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Porous nanomaterials can be used to load various anti-cancer drugs efficiently and deliver them to a particular location in the body with minimal toxicity. Biodegradable periodic mesoporous organosilica nanoparticles (BPMOs) have recently emerged as promising candidates for disease targeting and drug delivery. They have a large functional surface and well-defined pores with a biodegradable organic group framework. Multiple biodegradation methods have been explored, such as the use of redox, pH, enzymatic activity, and light. Various drug delivery systems using BPMO have been developed. This review describes recent advances in the biomedical application of BPMOs.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive loss of memory and dementia. The pathological hallmarks of AD include extracellular accumulation of amyloid-β peptides forming senile plaques and intracellular accumulation of Tau oligomers and filamentous species. Tau is a microtubule-binding protein that stabilizes tubulin to form microtubules under physiological condition. In AD/ pathological condition, Tau detaches from microtubules and aggregates to form oligomers of different sizes and filamentous species such as paired helical filaments. Microglia are the resident brain macrophages that are involved in the phagocytosis of microbes, cellular debris, misfolded and aggregated proteins. Chemokine receptor, CX3CR1 is mostly expressed on microglia and is involved in maintaining the microglia in a quiescent state by binding to its ligand, fractalkine (CX3CL1), which is expressed in neurons as both soluble or membrane-bound state. Hence, under physiological conditions, the CX3CR1/CX3CL1 axis plays a significant role in maintaining the central nervous system (CNS) homeostasis. Further, CX3CR1/CX3CL1 signalling is involved in the synthesis of anti-inflammatory cytokines and also has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation. In AD brain, the expression level of fractalkine is reduced, and hence Tau competes to interact with its receptor, CX3CR1. In microglia, phagocytosis and internalization of extracellular Tau species occurs in the presence of a chemokine receptor, CX3CR1 which binds directly to Tau and promotes its internalization. In this review, the pathophysiological roles of CX3CR1/fractalkine signalling in microglia and neurons at different stages of Alzheimer's disease and the possible role of CX3CR1/Tau signalling has been widely discussed., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Alzheimer's disease is the leading cause of dementia, effecting majority of aged people worldwide. The multifaceted effectors of Alzheimer's disease primarily include Tau, amyloid-β along with hyper activation of kinases, oxidative stress and mutations etc., makes it challenging to design therapeutics. Tau is a microtubule-associating protein, which is subjected to cellular stress resulting in the formation of neurofibrillary tangles, leading to loss of affinity for microtubules. This causes loss of microtubule stability and in turn alters axonal integrity. In the present work, emphasis towards understanding interaction of nickel with Tau was made. Metals such as iron, zinc, copper and lead etc., are known to modulate Tau conformation and enhance its aggregation. Our results showed the deliverance of Tau aggregation by nickel and its synthetic morpholine conjugate. Nickel prevents aggregation by inducing degradation of Tau as evidenced by SDS-PAGE and TEM. Nickel and the synthetic conjugate being non-toxic to neuro2a cells and prevent Tau aggregation, might direct these complexes to overcome AD., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2019. Published by Elsevier B.V.)

Tau aggregation and accumulation is a key event in the pathogenesis of Alzheimer's disease. Inhibition of Tau aggregation is therefore a potential therapeutic strategy to ameliorate the disease. Phytochemicals are being highlighted as potential aggregation inhibitors. Epigallocatechin-3-gallate (EGCG) is an active phytochemical of green tea that has shown its potency against various diseases including aggregation inhibition of repeat Tau. The potency of EGCG in altering the PHF assembly of full-length human Tau has not been fully explored. By various biophysical and biochemical analyses like ThS fluorescence assay, MALDI-TOF analysis and Isothermal Titration Calorimetry, we demonstrate dual effect of EGCG on aggregation inhibition and disassembly of full-length Tau and their binding affinity. The IC50 for Tau aggregation by EGCG was found to be 64.2 μM.

The intracellular Tau aggregates are known to be associated with Alzheimer's disease. The inhibition of Tau aggregation is an important strategy for screening of therapeutic molecules in Alzheimer's disease. Several classes of dyes possess a unique property of photo-excitation, which is applied as a therapeutic measure against numerous neurological dysfunctions. Rose Bengal is a Xanthene dye, which has been widely used as a photosensitizer in photodynamic therapy. The aim of this work was to study the protective role of Rose Bengal against Tau aggregation and cytoskeleton modulations. The aggregation inhibition and disaggregation potency of Rose Bengal and photo-excited Rose Bengal were observed by in-vitro fluorescence, circular dichroism, and electron microscopy. Rose Bengal and photo-excited Rose Bengal induce minimal cytotoxicity in neuronal cells. In our studies, we observed that Rose Bengal and photo-excited Rose Bengal modulate the cytoskeleton network of actin and tubulin. The immunofluorescence studies showed the increased filopodia structures after photo-excited Rose Bengal treatment. Furthermore, Rose Bengal treatment increases the connections between the cells. Rose Bengal and photo-excited Rose Bengal treatment-induced actin-rich podosome-like structures associated with cell membranes. The in-vivo studies on UAS E-14 Tau mutant Drosophila suggested that exposure to Rose Bengal and photo-excited Rose Bengal efficiency rescues the behavioural and memory deficit in flies. Thus, the overall results suggest that Rose Bengal could have a therapeutic potency against Tau aggregation.

In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occurs via the interaction of two hexapeptide motifs PHF* 275 VQIINK 280 and PHF 306 VQIVYK 311 as β-sheets. To understand the role of the constituent amino acids of PHF and PHF* in the aggregation, a set of 12 alanine mutant peptides was synthesized by replacing each amino acid in PHF and PHF* with alanine and they were characterized by nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM) and ThS/ANS fluorescence assay. Our studies show that while the aggregation was suppressed in most of the alanine mutant peptides, replacement of glutamine by alanine in both PHF and PHF* enhanced the fibrillization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Post-translational modification of Tau, a microtubule-associated protein in the neuronal cell, plays a major role in Alzheimer's disease. Tau is an axonal protein expressed in mature neurons that promote the self-assembly of tubulin into microtubules and its stabilization in neurons. Phosphorylation of Tau makes it prone to aggregation at the intra-neuronal region leading to impaired neurotransmission and dementia. Tau aggregates undergo trans-cellular propagation by the release of fibrillar species into the extra-cellular environment from damaged and infected neurons that can be internalized by neighbouring neuronal and glia cells and promotes aggregation in healthy cells. G-protein coupled receptors, the largest group of seven transmembrane receptors, are involved in neuronal signal transduction in response to various signals such as hormones and neurotransmitters. In Alzheimer's disease, GPCRs are involved in phosphorylation of Tau through various downstream kinases such as GSK-3β, CDK-5 and ERKs signalling cascade. Several neuronal GPCRs that are involved in Tau phosphorylation are elaborated in this review. The astrocytic GPCR, Tau phosphorylation mediated by CaS receptors and its propagation by exosomes are also elaborated. In the microglia, the extra-cellular Tau binding to a chemokine GPCR, CX3CR1 triggers its internalization, whereas Tau phosphorylation at specific sites decreases its binding affinity to this receptor. Here we highlight the role of GPCRs in Tau phosphorylation and Tau interaction in different cells of the nervous system. Hence, the role of GPCRs are attaining more attention in the therapeutic field of Alzheimer's disease. Specific agonists/antagonists and allosteric modulators could be the potential target for therapy against GPCR-mediated Tau phosphorylation in Alzheimer's disease., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Aggregation of Microtubule-associated protein Tau and its deposition in the form of neurofibrillary tangles (NFTs) is one of the pathological hallmarks of Alzheimer's disease (AD). Tau aggregation inhibition has been targeted in various studies including natural compounds and synthetic small molecules. Here, we have studied neurohormone- Melatonin against in vitro Tau aggregation and observed its effect on membrane topology, tubulin network and Tau phosphorylation in Neuro2A and N9 cell lines. The aggregation and conformation of Tau was determined by ThT fluorescence and CD spectroscopy respectively. The morphology of Tau aggregates in presence and absence of Melatonin was studied by transmission electron microscopy. Melatonin was found to reduce the formation of higher order oligomeric structures without affecting the overall aggregation kinetics of Tau. Melatonin also modulates and helps to maintain membrane morphology, independent on tubulin network as evidenced by FE-SEM and immunofluorescence analysis. Overall, Melatonin administration shows mild anti-aggregation and cytoprotective effects., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fibrosis is a complication of tendon injury where excessive scar tissue accumulates in and around the injured tissue, leading to painful and restricted joint motion. Unfortunately, fibrosis tends to recur after surgery, creating a need for alternative approaches to disrupt scar tissue. We posited a strategy founded on mechanobiological principles that collagen under tension generated by fibroblasts is resistant to degradation by collagenases. In this study, we tested the hypothesis that blebbistatin, a drug that inhibits cellular contractile forces, would increase the susceptibility of scar tissue to collagenase degradation. Decellularized tendon scaffolds (DTS) were treated with bacterial collagenase with or without external or cell-mediated internal tension. External tension producing strains of 2-4% significantly reduced collagen degradation compared with non-tensioned controls. Internal tension exerted by human fibroblasts seeded on DTS significantly reduced the area of the scaffolds compared to acellular controls and inhibited collagen degradation compared to free-floating DTS. Treatment of cell-seeded DTS with 50 mM blebbistatin restored susceptibility to collagenase degradation, which was significantly greater than in untreated controls (p < 0.01). These findings suggest that therapies combining collagenases with drugs that reduce cell force generation should be considered in cases of tendon fibrosis that do not respond to physiotherapy.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder with an alarming increase in the death rate every year. AD is characterised by an aberrant accumulation of proteins in the form of aggregates. The axonal microtubule-associated protein Tau and amyloid-β undergo structural transition to β-sheet rich structure and form aggregates in neuronal soma as well as in the extracellular region. The loss of Tau from microtubules leads to the disintegration of axon and causing neuronal degeneration. This led to the development of effective drugs against AD, to prevent Tau aggregation. Here, we synthesized and screen metal-based complexes to prevent Tau protein aggregation. ThS fluorescence and TEM suggested the role of synthetic cobalt complexes in inhibiting Tau aggregation. CD spectroscopy showed that these complexes prevented conformational changes in Tau to β-sheet. CBMCs were not toxic at lower concentrations and formed non-toxic Tau species. L1 and L2 prevented membrane leakage; whereas, higher concentrations of L3 caused membrane leakage as observed by LDH release assay. The overall results indicate the synthetic cobalt complexes to be a promising molecule against AD., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The development of MnO 2 -graphene (MnO 2- GR) composite by microwave irradiation method and its application as an electrode material for the selective determination of serotonin (SE), popularly known as "happy chemical", is reported. Anchoring MnO 2 nanoparticles on graphene, yielded MnO 2 -GR composite with a large surface area, improved electron transport, high conductivity and numerous channels for rapid diffusion of electrolyte ions. The composite was characterized by X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and scanning electron microscopy (SEM) for assessing the actual composition, structure and morphology. The MnO 2 -GR composite modified glassy carbon electrode (GCE) exhibited an excellent electrochemical activity towards the detection of SE in phosphate buffer saline (PBS) at physiological pH of 7.0. Under optimum conditions, the modified electrode could be applied to the quantification of serotonin by square wave voltammetry over a wide linear range of 0.1 to 800 µM with the lowest detection limit of 10 nM (S/N = 3). The newly fabricated sensor also exhibited attractive features such as good anti-interference ability, high reproducibility and long-term stability., Competing Interests: The authors declare no conflict of interest.

Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial cell phenotype and types of receptors on microglia. Reports suggest that dietary habits influence microglial polarization and the switching of microglial phenotype is very important in neurodegenerative diseases. Omega-3 fatty acids have more influence on the brain, and they are found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells. In Alzheimer's disease, one of the pathological proteins involved is Tau protein, and microtubule-associated protein upon abnormal phosphorylation detaches from the microtubule and forms insoluble aggregates. Aggregated proteins have a tendency to propagate within the neurons and also become one of the causes of neuroinflammation. We hypothesize that tuning microglia towards anti-inflammatory phenotype would reduce the propagation of Tau in Alzheimer's disease.

The Alzheimer's disease pathology is associated with accumulation of intracellular neurofibrillary tangles and extracellular senile plaques. The formation of initial nucleus triggers conformational changes in Tau and leads to its deposition. Hence, there is a need to eliminate these toxic proteins for proper functioning of neuronal cells. In this aspect, we screened the effect of basic limonoids such as gedunin, epoxyazadiradione, azadirone and azadiradione on inhibiting Tau aggregation as well as disintegration of induced Tau aggregates. It was observed that these basic limonoids effectively prevented aggregates formation by Tau and also exhibited the property of destabilizing matured Tau aggregates. The molecular docking analysis suggests that the basic limonoids interact with hexapeptide regions of aggregated Tau. Although these limonoids caused the conformational changes in Tau to β-sheet structure, the cytological studies indicate that basic limonoids rescued cell death. The dual role of limonoids in Tau aggregation inhibition and disintegration of matured aggregates suggests them to be potent molecules in overcoming Tau pathology. Further, their origin from a medicinally important plant neem, which known to possess remarkable biological activities was also found to play protective role in HEK293T cells. Basic limonoids were non-toxic to HEK293T cells and also aided in activation of HSF1 by inducing its accumulation in nucleus. Western blotting and immunofluorescence studies showed that HSF1 in downstream increased the transcription of Hsp70 thus, aggravating cytosolic Hsp70 levels that can channel clearance of aberrant Tau. All these results mark basic limonoids as potential therapeutic natural products.

Tau is the major neuronal protein involved in the stabilization of microtubule assembly. In Alzheimer's disease, Tau self-assembles to form intracellular protein aggregates which are toxic to cells. Various methods have been tried and tested to restrain the aggregation of Tau. Most of the agents tested for this purpose have limitations in their effectiveness and availability to neuronal cells. We have tested melatonin, a neurohormone secreted by pineal gland and a well-known anti-oxidant, for its ability to interact with the repeat domain of Tau using ITC and NMR. In aggregation inhibition and disaggregation studies of repeat Tau, melatonin was found to modulate the aggregation propensity of repeat Tau at a concentration of 5000 μM and was more effective in dissolving preformed aggregates rather than acting as an aggregation inhibitor. However, there were no major conformational changes in Tau in presence of melatonin as observed by CD spectroscopy. On the basis of our findings, we are proposing a mechanism by which melatonin can interact with the repeat domain of Tau and exhibit its disaggregation effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-β plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern., Methods: In this study, we have prepared and stabilized hTau40 WT oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1-sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-β sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40 WT oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis., Results: Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11 + Iba1 high microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau., Conclusion: The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.

Alzheimer's disease is a neuropathological condition with abnormal accumulation of extracellular Amyloid-β plaques and intracellular neurofibrillary tangles of Microtubule-associated protein Tau (Tau) in the brain. In pathological conditions, Tau undergoes post-translational modifications such as hyperphosphorylation by the activity of cellular kinases, which eventually leads to protein aggregation in neurons. Melatonin is a neuro-hormone that is mainly secreted from the pineal gland and functions to modulate the cellular kinases. In our study, we have checked the neuroprotective function of Melatonin by MTT and LDH assay, where Melatonin inhibited the Tau aggregates-mediated cytotoxicity and membrane leakage in Neuro2A cells. The potency of Melatonin has also been studied for the quenching of intracellular reactive oxygen species level by DCFDA assay and caspase 3 activity. Melatonin was shown to reduce the GSK3β mRNA and subsequent protein level as well as the phospho-Tau level (pThr181 and pThr212-pSer214) in okadaic acid-induced Neuro2A cells, as observed by western blot and immunofluorescence assay. Further, Melatonin has increased the cellular Nrf2 level and its nuclear translocation as an oxidative stress response in Tauopathy. The Melatonin was found to induce pro- and anti-inflammatory cytokines levels in N9 microglia. The mRNA level of cellular kinases such as as-GSK3β, MAPK were also studied by qRT-PCR assay in Tau-exposed N9 and Neuro2A cells. The immunomodulatory effect of Melatonin was evident as it induced IL-10 and TGF-β cytokine levels and activated MAP3K level in Tau-exposed microglia and neurons, respectively. Melatonin also downregulated the mRNA level of pro-inflammatory markers, IL-1β and Cyclooxygenase-2 in N9 microglia. Together, these findings suggest that Melatonin remediated the cytokine profile of Tau-exposed microglia, reduced Tau hyperphosphorylation by downregulating GSK3β level, and alleviated oxidative stress via Nrf2 nuclear translocation.

Background: Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer's disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications., Objective: In this study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau., Methods: Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy., Results: Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation., Conclusion: The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer's disease.

Ayurveda is the medicinal science, dealing with utilization of naturally available plant products for treatment. A wide variety of neuroprotective herbs have been reported in Ayurveda. Brahmi, Bacopa monnieri is a nootropic ayurvedic herb known to be effective in neurological disorders from ancient times. Numerous approaches including natural and synthetic compounds have been applied against Alzheimer's disease. Amyloid-β and Tau are the hallmarks proteins of several neuronal dysfunctions resulting in Alzheimer's disease. Tau is a microtubule-associated protein known to be involved in progression of Alzheimer's disease. The generation of reaction oxygen species, increased neuroinflammation and neurotoxicity are the major physiological dysfunctions associated with Tau aggregates, which leads to dementia and behavioural deficits. Bacoside A, Bacoside B, Bacosaponins, Betulinic acid, etc; are the bioactive component of Brahmi belonging to various chemical families. Each chemical component known have its significant role in neuroprotection. The neuroprotective properties of Brahmi and its bioactive components including reduction of ROS, neuroinflammation, aggregation inhibition of Amyloid-β and improvement of cognitive and learning behaviour. Here on basis of earlier studies we hypothesize the inhibitory role of Brahmi against Tau-mediated toxicity. The overall studies have concluded that Brahmi can be used as a lead formulation for treatment of Alzheimer's disease and other neurological disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disorder caused by protein misfolding, aggregation and accumulation in the brain. A large number of molecules are being screened against these pathogenic proteins but the focus for therapeutics is shifting towards the natural compounds as aggregation inhibitors, mainly due to their minimum adverse effects. Baicalein is a natural compound belonging to the class of flavonoids isolated from the Chinese herb Scutellaria baicalensis. Here we applied fluorescence, absorbance, microscopy, MALDI-TOF spectrophotometry and other biochemical techniques to investigate the interaction between Tau and Baicalein in vitro. We found the aggregation inhibitory properties of Baicalein for the repeat Tau. Overall, the potential of Baicalein in dissolving the preformed Tau oligomers as well as mature fibrils can be of utmost importance in therapeutics for Alzheimer's disease., (Copyright © 2019. Published by Elsevier Inc.)

The aggregates of microtubule-associated protein Tau are considered as a major hallmark of Alzheimer's disease. Tau aggregates accumulate intracellularly leading to neuronal toxicity. Numerous approaches have been targeted against Tau protein aggregation, which include application of synthetic and natural compounds. Toluidine blue is a basic dye of phenothiazine family, which on irradiation with a 630 nm light gets converted into a photoexcited form, leading to generation of singlet oxygen species. Methylene blue is the parent compound of toluidine blue, which has been reported to be potent against tauopathy. In the present work, we studied the potency of toluidine blue and photoexcited toluidine blue against Tau aggregation. Biochemical and biophysical analyses using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, ThS fluorescence, circular dichroism spectroscopy, and electron microscopy suggested that toluidine blue inhibited the aggregation of Tau in vitro. The photoexcited toluidine blue potentially dissolved the matured Tau fibrils, which indicated the disaggregation property of toluidine blue. The cell biology studies including the cytotoxicity assay and reactive oxygen species (ROS) production assay suggested toluidine blue to be a biocompatible dye as it reduced ROS levels and cell death. The photoexcited toluidine blue modulates the cytoskeleton network in cells, which was supported by immunofluorescence studies of neuronal cells. The studies in a UAS Tau E14 transgenic Drosophila model suggested that photoexcited toluidine blue was potent to restore the survival and memory deficits of Drosophila . The overall finding of our studies suggested toluidine blue to be a potent molecule in rescuing the Tau-mediated pathology by inhibiting its aggregation, reducing the cell death, and modulating the tubulin levels and behavioral characteristics of Drosophila . Thus, toluidine blue can be addressed as a potent molecule against Alzheimer's disease., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

The prominent pathological consequences of Alzheimer's disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-β and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-β-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of 'seed' constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-β and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4 + T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.

Tau is an axonal protein known to form abnormal aggregates and is the biomarker of Alzheimer's disease. Metal-based therapeutics for inhibition of Tau aggregation is limited and rarely reported in contemporary science. Here, we report the first example of rationally designed molecular cobalt(II)-complexes for effective inhibition of Tau and disaggregation of preformed Tau fibrils. The mechanistic studies reveal that prevention of Tau aggregation by cobalt-based metal complexes (CBMCs) is concentration-dependent and Tau seldom exhibits conformational changes. Interestingly, CBMCs play dual role in causing disassembly of preformed aggregates as well as inhibition of complete Tau aggregation. Furthermore, CBMCs were nontoxic and maintained the tubulin network intact. CBMCs also prevented okadaic acid-induced toxicity in SH-SY5Y cells thus, preventing hyperphosphorylation of Tau. We believe that this unprecedented finding by the newly developed molecular complexes has a potential toward metal-based therapeutics for Alzheimer's disease., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Phospholipid quantum dot micelles are useful for bio-applications because of their amphiphilicity and exceptional biocompatibilities. We investigated the uptake of phospholipid [polyethylene glycol (PEG), biotin, and folic acid terminated] modified CdSe/ZnS quantum dot micelles by cancer cells and its photostability under ultrviolet light in the C spectrum (UV-C) (254 nm) or UV-A (365 nm) light irradiation. The stability of micelles to the exposure of UV-C and UV-A light was assessed. Biotin-modified quantum dot micelles give photoluminescence enhancement under UV-C light irradiation. Folate modified micelle under UV-C and UV-A results show considerable photoluminescence enhancement. Photoluminescence lifetime measurements showed 7.04, 8.11 and 11.42 ns for PEG, folate, and biotin terminated phospholipid micelles, respectively. Folate and biotin-modified quantum dot micelles showed excellent uptake by HeLa cells under fluorescence confocal microscopy. Phospholipid CdSe/ZnS quantum dot micelles can be potentially used for diagnosis and treatment of cancer in the future., (© 2019 John Wiley & Sons, Ltd.)

The Alzheimer's disease (AD) therapeutic research is yielding a large number of potent molecules. The nanoparticle-based therapeutics against the protein aggregation in AD is also taking a lead especially with amyloid-β as a primary target. In this work, we have screened for the first time protein-capped (PC) metal nanoparticles for their potency in inhibiting Tau aggregation in vitro. We present a novel function of PC-Fe 3 O 4 and PC-CdS nanoparticles as potent Tau aggregation inhibitors by fluorescence spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and electron microscopy. We demonstrate that the biologically synthesized PC-metal nanoparticles, especially iron oxide do not affect the viability of neuroblastoma cells. Moreover, PC-CdS nanoparticles show dual properties of inhibition and disaggregation of Tau. Thus, the nanoparticles can take a lead as potent Tau aggregation inhibitors and can be modified for specific drug delivery due to their very small size. The current work presents unprecedented strategy to design anti-Tau aggregation drugs, which provides interesting insights to understand the role of biological nanostructures in Alzheimer's disease., Competing Interests: The authors declare no competing financial interest.

Tau is a phosphoprotein with natively unfolded conformation that functions to stabilize microtubules in axons. Alzheimer's disease pathology triggers several modifications in tau, which causes it to lose its affinity towards microtubule, thus, leading to microtubule disassembly and loss of axonal integrity. This elicit accumulation of tau as paired helical filaments is followed by stable neurofibrillary tangles formation. A large number of small molecules have been isolated from Azadirachta indica with varied medicinal applications. The intermediate and final limonoids, nimbin and salannin respectively, isolated from Azadirachta indica , were screened against tau aggregation. ThS and ANS fluorescence assay showed the role of intermediate and final limonoids in preventing heparin induced cross-β sheet formation and also decreased hydrophobicity, which are characteristic nature of tau aggregation. Transmission electron microscopy studies revealed that limonoids restricted the aggregation of tau to fibrils; in turn, limonoids led to the formation of short and fragile aggregates. Both the limonoids were non-toxic to HEK293T cells thus, substantiating limonoids as a potential lead in overcoming Alzheimer's disease., Competing Interests: The authors have no conflict of interest to report.

Protein conformational changes are associated with potential cytotoxicity upon interaction with small molecules or nanomaterials. Protein misfolding leads to protein-mediated diseases; thus, it is important to study the conformational changes in proteins using nanoparticles as drug carriers. In this study, the conformational changes in hemoglobin and thrombin were observed using fluorescence spectroscopy, circular dichroism spectroscopy and molecular modelling studies after interaction with non-toxic, water-soluble near-infrared silicon quantum dot micelles. The molecular docking results indicated that the binding affinities of hemoglobin and thrombin with Si QD micelles are good. In addition, molecular dynamics simulations were performed to obtain more detailed information., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Luminescence probe has been broadly used for bio-imaging applications. Among them, near-infrared (NIR) quantum dots (QDs) are more attractive due to minimal tissue absorbance and larger penetration depth. Above said reasons allowed whole animal imaging without slice scan or dissection. This review describes in vitro and in vivo imaging of NIR QDs in the regions of 650-900 nm (NIR-I) and 1000-1450 nm (NIR-II). Also, we summarize the recent progress in bio-imaging and discuss the future trends of NIR QDs including group II-VI, IV-VI, I-VI, I-III-VI, III-V, and IV semiconductors.

In this present study on understanding the taxol (PTX) binding interaction mechanism in both the β-tubulin and bovine serum albumin (BSA) molecule, various optical spectroscopy and computational techniques were used. The fluorescence steady-state emission spectroscopy result suggests that there is a static quenching mechanism of the PTX drug in both β-tubulin and BSA, and further time-resolved emission spectroscopy studies confirm that the quenching mechanism exists. The excitation-emission matrix (EEM), Fourier transform infrared, and resonance light scattering spectra (FT-IR) confirm that there are structural changes in both the BSA and β-tubulin molecule during the binding process of PTX. The molecular docking studies revealed the PTX binding information in BSA, β-tubulin, and modeled β-tubulin and the best binding pose to further subject the molecular dynamics simulation, and this study confirms the stability of PTX in the protein complex during the simulation. Density functional theory (DFT) calculations were performed between the free PTX drug and PTX drug (single point) in the protein molecule active site region to understand the internal stability.

The present study focuses on the determination of the biologically significant N-acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human α-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectroscopy result suggests that the fluorescence intensity of BSA and HAG was quenched by NANA in a static mode of quenching. Further time-resolved emission spectroscopy measurements confirm that mode of quenching mechanism of NANA in the BSA and HAG system. The FT-IR, excitation-emission matrix and circular dichroism (CD) analysis confirms the presence of NANA in the HAG, BSA system, and fluorescence resonance energy transfer analysis shows that NANA transfers energy between the HAG and BSA system. The molecular docking result shows good binding affinity in both protein complexes, and further molecular dynamics simulations and charge distribution analysis were performed to gain more insight into the binding interaction mechanism of NANA in the HAG and BSA complex.

Here, we report the engineering of a solid-state micro pH sensor based on polyaniline-functionalized, electrochemically reduced graphene oxide (ERGO-PA). Electrochemically reduced graphene oxide acts as the conducting layer and polyaniline acts as a pH-sensitive layer. The pH-dependent conductivity of polyaniline occurs by doping of holes during protonation and by the dedoping of holes during deprotonation. We found that an ERGO-PA solid-state electrode was not functional as such in fermentation processes. The electrochemically active species that the bacteria produce during the fermentation process interfere with the electrode response. We successfully applied Nafion as a proton-conducting layer over ERGO-PA. The Nafion-coated electrodes (ERGO-PA-NA) show a good sensitivity of 1.71 Ω/pH (pH 4 - 9) for chemiresistive sensor measurements. We tested the ERGO-PA-NA electrode in real-time in the fermentation of Lactococcus lactis. During the growth of L. lactis, the pH of the medium changed from pH 7.2 to pH 4.8 and the resistance of the ERGO-PA-NA solid-state electrode changed from 294.5 Ω to 288.6 Ω (5.9 Ω per 2.4 pH unit). The pH response of the ERGO-PA-NA electrode compared with the response of a conventional glass-based pH electrode shows that reference-less solid-state microsensor arrays operate successfully in a microbiological fermentation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss, caused by misfolding and accumulation of tau and Amyloid β-42. Cellular mechanisms involving phosphatases, chaperones, ubiquitin proteasome system (UPS) and aggresomes solubilize or remove these toxic aggregates. Chaperones such as Hsp70 and Hsp90 functions in folding tau to its native form or in the downstream degrade and eliminated tau from the cell. Chaperones are involved in lysosomal degradation of tau by a process called chaperone mediated autophagy (CMA). In pathological conditions, chaperones fail to remove the toxic tau species, leading to their accumulation. In this scenario, inhibiting the chaperone activity would aid in overcoming AD. Small molecules inhibitors against chaperone activity are known to be effective in the clearance of aberrant tau from cell. In this review, the aspects of inhibition and prevention of tau aggregates formation are discussed in terms of chaperone activity and their small molecule modulators.

Here we report for the first time highly flexible quantum dot light-emitting diodes (QLEDs), in which a layer of red-emitting colloidal silicon quantum dots (SiQDs) works as the optically active component, by replacing a rigid glass substrate with a thin sheet of polyethylene terephthalate (PET). The enhanced optical performance for electroluminescence (EL) at room temperature in air is achieved by taking advantage of the inverted device structure. Our QLEDs do not exhibit parasitic EL emissions from the neighboring compositional layers or surface states of QDs over a wide range of driving voltages and do not exhibit a shift in the EL peak position as the operational voltage increases. Compared to the previous Si-QLEDs with a conventional device structure, our QLED has a longer device operational lifetime and a long-lived EQE value. The currently obtained brightness (∼5000 cd/m 2 ), the 3.1% external quantum efficiency (EQE), and a turn-on voltage as low as 3.5 V are sufficiently high to encourage further developments of Si-QLEDs.

The microtubule-associated protein Tau plays a key role in the neuropathology of Alzheimer's disease by forming intracellular neurofibrillary tangles. Tau in the normal physiological condition helps stabilize microtubules and transport. Tau aggregates due to various gene mutations, intracellular insults and abnormal post-translational modifications, phosphorylation being the most important one. Other modifications which alter the function of Tau protein are glycation, nitration, acetylation, methylation, oxidation, etc. In addition to forming intracellular aggregates, Tau pathology might spread in a prion-like manner as revealed by several in vitro and in vivo studies. The possible mechanism of Tau spread can be via bulk endocytosis of misfolded Tau species. The recent studies elucidating this mechanism have mainly focussed on the aggregation and spread of repeat domain of Tau in the cell culture models. Further studies are needed to elucidate the prion-like propagation property of full-length Tau and its aggregates in a more intense manner in vitro as well as in vivo conditions. Varied post-translational modifications can have discrete effects on aggregation propensity of Tau as well as its propagation. Here, we review the prion-like properties of Tau and hypothesize the role of glycation in prion-like properties of Tau. This post-translationally modified Tau might have an enhanced propagation property due to differential properties conferred by the modifications.

In this study the interaction mechanism between newly synthesized 4-(3-acetyl-5-(acetylamino)-2-methyl-2, 3-dihydro-1,3,4-thiadiazole-2-yl) phenyl benzoate (thiadiazole derivative) anticancer active drug with calf thymus DNA was investigated by using various optical spectroscopy techniques along with computational technique. The absorption spectrum shows a clear shift in the lower wavelength region, which may be due to strong hypochromic effect in the ctDNA and the drug. The results of steady state fluorescence spectroscopy show that there is static quenching occurring while increasing the thiadiazole drug concentration in the ethidium bromide-ctDNA system. Also the binding constant (K), thermo dynamical parameters of enthalpy change (ΔH°), entropy change (ΔS°) Gibbs free energy change (ΔG°) were calculated at different temperature (293 K, 298 K) and the results are in good agreement with theoretically calculated MMGBSA binding analysis. Time resolved emission spectroscopy analysis clearly explains the thiadiazole derivative competitive intercalation in the ethidium bromide-ctDNA system. Further, molecular docking studies was carried out to understand the hydrogen bonding and hydrophobic interaction between ctDNA and thiadiazole derivative molecule. In addition the docking and molecular dynamics charge distribution analysis was done to understand the internal stability of thiadiazole derivative drug binding sites of ctDNA. The global reactivity of thiadiazole derivative such as electronegativity, electrophilicity and chemical hardness has been calculated., (Copyright © 2018 John Wiley & Sons, Ltd.)

Cell migration is an essential part of many (patho)physiological processes, including keratinocyte re-epithelialization of healing wounds. Physical forces and mechanical cues from the wound bed (in addition to biochemical signals) may also play an important role in the healing process. Previously, we explored this possibility and found that polyacrylamide (PA) gel stiffness affected human keratinocyte behaviour and that mechanical deformations in soft (approx. 1.2 kPa) PA gels produced by neighbouring cells appeared to influence the process of de novo epithelial sheet formation. To clearly demonstrate that keratinocytes do respond to such deformations, we conducted a series of experiments where we observed the response of single keratinocytes to a prescribed local substrate deformation that mimicked a neighbouring cell or evolving multicellular aggregate via a servo-controlled microneedle. We also examined the effect of adding either Y27632 or blebbistatin on cell response. Our results indicate that keratinocytes do sense and respond to mechanical signals comparable to those that originate from substrate deformations imposed by neighbouring cells, a finding that could have important implications for the process of keratinocyte re-epithelialization that takes place during wound healing. Furthermore, the Rho/ROCK pathway and the engagement of NM II are both essential to substrate deformation-directed keratinocyte migration., (© 2018 The Author(s).)

Introduction: Traditionally thought to serve active vs. passive mechanical functions, respectively, a growing body of evidence suggests that actin microfilament and keratin intermediate filament (IF) networks, together with their associated cell-cell and cell-matrix anchoring junctions, may have a large degree of functional interdependence. Therefore, we hypothesized that the loss of keratin IFs in a knockout mouse keratinocyte model would affect the kinematics of colony formation, i.e., the spatiotemporal process by which individual cells join to form colonies and eventually a nascent epithelial sheet., Methods: Time-lapse imaging and deformation tracking microscopy was used to observe colony formation for both wild type (WT) and keratin-deficient knockout (KO) mouse keratinocytes over 24 h. Cells were cultured under high calcium conditions on collagen-coated substrates with nominal stiffnesses of ~ 1.2 kPa (soft) and 24 kPa (stiff). Immunofluorescent staining of actin and selected adhesion proteins was also performed., Results: The absence of keratin IFs markedly affected cell morphology, spread area, and cytoskeleton and adhesion protein organization on both soft and stiff substrates. Strikingly, an absence of keratin IFs also significantly reduced the ability of mouse keratinocytes to mechanically deform the soft substrate. Furthermore, KO cells formed colonies more efficiently on stiff vs. soft substrates, a behavior opposite to that observed for WT keratinocytes., Conclusions: Collectively, these data are strongly supportive of the idea that an interdependence between actin microfilaments and keratin IFs does exist, while further suggesting that keratin IFs may represent an important and under-recognized component of keratinocyte mechanosensation and the force generation apparatus., (© Biomedical Engineering Society 2018.)

Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

Detection of disease-related gene expression by DNA hybridization is a useful diagnostic method. In this study a monolayer graphene field effect transistor (GFET) was fabricated for the detection of a particular single-stranded DNA (target DNA). The probe DNA, which is a single-stranded DNA with a complementary nucleotide sequence, was directly immobilized onto the graphene surface without any linker. The V Dirac was shifted to the negative direction in the probe DNA immobilization. A further shift of V Dirac in the negative direction was observed when the target DNA was applied to GFET, but no shift was observed upon the application of non-complementary mismatched DNA. Direct immobilization of double-stranded DNA onto the graphene surface also shifted the V Dirac in the negative direction to the same extent as that of the shift induced by the immobilization of probe DNA and following target DNA application. These results suggest that the further shift of V Dirac after application of the target DNA to the GFET was caused by the hybridization between the probe DNA and target DNA.

Alzheimer's disease (AD) is one of the neurodegenerative disease characterized by progressive neuronal loss in the brain. Its two major hallmarks are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs), formed by aggregation of amyloid β-42 (Aβ-42) and Tau protein respectively. Aβ-42 is a transmembrane protein, which is produced after the sequential action of β- and γ-secretases, thus obtained peptide is released extracellularly and gets deposited on the neuron forming senile plaques. NFTs are composed of microtubule-associated protein-Tau (MAPT). Tau protein's major function is to stabilize the microtubule that provides a track on which the cargo proteins are shuttled and the stabilized microtubule also maintains shape and integrity of the neuronal cell. Tau protein is subjected to various modifications such as phosphorylation, ubiquitination, glycation, acetylation, truncation, glycosylation, deamination, and oxidation; these modifications ultimately lead to its aggregation. Phosphorylation is the major modification and is extensively studied with respect to Tau protein. Tau protein, however, undergoes certain level of phosphorylation and dephosphorylation, which regulates its affinity for microtubule and ultimately leading to microtubule assembly and disassembly. Our main aim was to study the native state of longest isoform of Tau (hTau40WT-4R2N) and its shortest isoform, (hTau23WT-3R0N), at various temperatures such as 10, 25, and 37 °C. Raman spectroscopic results suggested that the proportion of random coils or unordered structure depends on the temperature of the protein environment. Upon increase in the temperature from 10 to 37 °C, the proportion of random coils or unordered structures increased in the case of hTau40WT. However, we did not find a significant effect of temperature on the structure of hTau23WT. This current approach enables one to analyze the global conformation of soluble Tau in solution.

Objective: Biofilm of Candida tropicalis denote as a complex cellular congregation with major implication in pathogenesis. This lifestyle of fungus as a biofilm can inhibit immune system and antifungal therapy in treatment of infectious disease especially medical device associated chronic disease. In this study effects of Zinc Oxide (ZnO) nanoparticles and EDTA were evaluated on C. tropicalis biofilm by using different techniques. ZnO nanoparticles were synthesized from Egg albumin., Design: To assay the formation of biofilm of yeast cells like Fluconazole-susceptible C. tropicalis (ATCC 13,803) and fluconazole-resistant standard strains of C. tropicalis (ATCC 750) were grown in 24 well plates and antifungal effect of ZnO and EDTA were evaluated on C. tropicalis biofilm using ATP bioluminescence and tetrasodium salt (XTT) reduction assays., Results: Synthesized ZnO NPs and EDTA had effective antifungal properties at the concentration of 5.2, 8.6μg/ml for Fluconazole susceptible strain and 5.42, 10.8μg/ml Fluconazole resistant strains of C. tropicalis biofilms compared to fluconazole drug., Conclusion: In present study we conclude, ZnO considered as a new agent in field of prevention C. tropicalis biofilms especially biofilms formed surface of medical device., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A native conformation of a protein is essential for its biological role. In certain conditions, some proteins show non-native conformations, leading to aggregation, which in turn may produce severe pathologies. Such physiological conditions are classified as protein misfolding diseases. Alzheimer's disease (AD) is the most common form of dementia. Extracellular senile plaques formed by Amyloid β and intracellular aggregates formed by microtubule-associated protein Tau (MAPT) are the hallmarks of AD. Physiological role of MAPT is to maintain the integrity and stability of microtubules, however it tends to self-aggregate forming intracellular paired helical filaments (PHFs) during AD. MAPT is also subjected to various post-translational modifications such as phosphorylation, glycosylation, truncation, and acetylation. Being natively unfolded, MAPT is prone to full characterization at atomic level. Small-angle X-ray scattering (SAXS) is often applied in combination with other biophysical methods, like nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, analytical ultracentrifugation (AUC), or dynamic light scattering (DLS) to characterize natively unfolded systems. Here we describe the practical aspects of MAPT characterization by SAXS and CD in detail as well as outline the inferred structural and functional implications.

A newly synthesized 1, 4-bis ((4-((4-heptylpiperazin-1-yl) methyl)-1H-1, 2, 3-triazol-1-yl) methyl) benzene from the family of piperazine derivative has good anticancer activity, antibacterial and low toxic nature; its binding characteristics are therefore of huge interest for understanding pharmacokinetic mechanism of the drug. The binding of piperazine derivative to bovine serum albumin (BSA) was investigated using fluorescence spectroscopy. The molecular distance r between the donor (BSA) and acceptor (piperazine derivative) was estimated according to Forster's theory of nonradiative energy transfer. The physicochemical properties of piperazine derivative, which induced structural changes in BSA, have been studied by circular dichroism and those chemical environmental changes were probed using Raman spectroscopic analysis. Further, the binding dynamics was expounded by synchronous fluorescence spectroscopy and molecular modeling studies explored the hydrophobic interaction and hydrogen bonding results, which stabilize the interaction., (© 2015 Wiley Periodicals, Inc.)

Chitosan functionalized luminescent rare earth doped terbium nanoparticles (LaF3:Tb(3+)/chi NPs) as a drug carrier for methotrexate (MTX) was designed using a simple chemical precipitation method. The synthesized chitosan functionalized nanoparticles were found to be spherical in shape with an average diameter of 10-12nm. They are water soluble and biocompatible, in which the hydroxyl and amino functional groups on its surface are utilized for the bioconjugation of the anticancer drug, the methotrexate. The nature of MTX binding with LaF3:Tb(3+)/chi nanoparticles were examined using X-ray diffraction, zeta potential analyzer and transmission electron microscopy. The other interactions due to complex formation between MTX and LaF3:Tb(3+)/chi NPs were carried out by UV-Visible, steady and excited state fluorescence spectroscopy. The photo-physical characterization revealed that the adsorption and release of MTX from LaF3:Tb(3+)/chi NPs is faster than gold nanoparticles and also confirms that this may be due to weak interaction i.e. the Vander Waals force of attraction between the carboxyl and amino group of drug and nanoparticles. The maximum percentage yield and entrapment efficiency of 85.91±0.71 and 83.82± 0.14 were achieved at a stochiometric ratio of 4:5 of MTX and LaF3:Tb(3+)/chi nanoparticles respectively. In addition, antitumoral activity study reveals that MTX conjugated LaF3:Tb(3+)/chi nanoparticles show higher cytotoxic effect on MCF-7 breast cancer cell lines than that of free MTX., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The receptor for advanced glycation end products (RAGE) is one of the most important proteins implicated in diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It is a pattern recognition receptor by virtue of its ability to interact with multiple ligands, RAGE activates several signal transduction pathways through involvement of various kinases that phosphorylate their respective substrates. Only few substrates have been known to be phosphorylated in response to activation by RAGE (e.g., nuclear factor kappa B); however, it is possible that these kinases can phosphorylate multiple substrates depending upon their expression and localization, leading to altered cellular responses in different cell types and conditions. One such example is, glycogen synthase kinase 3 beta which is known to phosphorylate glycogen synthase, acts downstream to RAGE, and hyperphosphorylates microtubule-associated protein tau causing neuronal damage. Thus, it is important to understand the role of various RAGE-activated kinases and their substrates. Therefore, we have reviewed here the details of RAGE-activated kinases in response to different ligands and their respective phosphoproteome. Furthermore, we discuss the analysis of the data mined for known substrates of these kinases from the PhosphoSitePlus (http://www.phosphosite.org) database, and the role of some of the important substrates involved in cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In summary, this review provides information on RAGE-activated kinases and their phosphoproteome, which will be helpful in understanding the possible role of RAGE and its ligands in progression of diseases., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Semiconductor nanoparticles (or quantum dots, QDs) exhibit unique optical and electronic properties such as size-controlled fluorescence, high quantum yields, and stability against photobleaching. These properties allow QDs to be used as optical labels for multiplexed imaging and in drug delivery detection systems. Luminescent silicon QDs and surface-modified silicon QDs have also been developed as potential minimally toxic fluorescent probes for bioapplications. Silicon, a well-known power electronic semiconductor material, is considered an extremely biocompatible material, in particular with respect to blood. This review article summarizes existing knowledge related to and recent research progress made in the methods for synthesizing silicon QDs, as well as their optical properties and surface-modification processes. In addition, drug delivery systems and in vitro and in vivo imaging applications that use silicon QDs are also discussed., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chitosan-silica/CpG oligodeoxynucleotide (ODN) nanohybrids were synthesized to stimulate Toll-like receptor 9-mediated induction of interleukin-6 (IL-6). The chitosan-silica hybrid was first synthesized from a mixture of chitosan and 3-glycidoxypropyl trimethoxysilane under acidic conditions via a sol-gel process, and then used to condense CpG ODN2006x3-PD to yield chitosan-silica/CpG ODN nanohybrids. Scanning electron microscopy and atomic force microscopy showed that the chitosan-silica/CpG ODN nanohybrids had an elliptic shape with a diameter of 100-200 nm. After soaking in HAc-NaAc buffer solution (pH5.5), the nanohybrids exhibited sustained release of CpG ODN. When the nanohybrids were separately exposed to 293XL-hTLR9 cells and peripheral blood mononuclear cells, no significant toxicity was observed. An immunochemical assay for cellular uptake revealed that the nanohybrids were taken up by the cells and located in endolysosomes. An enzyme-linked immunosorbent assay for cytokines indicated that the nanohybrids effectively stimulated the induction of IL-6. Chitosan-silica/CpG ODN nanohybrids underwent cellular uptake and enhanced induction of IL-6 to a greater degree than conventional chitosan/CpG ODN nanocomplexes, indicating that they have an enhanced delivery efficiency., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Free-standing, micropatterned silica nanotube membranes are in situ fabricated using a micropatterned silica-coated collagen hybrid hydrogel as template. They are substrate-free, and not only maintained their micropatterned microstructure well, but also exhibited strong cell contact guidance ability to direct cell alignment and differentiation, indicating their good potential for biomedical applications., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Silica nanotubes have been extensively applied in the biomedical field. However, very little attention has been paid to the fabrication and application of micropatterned silica nanotubes. In the present study, microgrooved silica nanotube membranes were fabricated in situ by microgrooving silica-coated collagen hybrid fibril hydrogels in a Teflon microfluidic chip followed by calcination for removal of collagen fibrils. Scanning electron microscopy images showed that the resulting silica nanotube membranes displayed a typical microgroove/ridge surface topography with ∼50 μ m microgroove width and ∼120 μ m ridge width. They supported adsorption of bone morphogenetic protein 2 (BMP-2) and exhibited a sustained release behavior for BMP-2. After culturing with osteoblast MC3T3-E1 cells, they induced an enhanced osteoblast differentiation due to the release of biologically active BMP-2 and a strong contact guidance ability to directly align and elongate osteoblasts due to the presence of microgrooved surface topography, indicating their potential application as a multi-functional cell-supporting matrix for tissue generation.

One of the hallmarks of Alzheimer's disease is the self-assembly of the microtubule-associated protein tau into fibers termed "paired helical filaments" (PHFs). However, the structural basis of PHF assembly at atomic detail is largely unknown. Here, we applied solid-state nuclear magnetic resonance (ssNMR) spectroscopy to investigate in vitro assembled PHFs from a truncated three-repeat tau isoform (K19) that represents the core of PHFs. We found that the rigid core of the fibrils is formed by amino acids V306 to S324, only 18 out of 99 residues, and comprises three β-strands connected by two short kinks. The first β-strand is formed by the well-studied hexapeptide motif VQIVYK that is known to self-aggregate in a steric zipper arrangement. Results on mixed [(15)N:(13)C]-labeled K19 fibrils show that β-strands are stacked in a parallel, in-register manner. Disulfide bridges formed between C322 residues of different molecules lead to a disturbance of the β-sheet structure, and polymorphism in ssNMR spectra is observed. In particular, residues K321-S324 exhibit two sets of resonances. Experiments on K19 C322A PHFs further confirm the influence of disulfide bond formation on the core structure. Our structural data are supported by H/D exchange NMR measurements on K19 as well as a truncated four-repeat isoform of tau (K18). Site-directed mutagenesis studies show that single-point mutations within the three different β-strands result in a significant loss of PHF aggregation efficiency, highlighting the importance of the β-structure-rich regions for tau aggregation.

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.