Syntheses,neural protective activities,and inhibition of glycogen synthase kinase-3β of substituted quinolines

A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer’s disease mouse model.     

Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer’s disease

A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC₅₀ values of 2.11 μM and 1.56 μM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC₅₀ value of 2.68 μM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer’s disease.     

A new westward migration route in an Asian passerine bird

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New insight into Parkinson’s disease pathogenesis from reactive oxygen species-mediated extracellular Zn2+ influx

BackgroundParkinson’s disease (PD) is the common neurodegenerative disorder in the elderly characterized by motor symptoms such as tremors, which is caused by selective loss of nigral dopaminergic neurons. Oxidative stress induced by the auto-oxidation of dopamine has been implicated as a key cause of the selective loss of dopaminergic neurons.MethodsTo understand the selective loss of nigral dopaminergic neurons, the PD pathogenesis is reviewed focused on paraquat (PQ) and 6-hydroxydopamine (6-OHDA)-induced PD in rats.ResultsReactive oxygen species (ROS), which are produced by PQ and 6-OHDA, are retrogradely transported to presynaptic glutamatergic neuron terminals. ROS activate presynaptic transient receptor potential melastatin 2 (TRPM2) cation channels and induce extracellular glutamate accumulation in the substantia nigra pars compacta (SNpc), followed by age-related intracellular Zn²⁺ dysregulation. Loss of nigral dopaminergic neurons is accelerated by age-related intracellular Zn²⁺ dysregulation in the SNpc of rat PD models. The intracellular Zn²⁺ dysregulation in nigral dopaminergic neurons is linked with the rapid influx of extracellular Zn²⁺ via postsynaptic AMPA receptor activation, suggesting that PQ- and 6-OHDA-induced pathogenesis is linked with age-related intracellular Zn²⁺ dysregulation in the SNpc. Postsynaptic TRPM2 channels may be also involved in intracellular Zn²⁺ dysregulation in the SNpc.ConclusionA novel mechanism of nigral dopaminergic degeneration, in which ROS induce rapid intracellular Zn²⁺ dysregulation, figures out the PD pathogenesis induced by PQ and 6-OHDA in rats. This review deals with new insight into PD pathogenesis from ROS-mediated extracellular Zn²⁺ influx and its proposed defense strategy.     

The first confirmed decline of a delphinid population from Brazilian waters: 2000–2015 abundance of Sotalia guianensis in Guanabara Bay,South-eastern Brazil

The abundance of Guiana dolphins (Sotalia guianensis) in Guanabara Bay, Rio de Janeiro, South-eastern Brazil, was investigated during the period 2000–2015 using mark-recapture models applied to photo-identification data. A combination of Pradel’s model and Pollock’s robust design was applied to estimate abundance and other population parameters, such as apparent survival (Φ), capture probability (p) and seniority probability (γ). Total population size was estimated by correcting the estimates derived from the Pradel robust design model for the proportion of marked individuals in the population. The corrected abundance estimates decreased drastically (37%) between 2000 (62, 95% CI 59–65) and 2015 (39, 95% CI 37–40), and can be explained by a combination of low survival and recruitment rates. Determining the ultimate causes for the decline in this Guiana dolphin population is difficult, but the likely reasons are of anthropogenic nature, such as by-catch, habitat degradation, intense traffic of vessels and exposure to immunosuppressive and endocrine-disrupting pollutants. We provide the first quantitative evidence of population decline in a delphinid from Brazilian waters. Conservation and management actions are urged to change this scenario. Other local dolphin populations in Brazil, which are exposed to the same impacts, may also be currently declining or are expected to do so in the near future. For this reason, we emphasize that anthropogenic impacts upon estuarine/coastal species that exhibit site fidelity warrant greater attention, because such impacts may lead to the same negative scenario observed in Guanabara Bay.     

Selenium speciation analysis in the cerebrospinal fluid of patients with Parkinson’s disease

BackgroundThe aim of the study was to investigate if speciation analysis by liquid chromatography coupled to mass spectrometry could be used to detect organic and inorganic binding forms of selenium in the cerebrospinal fluid (CSF) of patients with Parkinson’s disease (PD) and age-matched control subjects (AMC).MethodsPD patients and control subjects were enrolled from three different neurological departments. CSF samples were collected according to standardized biomarker protocols and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for total selenium determination and ion exchange chromatography (IEC) hyphenated to ICP-MS for selenium speciation analysis.Results75 PD patients and 68 age-matched controls were enrolled for speciation analysis. 8 different species could be detected, but only selenoprotein P (SELENOP), human serum albumin-bound Se (Se-HSA), selenomethionine (Se-Met) and an unidentified Se-compound (U2) presented with more than 50% values above the limit of quantification, without showing significant differences between both groups (p > 0.05). The Se-HSA / Se-Met ratio yielded a significant difference between PD and AMC (p = 0.045). The inorganic species Se-IV and Se-VI were only detectable in a minor part of PD and AMC samples. A highly significant correlation between total selenium levels and SELENOP (PD p < 0.0001; AMC p < 0.0001) and Se-HSA (PD p < 0.0001; AMC p < 0.0001) could be demonstrated, respectively.ConclusionsSpeciation analysis yielded new insight into selenium homeostasis in PD but cannot be used to establish a diagnostic biomarker. The small number of detectable values for Se-IV and Se-VI suggests an inferior role of these potentially neurotoxic binding forms in PD pathology in contrast to other neurodegenerative disorders.     

Quantification of the Thyroid Scan (TS) and correlation to Multiparametric Ultrasounds (MPUS): A textbook case of nuclear molecular imaging

For decades, thyroid scintigraphy (TS) has been considered an interesting tool, especially in the field of hyperthyroidism. In recent years, TS has rapidly gained importance since it provides unique molecular information that cannot be obtained by any other modality. In fact, despite a limited 6 mm spatial resolution, it can highlight molecular and histo-functional changes that characterize most thyroid function disorders. However, to become such a powerful molecular image, the TS must be quantified. How much iodine is taken-up characterizes the Uptake (Up), while where iodine distributes characterizes the Spatial Targeting (ST). Methodology, results and limits of the thyroid Uptake are presented, including suppressed tests. Methods to determine the anatomical thyroid volume are revisited with special focus on planar scintigraphy. Recent developments in quantification make the ¹²³I-TS a new molecular imaging procedure. Since ¹²³I targets the sodium iodide symporter (NIS) and tracks the whole organification process, we derived a fundamental linear relationship between the TSH and the precocious (120–240 min) Uptake (p¹²³IUp). This relationship indicates whether the ¹²³I input follows the physiological TSH stimulation or is predictive of a non TSH-suppressible function, whatever the imaging pattern. This allows identification of toxic or compensated (TSH > 0.1 mU/L) Thyroid Functional Autonomy (TFA), even at baseline. Spatial Targeting, measured with the aid of computational algorithms, provides a reproducible Spatial Targeting Index (STI). This allows estimating a functional thyroid volume, that is likely more informative than the anatomical one. Most aspects of TS quantification and the interest to compare the structure (mostly MultiParametric US) and the function (molecular ¹²³I-TS) are presented.     

Archaeological records indicate a complex history of Pleistocene hunter-gatherer societies in Arabia

Paleolithic research on the Arabian Peninsula is still in its early stage. During the last decade, however, an increasing number of field projects were conducted and added significant data to the record. This development in addition to substantial paleoenvironmental research on Pleistocene climate and habitat changes creates a promising setting for research on human evolution in arid landscapes. Here I provide an overview of the main Paleolithic field projects conducted in Arabia and summarize their results.     

治沟造地背景下延安市农业生态经济系统耦合发展分析

治沟造地是继退耕还林工程后延安市实施的又一项重大生态环境治理工程。研究治沟造地工程背景下延安市农业生态经济系统耦合关系的发展变化,对科学评价治沟造地工程生态经济效益和黄土高原地区农业生态经济协调与可持续发展具有重要意义。本研究通过构建农业生态经济系统耦合协调度模型和耦合度模型,定量分析了2010—2018年延安市农业生态与农业经济系统的综合评价指数变化、耦合协调状态及耦合度演变趋势。结果表明: 2010—2018年间,延安市农业生态系统综合评价指数和农业经济系统综合评价指数均呈现S型增长曲线,两者变化趋势较为一致;农业生态经济系统耦合协调度指数由0.51增长至0.72,耦合协调状态由初级协调水平发展为良好协调水平,说明该区域农业生态与经济关系不断改善,系统耦合关系向相互协调的方向发展;研究期间,延安市农业生态经济系统耦合演变过程较为复杂,系统耦合趋势经历了“衰退耦合、协调耦合、修复耦合、协调耦合”阶段,2018年耦合关系处于经济快速增长的协调发展阶段。治沟造地工程促进了农业生态经济系统的耦合协调发展,但其生态经济效益具有一定的滞后性。