Molecular interplay between leptin, insulin-like growth factor-1, and β-amyloid in organotypic slices from rabbit hippocampus

<p>Abstract</p> <p>Background</p> <p>Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce β-amyloid (Aβ) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Aβ reduces leptin by inhibiting the mTORC1 pathway and Aβ was also suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. As IGF-1 can activate mTORC1 and leptin can modulate JAK/STAT pathway, we determined the extent to which IGF-1 and leptin can upregulate the expression of one another and protect against Aβ-induced downregulation.</p> <p>Results</p> <p>We demonstrate that incubation of organotypic slices from adult rabbit hippocampus with Aβ42 downregulates IGF-1 expression by inhibiting JAK2/STAT5 pathway. Leptin treatment reverses these Aβ42 effects on IGF-1 and treatment with the STAT5 inhibitor completely abrogated the leptin-induced increase in IGF-1. Furthermore, EMSA and ChIP analyses revealed that leptin increases the STAT5 binding to the IGF-1 promoter. We also show that IGF-1 increases the expression of leptin and reverses the Aβ42-induced attenuation in leptin expression via the activation of mTORC1 signaling as the mTORC1 inhibitor rapamycin completely precluded the IGF-1-induced increase in leptin expression.</p> <p>Conclusion</p> <p>Our results demonstrate for the first time that Aβ42 downregulates IGF-1 expression and that leptin and IGF-1 rescue one another from downregulation by Aβ42. Our study provides a valuable insight into the leptin/IGF-1/Aβ interplay that may be relevant to the pathophysiology of AD.</p

Cholesterol-enriched diet causes age-related macular degeneration-like pathology in rabbit retina

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological hallmarks including β-amyloid (Aβ) accumulation, oxidative stress, and apoptotic cell death. The causes of AD and AMD are likely multi-factorial with several factors such as diet, environment, and genetic susceptibility participating in the pathogenesis of these diseases. Epidemiological studies correlated high plasma cholesterol levels with high incidence of AD, and feeding rabbits with a diet rich in cholesterol has been shown to induce AD-like pathology in rabbit brain. High intake of cholesterol and saturated fat were also long been suspected to increase the risk for AMD. However, the extent to which cholesterol-enriched diet may also cause AMD-like features in rabbit retinas is not well known.</p> <p>Methods</p> <p>Male New Zealand white rabbits were fed normal chow or a 2% cholesterol-enriched diet for 12 weeks. At necropsy, animals were perfused with Dulbecco's phosphate-buffered saline and the eyes were promptly removed. One eye of each animal was used for immunohistochemistry and retina dissected from the other eye was used for Western blot, ELISA assays, spectrophotometry and mass spectrometry analyses.</p> <p>Results</p> <p>Increased levels of Aβ, decreased levels of the anti-apoptotic protein Bcl-2, increased levels of the pro-apoptotic Bax and gadd153 proteins, emergence of TUNEL-positive cells, and increased generation of reactive oxygen species were found in retinas from cholesterol-fed compared to normal chow-fed rabbits. Additionally, astrogliosis, drusen-like debris and cholesterol accumulations in retinas from cholesterol-fed rabbits were observed. As several lines of evidence suggest that oxidized cholesterol metabolites (oxysterols) may be the link by which cholesterol contributes to the pathogenesis of AMD, we determined levels of oxysterols and found a dramatic increase in levels of oxysterols in retinas from cholesterol-fed rabbits.</p> <p>Conclusions</p> <p>Our results suggest that cholesterol-enriched diets cause retinal degeneration that is relevant to AMD. Furthermore, our data suggests high cholesterol levels and subsequent increase in the cholesterol metabolites as potential culprits to AMD.</p

Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells

<p>Abstract</p> <p>Background</p> <p>Activation of the liver × receptors (LXRs) by exogenous ligands stimulates the degradation of β-amyloid 1–42 (Aβ42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Aβ42 levels are not well known.</p> <p>Results</p> <p>We determined the effect of 24-OHC and/or 27-OHC on Aβ generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Aβ42, 24-OHC did not affect levels of this peptide. Increased Aβ42 levels with 27-OHC are associated with increased levels of β-amyloid precursor protein (APP) as well as β-secretase (BACE1), the enzyme that cleaves APP to yield Aβ. Unchanged Aβ42 levels with 24-OHC are associated with increased levels of sAPPα, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.</p> <p>Conclusion</p> <p>These results suggest that cholesterol metabolites are linked to Aβ42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Aβ42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Aβ42 levels in AD.</p

Local perceptions and adaptation of indigenous communities to climate change: Evidences from High Mountain Pangi valley of Indian Himalayas

58-67The present study was undertaken with aim to understand the perceptions of indigenous communities about climate change pattern and its local impacts on climate variables, seasons, agriculture, biodiversity and adaptive strategies in geographical and technological-isolated Pangi valley situated in Chamba district, Himachal Pradesh. Randomly selected 120 respondents were interviewed and their perceptions were recorded on pre-designed questionnaire. The climate change impacts are experienced in the form of decreased snowfall (98.3%), temperature rise (97.5%), late onset of monsoon (90.8%), decreased rainfall (76.7%), reduced snow-melted water availability (86.7%) and increased drought incidences (85.8%) of over the years. Further, these climatic changes affecting agriculture through early shifts in crop season (80.8%), shorter growing season (91.7%), introduction of fruit and vegetable crops (90.8%), increased incidence of insect-pest (81.2%) and diseases (84.2%) and thereby decline in crop yield (70%). However, majority of the respondents undertaken adaptive strategies such as crop diversification, traditional mixed-cropping, mixed farming, crop rotation and agro-forestry/agro-horticulture systems to cope with climate change but they are either little or unaware of modern farming practices such as snow water/glacier runoff harvesting, agro advisory services, mulching and zero tillage as adaptation strategies

Exploring the chemical properties and microstructural characterisations of hybrid asphalt binders for enhanced performance

Approximately 3 billion metric tonnes of garbage involving industrial and agricultural waste is expected to be generated by 2030, posing a significant environmental hazard. Notably, recycling or reusing asphalt modification components (palm oil fuel ash (POFA), garnet waste, and sawdust) in pavement construction encounter ongoing challenges. This study comprehensively assessed the chemical characteristics and microstructure analysis of individual wastes and various hybrid asphalt binder and mixtures incorporated with these components. The mixture consisted of asphalt grade 60/70 blended with varying amounts (0%, 3%, 6%, and 9%) of POFA, garnet waste, and sawdust. Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence (XRF), and X-ray diffraction (XRD) analyses were also employed to examine the chemical compositions of the raw waste materials. Meanwhile, the microstructure properties of various hybrid asphalt binder mixtures were analysed utilising Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Consequently, this study presented that the correlation between the 6% POFA, 6% garnet waste, and 6% sawdust substantially impacted the chemical composition and morphology of the mixture. The findings of this study demonstrated that including POFA, garnet waste, and sawdust in a hybrid asphalt binder and mixture could enhance performance and engineering properties

The Use of Waste Polymers in Asphalt Mixtures: Bibliometric Analysis and Systematic Review

Asphalt is widely employed in road construction due to its durability and ability to withstand heavy traffic. However, the disposal of waste polymers has emerged as a significant environmental concern. Recently, researchers have used polymer waste to modify asphalt pavements as a new approach. This approach aims to improve pavement performance and address the environmental concerns of polymer waste. Researchers have demonstrated that incorporating polymeric waste into asphalt mixtures can lead to performance improvements in asphalt pavements, particularly in mitigating common distresses including permanent deformation and thermal and fatigue cracking. The current comprehensive review aims to summarize the recent knowledge on the usage of waste polymers in asphalt mixtures, encompassing their impact on performance properties and mixture design. The review also addresses different types of waste polymers, their potential benefits, challenges, and future research directions. By analyzing various studies, this review offers insights into the feasibility, effectiveness, and limitations of incorporating waste polymers into asphalt mixtures. Ultimately, this contributes to the advancement of sustainable and environmentally friendly road construction practices

Use of calcium carbonate nanoparticles in production of nano-engineered foamed concrete

Researchers have shown significant interest in the incorporation of nanoscale components into concrete, primarily driven by the unique properties exhibited by these nanoelements. A nanoparticle comprises numerous atoms arranged in a cluster ranging from 10 nm to 100 nm in size. The brittleness of foamed concrete (FC) can be effectively mitigated by incorporating nanoparticles, thereby improving its overall properties. The objective of this investigation is to analyze the effects of incorporating calcium carbonate nanoparticles (CCNPs) into FC on its mechanical and durability properties. FC had a 750 kg/m3 density, which was achieved using a binder-filler ratio of 1:1.5 and a water-to-binder ratio of 0.45. The CCNPs material exhibited a purity level of 99.5% and possessed a fixed grain size of 40 nm. A total of seven mixes were prepared, incorporating CCNPs in FC mixes at the specific weight fractions of 0% (control), 1%, 2%, 3%, 4%, 5%, and 6%. The properties that were assessed included the slump, bulk density, flexural strength, splitting tensile strength, compressive strength, permeable porosity, water absorption, drying shrinkage, softening coefficient, and microstructural characterization. The results suggested that incorporating CCNPs into FC enhanced its mechanical and durability properties, with the most optimal improvement observed at the CCNPs addition of 4%. In comparison to the control specimen, it was witnessed that specimens containing 4% CCNPs demonstrated remarkably higher capacities in the compressive, splitting tensile, and flexural tests, with the increases of 66%, 52%, and 59%, respectively. The addition of CCNPs resulted in an improvement in the FC porosity and water absorption. However, it also led to a decrease in the workability of the mixtures. Furthermore, the study provided the correlations between the compressive strength and splitting tensile strength, as well as the correlations between the compressive strength and flexural strength. In addition, an artificial neural network approach was employed, utilizing k-fold cross-validation, to predict the compressive strength. The confirmation of the property enhancement was made through the utilization of a scanning electron microscope

Innovative geopolymer-based cold asphalt emulsion mixture as eco-friendly material

In recent years, there has been a growing interest in cold asphalt emulsion mixture (CAEM) due to its numerous advantages, including reduced CO2 emissions, energy savings, and improved safety during construction and application. However, CAEM has often been considered inferior to hot mix asphalt (HMA) in terms of performance. To address this issue and achieve desirable performance characteristics, researchers have been exploring the modification of CAEM using high-cost additives like ordinary Portland cement. In this study, the focus was on investigating the effects of utilizing waste alkaline Ca(OH)2 solution, ground granulated blast-furnace slag (GGBFS), and calcium carbide residue (CCR) as modifiers to enhance the properties of CAEM. The aim was to develop an innovative geopolymer geopolymer-based cold asphalt emulsion mixture (GCAE). The results of the study revealed that the use of waste alkaline Ca(OH)2 solution led to an increase in early hydration, which was confirmed through scanning electron microscopy. Furthermore, the experimental findings demonstrated that waste alkaline Ca(OH)2 solution significantly contributed to the rapid development of early-age strength in GCAE. As a result, GCAE showed great potential for utilization in pavement applications, particularly for roads subjected to harsh service conditions involving moisture and temperature. By exploring these alternative modifiers, the study highlights a promising avenue for enhancing the performance of CAEM and potentially reducing the reliance on expensive additives like ordinary Portland cement. The development of GCAE has the potential to offer improved performance and durability in pavement applications, thus contributing to sustainable and efficient road infrastructure

Investigating the Potential of High-Density Polyethylene and Nano Clay Asphalt-Modified Binders to Enhance the Rutting Resistance of Asphalt Mixture

This study investigates the potential of two bitumen modifiers, high-density polyethylene (HDPE) and nano clay (NC), to enhance the rutting resistance of asphalt mixture. Four HDPE asphalt binders were prepared by mixing the HDPE at percentages of 2%, 4%, 6%, and 8% with the virgin binder, while four NC asphalt binders were produced by mixing the NC at percentages of 1%, 2%, 3%, and 4%. The consistency and flow of virgin binder, HDPE binders, and NC binders were evaluated by penetration, softening point, and viscosity tests. The results show a gradual increment in the binder stiffness by increasing the percentage of both modifiers. The static creep test was conducted at a temperature of 40 °C to evaluate the rutting resistance. The results confirm that both modifiers can greatly improve the rutting resistance of the asphalt mixture, where 8% HDPE and 3% NC modifications reduce the strains provoked in the asphalt mixture under loading by about 50%. According to the correlation analysis, the mixture rutting performance is highly attributed to the binder stiffness, where the lower the penetration value of the asphalt binder, the lower the strains in the asphalt mixture and the higher the stiffness modulus of the asphalt mixture

Knock Down of Heat Shock Protein 27 (HspB1) Induces Degradation of Several Putative Client Proteins

Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions