate intraneural angiogenic response following injury. These findings provide new evidence of possible interdependent relationships between VEGF, angiogenesis, and nerve function and regeneration and may provide new important information on the role of apoE in the nervous system. 相似文献
94.
Multiple shifts in the representation of a motor sequence during the acquisition of skilled performance
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Korman M Raz N Flash T Karni A 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(21):12492-12497
When do learning-related changes in performance occur? Here we show that the knowledge of a sequence of movements evolves through several distinctive phases that depend on two critical factors: the amount of practice as well as the passage of time. Our results show the following. (i) Within a given session, large performance gains constituted a signature for motor novelty. Such gains occurred only for newly introduced conditions irrespective of the absolute level of performance. (ii) A single training session resulted in both immediate but also time-dependent, latent learning hours after the termination of practice. Time in sleep determined the time of expression of these delayed gains. Moreover, the delayed gains were sequence-specific, indicating a qualitative change in the representation of the task within 24 h posttraining. (iii) Prolonged training resulted in additional between-session gains that, unlike the effects of a single training session, were confined to the trained hand. Thus, the effects of multisession training were qualitatively different than the immediate and time-dependent effects of a single session. Altogether, our results indicate multiple time-dependent shifts in the representation of motor experience during the acquisition of skilled performance. 相似文献
95.
Evolution of genomic diversity and sex at extreme environments: fungal life under hypersaline Dead Sea stress
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Kis-Papo T Kirzhner V Wasser SP Nevo E 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(25):14970-14975
We have found that genomic diversity is generally positively correlated with abiotic and biotic stress levels (1-3). However, beyond a high-threshold level of stress, the diversity declines to a few adapted genotypes. The Dead Sea is the harshest planetary hypersaline environment (340 g.liter-1 total dissolved salts, approximately 10 times sea water). Hence, the Dead Sea is an excellent natural laboratory for testing the "rise and fall" pattern of genetic diversity with stress proposed in this article. Here, we examined genomic diversity of the ascomycete fungus Aspergillus versicolor from saline, nonsaline, and hypersaline Dead Sea environments. We screened the coding and noncoding genomes of A. versicolor isolates by using >600 AFLP (amplified fragment length polymorphism) markers (equal to loci). Genomic diversity was positively correlated with stress, culminating in the Dead Sea surface but dropped drastically in 50- to 280-m-deep seawater. The genomic diversity pattern paralleled the pattern of sexual reproduction of fungal species across the same southward gradient of increasing stress in Israel. This parallel may suggest that diversity and sex are intertwined intimately according to the rise and fall pattern and adaptively selected by natural selection in fungal genome evolution. Future large-scale verification in micromycetes will define further the trajectories of diversity and sex in the rise and fall pattern. 相似文献
96.
The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: a cohort study 总被引:2,自引:0,他引:2
Psoralen+ultraviolet A-treated psoriasis patients are at increased risk for nonmelanoma skin cancer. To assess the persistence of cancer risk among patients who have discontinued psoralen+ultraviolet A and the risk of a first tumor with the passage of time, we prospectively studied the incidence in a cohort of 1,380 psoriasis patients treated with psoralen+ultraviolet A. We observed a total of 27,840 person-years of which 59.4% were considered years without psoralen+ultraviolet. No significant decrease in risk was noted during the first 15 years after psoralen+ultraviolet A was discontinued. Subsequently, the risk of squamous cell carcinoma was reduced (incidence rate ratio=0.79; 95%CI=0.62, 1.01 on treatment vs >15 years off). After 25 years, about 7% of patients with < or =200 psoralen+ultraviolet A treatments and more than half of the patients with > or =400 treatments develop at least one squamous cell carcinoma. After 25 years, almost one third of the patients exposed to > or =200 treatments developed at least one basal cell carcinoma. In conclusion, substantial exposure to psoralen+ultraviolet A dramatically increases the risk of nonmelanoma skin cancer and prior exposure to psoralen+ultraviolet A remains an important issue in the management of patients because the cancer risk associated with psoralen+ultraviolet A is persistent. 相似文献
97.
Kung MP Hou C Zhuang ZP Skovronsky DM Zhang B Gur TL Trojanowski JQ Lee VM Kung HF 《Journal of molecular neuroscience : MN》2002,19(1-2):7-10
Development of probes for β-amyloid (Aβ) plaques, a critical factor associated with Alzheimer’s disease (AD), provides important
tools for studying their role in AD. Previously, we reported [125I]IMSB and [125I]ISB as excellent probes for Aβ plaque labeling. Despite their exquisite in vitro binding characteristics, low brain uptakes
(likely due to two ionizable carboxylic acid groups) limited their potential as in vivo imaging agents. To improve brain penetration,
we have successfully prepared a neutral radioiodinated probe [125I]3. The improved probe displayed good binding affinity for Aβ aggregates (Ki=2.0 ± 0.2 using Aβ40 aggregates). In addition, the brominated counterpart displayed fluorescent-staining properties of Aβ
plaques in postmortem AD brain sections similar to BSB, a fluoroscent probe reported previously. [125I]3 gave excellent plaque labeling by film autoradiography of AD brain sections. Unlike [125I]IMSB (which preferentially detects Aβ40 plaques), the improved radioioinated probe, [125I]3, can readily detect plaques containing aggregates of both Aβ40 and Aβ42. The initial brain uptake of [125I]3 in normal mice at 2 min p.i. was moderate (0.18% ID) and displayed a very slow washout from the brain (0.11 %.ID at 4 h p.i).
Taken together, these data suggest that [125I]3 is useful for in vitro plaque detection, it may not be suitable for in vivo monitoring of Aβ progression and deposition. 相似文献
98.
Intranasal immunization with synthetic recombinant vaccine containing multiple epitopes of influenza virus 总被引:11,自引:0,他引:11
The oligonucleotides coding for three epitopes (HA91-108, NP55-69, and NP 147-158) of influenza virus, stimulating B-cells, T-helper cells and cytotoxic T lymphocytes (CTLs), respectively, were previously employed for expressing each epitope in flagella that induced specific humoral and cellular immune responses. We have constructed new plasmids expressing all three epitopes as a single recombinant product. Two versions have been prepared-a longer one (Fla-HNN) comprising hybrid flagella containing the epitopes, and a shorter version (HNN). Immunization of BALB/c mice with either constructs induced significant humoral immune response against influenza virus. The mice immunized with these peptides also induced higher T-helper activity, including Th1 type-cytokine (IL-2 and IFN-gamma) release. In addition, the mice immunized with HNN peptide demonstrated significant protection against sublethal viral challenge. Furthermore, this vaccine fully protected mice from lethal challenge and enhanced their recovery process. Our results indicate that a single construct expressing multiple epitopes, which stimulate different arms of the immune system, might be an appropriate candidate when the synthetic recombinant vaccine approach is considered. 相似文献
99.
The core value guiding the work of physicians and health workers, including those in Environmental and Occupational Epidemiology and Medicine and Injury Prevention, is to protect the health of the public, especially its most vulnerable individuals. In these fields, we emphasize teaching the use of epidemiology, the core discipline of public health, as a tool for early detection and prevention of disease and injury, as well as an instrument for hypothesis testing. The classic core topics are toxic and physical exposures and their effects, and strategies for their prevention; emerging issues are child labor, mass violence, and democide. In environmental health, students need to be prepared for the reality that the most important and severe problems are often the most difficult to investigate, solve, and evaluate. The following are some recommendations for producing graduates who are effective in protecting communities from environmental hazards and risks: (1) Teach the precautionary principle and its application; (2) Evaluate programs for teaching environmental and occupational health, medicine and epidemiology in schools of public health by their impact on the WHO health indicators and their impact on measures of ecosystem sustainability; (3) Develop problem-oriented projects and give academic credit for projects with definable public health impact and redefine the role of the health officer as the chief resident for Schools of Public Health and Community Medicine; (4) Teach the abuses of child labor and working conditions of women in the workplace and how to prevent the hazards and risks from the more common types of child work; (5) Upgrade teaching of injury prevention and prevention of deaths from external causes; (6) Teach students to recognize the insensitivity of epidemiology as a tool for early detection of true risk; (7) Teach the importance of context in the use of tests of statistical significance; (8) Teach the epidemiologic importance of short latency periods from high exposures as sentinel events for later group risk for cancer and stating the case for action; (9) Protect students and colleagues who are whistleblowers in environmental health from harassment and punishment; (10) Develop curricula and workshops that promote the use of epidemiologic tools for preventing genocide, democide, and their precursors. Schools of Public Health and Community Medicine are at the interface between the resources of academic power and the major problems of community health. Implementing the above recommendations will strengthen academic investigation and impact. 相似文献
100.
Mammalian heparanase: involvement in cancer metastasis,angiogenesis and normal development 总被引:24,自引:0,他引:24
Vlodavsky I Goldshmidt O Zcharia E Atzmon R Rangini-Guatta Z Elkin M Peretz T Friedmann Y 《Seminars in cancer biology》2002,12(2):121-129
Cleavage of heparan sulphate proteoglycans (HSPGs) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase, degrading heparan sulphate (HS) at specific intrachain sites, is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase enzyme is preferentially expressed in human tumours and its overexpression in low-metastatic tumour cells confers a highly invasive phenotype in experimental animals. Heparanase also releases angiogenic factors and accessory fragments of HS from the tumour microenvironment and induces an angiogenic response in vivo. Heparanase may thus facilitate tumour cell invasion, vascularization and survival in a given microenvironment, all critical events in cancer progression. These observations, the anticancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a single predominant functional heparanase suggest that the enzyme is a promising target for drug development. 相似文献