Carotenoids as Novel Therapeutic Molecules Against Neurodegenerative Disorders: Chemistry and Molecular Docking Analysis

Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that affects the aging population worldwide. Endogenous and exogenous factors are involved in triggering this complex and multifactorial disease, whose hallmark is Amyloid-β (Aβ), formed by cleavage of amyloid precursor protein by β- and γ-secretase. While there is no definitive cure for AD to date, many neuroprotective natural products, such as polyphenol and carotenoid compounds, have shown promising preventive activity, as well as helping in slowing down disease progression. In this article, we focus on the chemistry as well as structure of carotenoid compounds and their neuroprotective activity against Aβ aggregation using molecular docking analysis. In addition to examining the most prevalent anti-amyloidogenic carotenoid lutein, we studied cryptocapsin, astaxanthin, fucoxanthin, and the apocarotenoid bixin. Our computational structure-based drug design analysis and molecular docking simulation revealed important interactions between carotenoids and Aβ via hydrogen bonding and van der Waals interactions, and shows that carotenoids are powerful anti-amyloidogenic molecules with a potential role in preventing AD, especially since most of them can cross the blood-brain barrier and are considered nutraceutical compounds. Our studies thus illuminate mechanistic insights on how carotenoids inhibit Aβ aggregation. The potential role of carotenoids as novel therapeutic molecules in treating AD and other neurodegenerative disorders are discussed.Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that affects the aging population worldwide. Endogenous and exogenous factors are involved in triggering this complex and multifactorial disease, whose hallmark is Amyloid-β (Aβ), formed by cleavage of amyloid precursor protein by β- and γ-secretase. While there is no definitive cure for AD to date, many neuroprotective natural products, such as polyphenol and carotenoid compounds, have shown promising preventive activity, as well as helping in slowing down disease progression. In this article, we focus on the chemistry as well as structure of carotenoid compounds and their neuroprotective activity against Aβ aggregation using molecular docking analysis. In addition to examining the most prevalent anti-amyloidogenic carotenoid lutein, we studied cryptocapsin, astaxanthin, fucoxanthin, and the apocarotenoid bixin. Our computational structure-based drug design analysis and molecular docking simulation revealed important interactions between carotenoids and Aβ via hydrogen bonding and van der Waals interactions, and shows that carotenoids are powerful anti-amyloidogenic molecules with a potential role in preventing AD, especially since most of them can cross the blood-brain barrier and are considered nutraceutical compounds. Our studies thus illuminate mechanistic insights on how carotenoids inhibit Aβ aggregation. The potential role of carotenoids as novel therapeutic molecules in treating AD and other neurodegenerative disorders are discussed

Interactive flow behaviour and heat transfer enhancement in a microchannel with cross flow synthetic jet

This paper examines the effectiveness in combining a pulsating fluid jet for thermal enhancement in microchannel heat sinks. The proposed arrangement utilises an oscillating diaphragm to induce a high-frequency periodic fluid jet with zero net mass output at the jet orifice hence, termed "synthetic jet". The pulsed jet interacts with the fluid flow through microchannel passages altering their flow characteristics. The present study develops a 2-dimensional finite volume numerical simulation based on unsteady Reynolds-averaged Navier-Stokes equations for examining the microchannel-synthetic jet flow interaction. For a range of parametric conditions, the behaviour of this periodic flow with its special features is identified and the associated convective heat transfer rates are predicted. The results indicate that the pulsating jet leads to outstanding thermal performance in microchannel flow increasing its heat dissipation rate by about 4.3 times compared to a microchannel without jet interaction within the tested parametric range. The degree of thermal enhancement is seen to grow continuously to reach a steady value in the absence of fluid compressibility. The proposed strategy has an intrinsic ability for outstanding thermal characteristics without causing pressure drop increases in microchannel fluid passages, which is identified as a unique feature of the technique.The study also examines and presents the effects of fluid compressibility on the heat removal capacity of this arrangement. The technique is envisaged to have application potential in miniature electronic devices where localised cooling is desired over a base heat dissipation load

Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer’s drug discovery

Alzheimer’s disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD.Alzheimer’s disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD

Impact of H1N1 on Socially Disadvantaged Populations: Systematic Review

The burden of H1N1 among socially disadvantaged populations is unclear. We aimed to synthesize hospitalization, severe illness, and mortality data associated with pandemic A/H1N1/2009 among socially disadvantaged populations.Studies were identified through searching MEDLINE, EMBASE, scanning reference lists, and contacting experts. Studies reporting hospitalization, severe illness, and mortality attributable to laboratory-confirmed 2009 H1N1 pandemic among socially disadvantaged populations (e.g., ethnic minorities, low-income or lower-middle-income economy countries [LIC/LMIC]) were included. Two independent reviewers conducted screening, data abstraction, and quality appraisal (Newcastle Ottawa Scale). Random effects meta-analysis was conducted using SAS and Review Manager.Sixty-two studies including 44,777 patients were included after screening 787 citations and 164 full-text articles. The prevalence of hospitalization for H1N1 ranged from 17-87% in high-income economy countries (HIC) and 11-45% in LIC/LMIC. Of those hospitalized, the prevalence of intensive care unit (ICU) admission and mortality was 6-76% and 1-25% in HIC; and 30% and 8-15%, in LIC/LMIC, respectively. There were significantly more hospitalizations among ethnic minorities versus non-ethnic minorities in two studies conducted in North America (1,313 patients, OR 2.26 [95% CI: 1.53-3.32]). There were no differences in ICU admissions (n = 8 studies, 15,352 patients, OR 0.84 [0.69-1.02]) or deaths (n = 6 studies, 14,757 patients, OR 0.85 [95% CI: 0.73-1.01]) among hospitalized patients in HIC. Sub-group analysis indicated that the meta-analysis results were not likely affected by confounding. Overall, the prevalence of hospitalization, severe illness, and mortality due to H1N1 was high for ethnic minorities in HIC and individuals from LIC/LMIC. However, our results suggest that there were little differences in the proportion of hospitalization, severe illness, and mortality between ethnic minorities and non-ethnic minorities living in HIC

Interaction of Co, Mn, Mg and Al with d(GCCCATGGC) and d(CCGGGCCCGG): a spectroscopic study

Spectroscopic study of the interactions of metal ions, Co, Mn, Mg and Al with d(GCCCATGGGC) and d(CCGGGCCCGG) revealed the following. Metal ions Mn, Al and Mg at the lowest concentrations enhanced the t(m) of oligomers, whereas Mn and Mg at higher concentrations decreased the t(m). Co enhanced the t(m) of oligomers at higher concentrations. The studies have also indicated that Mn at lower concentrations displaced EtBr fluorescence, Mg and Co at moderate concentrations and Al only at higher concentrations. Addition of Co, Mn, Mg and Al altered the bands of the circulars dichroism (CD) spectra of the oligomers in a concentration-dependent manner. The CD spectra of d(GCCCATGGGC) and d(CCGGGCCCGG) indicated B and Z forms of DNA, respectively, in contrast to the A form observed in the crystal structures. Mg and Co at different ionic strength induced Z-B transition in d(CCGGGCCCGG), while Al at higher concentrations induced a Z-A transition. Mn did not induce any transition. This is the first report to show that Al causes structural transitions in sequence specific oligomers and has strong binding ability with CC-rich euchromatin oligomers

Interaction of Co, Mn, Mg and AI with d(GCGTACGC): a spectroscopic study

Spectroscopic study on the interactions of trace elements Co, Mn, Mg and Al with d(GCGTACGC) indicated the following: Al and Mg did not alter T-m values. Mn enhanced T-m at lower concentration and decreased it at higher concentrations. Interestingly Co at higher concentration elevated the T-m. These studies also showed lower concentrations of Mn displaced EtBr, whereas Al could displace it at higher ionic strength. Mg and Co displaced EtBr fluorescence at moderate concentrations. The binding constant values and CD spectra clearly indicated strong binding of these elements to DNA

Interaction of Co, Mn, Mg and Al with d(GCGTACGC): a spectroscopic study

Spectroscopic study on the interactions of trace elements Co, Mn, Mg and Al with d(GCGTACGC) indicated the following: Al and Mg did not alter Tm values. Mn enhanced Tm at lower concentration and decreased it at higher concentrations. Interestingly Co at higher concentration elevated the Tm. These studies also showed lower concentrations of Mn displaced EtBr, whereas Al could displace it at higher ionic strength. Mg and Co displaced EtBr fluorescence at moderate concentrations. The binding constant values and CD spectra clearly indicated strong binding of these elements to DNA

Effect of Wrapping on Post-Tensioned Beams Strengthened with Natural Sisal and Jute FRP Using Finite Element Analysis

Existing buildings are retrofitted to formulate them to be more resistant to seismic activity, earth motion, and other natural disasters. Many available reinforced concrete buildings across the globe are in desperate need of rehabilitation, repair, or replacement owing to degradation caused by a variety of reasons such as corrosion, lack of detailing, and failure of beam-column bonding, among others. In the construction sector, fibre reinforced polymer (FRP) composites have been recognized as a potential option for repairing and increasing the strength of existing structures. In this study, comparisons are done in terms of load bearing capability of the beams for configurations between FE model predictions and field data (experimental). To assess the FRP retrofit, structural responses for strengthened and control post tensioned concrete (PTC) beams are compared, with strengthening using various wrapping methods. The load bearing capacities of the beams retrofitted with sisal and jute fibre employing strip and full wrapping procedures around all four sides is increased by 35.55 percent and 42.85 percent for sisal FRP and 7.14 percent and 12.01 percent for jute FRP, respectively, as compared to the control specimen. The FRP retrofit model is expected to result in a considerable increase in structural performance

Risk Prediction of Peer-to-Peer Lending Market by a LSTM Model with Macroeconomic Factor

In the peer to peer (P2P) lending platform, investors hope to maximize their return while minimizing the risk through a comprehensive understanding of the P2P market. A low and stable average default rate across all the borrowers denotes a healthy P2P market and provides investors more confidence in a promising investment. Therefore, having a powerful model to describe the trend of the default rate in the P2P market is crucial. Different from previous studies that focus on modeling the default rate at the individual level, in this paper, we are the first to comprehensively explore the monthly trend of the default rate at the aggregative level for the P2P data from October 2007 to January 2016 in the US. We use the long short term memory (LSTM) approach to sequentially predict the default risk of the borrowers in Lending Club, which is the largest P2P lending platform in the US. Although being first applied in modeling the P2P sequential data, the LSTM approach shows its great potential by outperforming traditionally utilized time series models in our experiments. Furthermore, incorporating the macroeconomic feature unemp_rate (i.e., unemployment rate) can improve the LSTM performance by decreasing RMSE on both the training and the testing datasets. Our study can broaden the applications of the LSTM algorithm by using it on the sequential P2P data and guide the investors in making investment strategies