Monitoring the early aggregatory behaviour and size of Aβ1-42 in the absence & presence of metal ions using dynamic light scattering

Background and aimAβ₁₋₄₂ is an amyloidogenic peptide found within senile plaques extracted from those who died with a diagnosis of Alzheimer’s disease. The potent neurotoxicity of this peptide is related to its propensity to form aggregated conformations in vivo, a process that is influenced by the species and concentration of metal ions present within the local environment. This study examines the impact of different metals upon the early aggregatory behaviour and size of Aβ₁₋₄₂ under simulated physiological conditions.MethodsThe size and aggregatory behaviour of Aβ₁₋₄₂ in the presence and absence of metal ions was monitored during the initial 30 min of fibril formation in real-time using dynamic light scattering.ResultsIntensity scattering measurements showed a clear tendency towards aggregation with regards to Aβ₁₋₄₂ only solutions (10 μM). Both equimolar Al³⁺ & Cu²⁺ lowered and stabilised the dimensions of Aβ₁₋₄₂ aggregates; however, a diminutive but significant increase in size was still observed over a 30-min period. While excess Al³⁺ continued to supress the size of Aβ_1−42, a 10-fold increase in the concentration of Cu²⁺ accelerated peptide aggregation relative to that observed for equimolar metal but not compared to Aβ₁₋₄₂ alone.ConclusionThese results infer that Al³⁺ ions stabilise and aid in the maintenance of smaller, toxic intermediates while excess Cu²⁺ facilitates the formation of larger, more inert, amorphous species exceeding 1 μm in size. Furthermore, we propose that metal-induced toxicity of Aβ₁₋₄₂ is reflective of their ability to preserve smaller oligomeric species in vitro.     

Dysregulation of neural calcium signaling in Alzheimer disease,bipolar disorder and schizophrenia

Neurons have highly developed Ca²⁺ signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca²⁺ signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca²⁺ signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca²⁺ signaling, have proved successful in alleviating the symptoms of some of these neural diseases.     

Burden of disease due to cancer in a Southern Brazilian state

Background: Despite the considerable epidemiological relevance of cancer in developing countries, there are very few studies of the burden related to cancer. The aim of this study was to present and discuss data from a burden-of-cancer study performed in a Southern Brazilian state. Methods: An epidemiological study of ecological design was performed to calculate the disability-adjusted life year (DALY) index. The study was based on records of individuals admitted and treated for cancer in the Brazilian National Health System Hospitals, or individuals who had died of cancer while residing in the state of Santa Catarina in 2008. Results: A total of 73,872.9 DALYs were estimated, which generated a rate of 1220.5 DALYs/100,000 inhabitants. The highest DALYs were those for cancer of the trachea, bronchus and lung with 179.0/100,000 inhabitants, gastric cancer with 101.7/100,000 inhabitants, and breast cancer with 99.7/100,000 inhabitants. The percentage contribution of the DALY component varied according to cancer type; however, mortality was the major component in all types. The highest rates were observed in 60–69-year-olds with 6071.3/100,000 inhabitants, in 70–79-year-olds with 5095.4/100,000 inhabitants, and in 45–59-year-olds with 3189.0 DALY/100,000 inhabitants; 53.7% of DALYs occurred in males. Conclusions: The greatest burden of disease due to cancer in Santa Catarina was attributed to cancer of the trachea, bronchus and lung, followed by gastric and breast cancers. The mortality component was responsible for the greatest burden.     

Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity

In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.     

Deciduous enamel defects and caries susceptibility in a prehistoric Ohio population

Clinical studies of the relationship between developmental enamel defects and caries susceptibility have often produced conflicting results. This has been due in part to a failure to distinguish between different types of defects. Studies of this association in prehistoric populations have been rare. The complete deciduous dentitions of 57 subadults from the Libben site, a large Late Woodland cemetery in Ottawa County, Ohio, were selected for analysis. Defects were classified as either hypoplasias (deficiencies in matrix apposition) or hypocalcifications (deficiencies in mineralization) and were graded for severity. The presence or absence of carious lesions was recorded for each tooth. Results indicate a strong positive relationship between hypocalcifications and caries susceptibility. The elevated caries susceptibility of hypocalcified teeth may be related to high levels of magnesium or altered enamel microcrystallite orientation within these teeth. Variations in the frequency of hypocalcifications may partially explain differences in caries rates that have been observed in different prehistoric populations.     

Neuronal calcium signaling via store-operated channels in health and disease

Store-operated calcium entry (SOCE) is the flow of calcium ions (Ca²⁺) into cells in response to the depletion of intracellular Ca²⁺ stores that reside predominantly in the endoplasmic reticulum (ER). The role of SOCE has been relatively well understood for non-excitable cells. It is mediated mostly by the ER Ca²⁺ sensor STIM1 and plasma membrane Ca²⁺ channel Orai1 and serves to sustain Ca²⁺ signaling and refill ER Ca²⁺ stores. In contrast, because of the complexity of Ca²⁺ influx mechanisms that are present in excitable cells, our knowledge about the function of neuronal SOCE (nSOCE) is still nascent. This review summarizes the available data on the molecular components of nSOCE and their relevance to neuronal signaling. We also present evidence of disturbances of nSOCE in neurodegenerative diseases (namely Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease) and traumatic brain injury. The emerging important role of nSOCE in neuronal physiology and pathology makes it a possible clinical target.     

Quantitative proteomic profiling identifies global protein network dynamics in murine embryonic heart development

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Alveolar bone loss in wild baboons

Radiograph-based methods were used to assess alveolar bone loss in 12 juvenile and 18 adult baboons (Papio hamadryas, sensu lato) living in the Awash National Park, Ethiopia. Alveolar bone loss, as measured from the cementoenamel junction to the alveolar crest, averaged about 1 mm in juveniles and about 1.5 mm in adults. Densitometry of alveolar bone from the radiographs provides a baseline for comparisons with other adult baboons. Periodontal disease surveys of baboon populations using such methods may identify potential etiological agents. Such knowledge may contribute to a better understanding of periodontal disease etiology in humans. © 1993 Wiley-Liss, Inc.     

Development of bivalent compounds as potential neuroprotectants for Alzheimer’s disease

In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC₅₀ of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease.