Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aß aggregation.

Neuroprotective Activity of a Novel Synthetic Rhodamine-Based Hydrazone against Cu2+-Induced Alzheimer's Disease in Drosophila.

A new rhodamine-based probe 3,5-di-tert-butylsalicylaldehyde rhodamine hydrazone (RHTB) has been synthesized and well characterized using spectroscopic techniques and single-crystal X-ray crystallography. Among several metal ions, it selectively detects Cu2+ ions as monitored by UV-Vis and emission spectral titrations. It displays "turn on" behavior owing to the opening of a spirolactum ring and the presence of 3,5-di-tert-butyl as an electron releasing group. Further, Cu2+ ions play a pivotal role in extracellular aggregation of Aß42 peptides. So far, we know probably that there are no promising drugs available in this regard. Hence, countering the Cu2+ ions by RHTB chelation against orally administered Cu2+ ion-induced neurotoxicity in the eye tissue of Drosophila expressing human Aß42 (amyloid-ß42) has been tested. The present study involves in vivo and in silico approaches. They reveal the therapeutic potential of RHTB against Cu2+ ion-induced Aß42 toxicity in Alzheimer's disease (AD) model of Drosophila.

Neuroprotective potential of flavonoid rich Ascophyllum nodosum (FRAN) fraction from the brown seaweed on an Aß42 induced Alzheimer's model of Drosophila.

BACKGROUND: In Alzheimer Disease (AD) pathogenesis, aggregation of Aß42 fibrils strongly correlates with memory dysfunction and neurotoxicity. Till date, no promising cures for AD. Report shows that flavonoids contributed anti-oxidant, anti-cancer and neuroprotection activity by regulating the mitochondrial machinery. Here, we first report the identification of flavonoids from Ascophyllum nodosum as having the ability to dissolve Aß42 fibrils in an AD model of Drosophila. FRAN could be superior anti-AD agents for neuroprotection, their underlying mechanism and how they collectively halted amyloidogenesis is currently being investigated. PURPOSE: This study aimed to investigate the neuroprotective role of FRAN in the Aß42 expressing AD model of Drosophila. METHODS: Drosophila stocks: OregonR+, ey-GAL4/CyO, elavc155-GAL4, UAS-mitoGFP, UAS-mcherry.mito.OMM, UAS-Aß42/CyO were used, cultured at 28±1 °C in a BOD incubator. Ascophyllum extract rich in flavonoids as revealed by LC-MS study and employed against the AD flies. The validation of Aß42 expression was done by immunostaining and q-RT PCR. The eye roughness of AD flies was scored in a dose-dependent manner. Further, In vivo and in silico studies of FRAN extract was executed against Aß42 induced neurotoxicity. RESULTS: In order to determine the most effective lethal dose of FRAN extract concentration 1, 2, 5, 10 mg/ml were screened using OregonR+flies. Extract 1 and 2 mg/ml did not show any lethality. Hence, extract 2 mg/ml was employed on AD flies and a ≥ 50% rescue in the eye phenotype was observed using SEM images. This dose had a strong effect on cell apoptosis, viability, longevity, mitochondrial dysfunction and oxidative stress by regulating mitochondrial dynamic markers in comparable to control. Extract also scavenging free radicals in order to maintain in situ cellular ROS and prevent Aß42-induced neurotoxicity in vivo and in silico. Hence, we suggest its great potential as a future therapeutic agent for AD treatment. CONCLUSION: In conclusion, FRAN extract rich in flavonoids as having largest neuroprotective activity against Aß42 aggregation in eye tissue of Drosophila. Extract shows strong effect against Aß42-induced neurotoxicity by altering the various cellular and molecular events. So, it could be considered as strong anti-AD agents for neuroprotection.

Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid ß Induced Neurotoxicity in Alzheimer's Disease Models.

The pathological hallmarks of Alzheimer's disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-ß protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aß1-42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivoDrosophila model by rescuing eye phenotypes from degeneration caused by Aß toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aß1-42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting Aß1-42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management.

Retraction of "Fabrication of Graphene Nanoplatelet-Incorporated Porous Hydroxyapatite Composites: Improved Mechanical and in Vivo Imaging Performances for Emerging Biomedical Applications".

[This retracts the article DOI: 10.1021/acsomega.8b03473.].

Fabrication of Graphene Nanoplatelet-Incorporated Porous Hydroxyapatite Composites: Improved Mechanical and in Vivo Imaging Performances for Emerging Biomedical Applications.

Three-dimensional nanocomposites exhibit unexpected mechanical and biological properties that are produced from two-dimensional graphene nanoplatelets and oxide materials. In the present study, various composites of microwave-synthesized nanohydroxyapatite (nHAp) and graphene nanoparticles (GNPs), (100 - x)HAp-xGNPs (x = 0, 0.1, 0.2, 0.3, and 0.5 wt %), were successfully synthesized using a scalable bottom-up approach, that is, a solid-state reaction method. The structural, morphological and mechanical properties were studied using various characterization techniques such as X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and universal testing machine (UTM). XRD studies revealed that the prepared composites have high-order crystallinity. Addition of GNPs into nHAp significantly improved the mechanical properties. Three-dimensional nanocomposite 99.5HAp-0.5GNPs exhibited exceptionally high mechanical properties, for example, a fracture toughness of ∼116 MJ/m3, Young's modulus of ∼98 GPa, and compressive strength of 96.04 MPa, which were noticed to be much greater than in the pure nHAp. The MTT assay and cell imaging behaviors were carried out on the gut tissues of Drosophila third instars larvae and on primary rat osteoblast cells for the sample 99.5HAp-0.5GNPs that have achieved the highest mechanical properties. The treatment with lower concentrations of 10 µg/mL on the gut tissues of Drosophila and 1 and 5 µg/mL of this composite sample showed favorable cell viability. Therefore, owing to the excellent porous nature, interconnected surface morphology, and mechanical and biological properties, the prepared composite sample 99.5HAp-0.5GNPs stood as a promising biomaterial for bone implant applications.

MoS2-Modified Curcumin Nanostructures: The Novel Theranostic Hybrid Having Potent Antibacterial and Antibiofilm Activities against Multidrug-Resistant Hypervirulent Klebsiella pneumoniae.

The recent emergence of hypervirulent clinical variants of Klebsiella pneumoniae (hvKP) causing community-acquired, invasive, metastatic, life-threatening infections of lungs, pleura, prostate, bones, joints, kidneys, spleen, muscles, soft-tissues, skin, eyes, central nervous system (CNS) including extrahepatic abscesses, and primary bacteremia even in healthy individuals has posed stern challenges before the existing treatment modalities. There is therefore an urgent need to look for specific and effective therapeutic alternatives against the said bacterial infection or recurrence. A new type of MoS2-modified curcumin nanostructure has been developed and evaluated as a potential alternative for the treatment of multidrug-resistant isolates. The curcumin quantum particles have been fabricated with MoS2 via a seed-mediated hydrothermal method, and the resulting MoS2-modified curcumin nanostructures (MQCs) have been subsequently tested for their antibacterial and antibiofilm properties against hypervirulent multidrug-resistant Klebsiella pneumoniae isolates. In the present study, we found MQCs inhibiting the bacterial growth at a minimal concentration of 0.0156 µg/mL, while complete inhibition of bacterial growth was evinced at concentration 0.125 µg/mL. Besides, we also investigated their biocompatibility both in vitro and in vivo. MQCs were found to be nontoxic to the SiHa cells at a dose as high as 1024 µg/mL on the basis of the tested adhesion, spreading of the cells, and also on the various serological, biochemical, and histological investigations of the vital organs and blood of the Charles Foster Rat. These results suggest that MQCs have potent antimicrobial activities against hvKP and other drug resistant isolates and therefore may be used as broad spectrum antibacterial and antibiofilm agents.

Classification of Clinical Isolates of Klebsiella pneumoniae Based on Their in vitro Biofilm Forming Capabilities and Elucidation of the Biofilm Matrix Chemistry With Special Reference to the Protein Content.

Klebsiella pneumoniae is a human pathogen, capable of forming biofilms on abiotic and biotic surfaces. The limitations of the therapeutic options against Klebsiella pneumoniae is actually due to its innate capabilities to form biofilm and harboring determinants of multidrug resistance. We utilized a newer approach for classification of biofilm producing Klebsiella pneumoniae isolates and subsequently we evaluated the chemistry of its slime, more accurately its biofilm. We extracted and determined the amount of polysaccharides and proteins from representative bacterial biofilms. The spatial distribution of sugars and proteins were then investigated in the biofilm matrix using confocal laser scanning microscopy (CLSM). Thereafter, the extracted matrix components were subjected to sophisticated analysis incorporating Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, one-dimensional gel-based electrophoresis (SDS-PAGE), high performance liquid chromatography (HPLC), and MALDI MS/MS analysis. Besides, the quantification of its total proteins, total sugars, uronates, total acetyl content was also done. Results suggest sugars are not the only/major constituent of its biofilms. The proteins were harvested and subjected to SDS-PAGE which revealed various common and unique protein bands. The common band was excised and analyzed by HPLC. MALDI MS/MS results of this common protein band indicated the presence of different proteins within the biofilm. The 55 different proteins were identified including both cytosolic and membrane proteins. About 22 proteins were related to protein synthesis and processing while 15 proteins were identified related to virulence. Similarly, proteins related to energy and metabolism were 8 and those related to capsule and cell wall synthesis were 4. These results will improve our understanding of Klebsiella biofilm composition and will further help us design better strategies for controlling its biofilm such as techniques focused on weakening/targeting certain portions of the slime which is the most common building block of the biofilm matrix.