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Amino acid sequence of human amyloid beta 1-42 peptide (A_1-42) and schematic representation of a molecule of A_1-42 in a hairpin shape. The residues 1-17 comprise the disordered region. The residues 18-42 comprise the β_-sheet region. The figure was adapted from Masman M F et al. 2009 (doi: 10.1021/jp901057w).
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Background:
Alzheimer's disease (AD) as the most common cause of dementia among older people has aroused the universal concern of the whole world. However, until now there is still none effective treatments. Consequently, the development of new drugs targeting this complicated brain disorder is urgent and needs more efforts. In this review, we det...
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... with age and relate with devel- opment of tau pathology [32,33]. The Aβ oligomers provide a substantive molecular basis for the origin, treatment and diagnosis of AD [34]. Genetic mutation of the APP and pre- senilin (PS1 and PS2) induces Aβ overproduction and subse- quently accumulation into plaques in the brain of AD pa- tients [35,36]. From Fig. (2), we observed that the Aβ42 differed from Aβ40 only in two residues Ile 41 and Ala42 at C-terminus. The researchers using the combined in silico and in vitro approaches found that the hydrophobic residue at the position 42 is the major contributor to the increased fibril formation rates and neurotoxicity [37]. Although the cause of Aβ ...
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Citations
... 56,57 Combining in silico with in vitro techniques is a relatively new approach, but it shows enormous potential in drug repurposing and drug discovery. 58 In particular, the coronavirus disease 2019 (COVID-19) pandemic has helped to rapidly advance these approaches, but it has also highlighted its limitations. 59 Models are currently limited to what information is present in databases and their underlying network, while limited capabilities restrict what can be validated in in vitro experiments. ...
The high number of failed pre-clinical and clinical studies for compounds targeting Alzheimer disease (AD) has demonstrated that there is a need to reassess existing strategies. Here, we pursue a holistic, mechanism-centric drug repurposing approach combining computational analytics and experimental screening data. Based on this integrative workflow, we identified 77 druggable modifiers of tau phosphorylation (pTau). One of the upstream modulators of pTau, HDAC6, was screened with 5,632 drugs in a tau-specific assay, resulting in the identification of 20 repurposing candidates. Four compounds and their known targets were found to have a link to AD-specific genes. Our approach can be applied to a variety of AD-associated pathophysiological mechanisms to identify more repurposing candidates.
... All of the above provide us with a new idea for treatment in psychoactive substances induced CDs and the application, which would have broad social benefits and clinical significance. Fortunately, many new kinds of drugs targeting the prevention of tau aggregation and denaturation, with the purpose of treating CDs like AD, have been described in diverse studies with satisfactory results in recent years [214]. Nanotechnology also plays a promising role in tau-targeted pharmacotherapy because nanocarriers can improve the blood brain barrier (BBB) permeability of these new drugs [215]. ...
Psychoactive substances are a class of chemical substances which could cause public health threats. Cognitive disorders are a category of mental health disorders that primarily affect cognitive abilities. Tau protein could maintain neuronal cytoskeleton stabilization. Post-translational modification of tau, especially phosphorylation, is an important way to regulate the structure and function of tau and phosphorylated tau is closely related to cognitive function. Lots of studies have reported the phenomenon that psychoactive substances can cause cognitive function impairment. We reviewed recent related studies and discussed them by drug classification. We mainly focused on cognitive disorders caused by acute or chronic exposure of each drugs, animal experiments and the mechanisms associated with tau phosphorylation, then compared the similarities and differences among them, trying to find out the common rules. The results suggested that tau phosphorylation is involved in psychoactive substance-induced cognitive disorder and different psychoactive substances may act by affecting amount or activity of different kinases and phosphatases in the metabolic pathway of tau. We demonstrated that tau protein is a potential target for psychoactive substances induced cognitive disorder treatments.
... It can also cause AD symptoms such as memory loss, mental disorders, and movement disorders through the corresponding cascade reaction [18,19]. Hence, Aβ plays a vital role in the early onset of AD, which is of great significance to use Aβ as the target to find effective prevention and treatment measures in the early onset of AD [20]. Aβ plays an important role and essential to find effective prevention and control measures as a target in the early stage of AD. ...
Background. Aβ deposition abnormally in the mitochondria can damage the mitochondrial respiratory chain and activate the mitochondrial-mediated apoptosis pathway, resulting in AD-like symptoms. Objective. To observe the protective effects of Dendrobium nobile Lindl. alkaloids (DNLA) on Aβ25-35-induced oxidative stress and apoptosis in PC12 cells explore its possible protective mechanisms. Methods. PC12 cells were treated with DNLA with different concentrations (0.035 mg/L, 0.3 mg/L, and 3.5 mg/L) for 6 h, followed by administration with Aβ25-35 (10 μM) for 24 h. MTT assay and flow cytometer observe the effect of DNLA on Aβ25-35-induced cytotoxicity and apoptosis of PC12 cell. Based on the mitochondrial apoptosis pathway to study the antiapoptotic effect of DNLA on this model and its relationship with oxidative stress, flow cytometer detected the level of reactive oxygen species (ROS), and ELISA kits were used to detect superoxide dismutase activity (SOD) and glutathione (GSH) content in cells. The JC-1 fluorescent staining observed the effect of DNLA on the mitochondrial membrane potential (MMP) with inverted immunofluorescence microscopy. Western blot was used to detect the levels of mitochondrial apoptosis pathway-related protein and its major downstream proteins Bax, Bcl-2, cleaved-caspase-9, and cleaved-caspase-3. Results. DNLA can significantly improve the viability and apoptosis rate of PC12 cell damage induced by Aβ25-35. It also can restore the reduced intracellular ROS content and MMP, while SOD activity and GSH content increase significantly. The expression of apoptosis-related protein Bax, cleaved-caspase-9, and cleaved-caspase-3 decreased when the Bcl-2 protein expression was significantly increased. Conclusion. These findings suggest that it can significantly inhibit the apoptosis of PC12 cell damage induced by Aβ25-35. The mechanism may reduce the level of cellular oxidative stress and thus inhibit the mitochondrial-mediated apoptosis pathway.
... [22][23][24] These methods can be endorsed through adding new components that are able to estimate the b-sheet confirmations out of the equilibrium; up to date, some of the small molecules that are synthesized inhibited and reduced the Ab aggregations. [25][26][27] The core peptide residues of Ab hydrophilic peptides are 17 to 21 and 30 to 42 which have been connected to the aggregation methods, so that 17 to 21 residues inhibit similar degree of the hydrophobic environments yet have a very less ratio to adopt the b-sheet confirmations. [28][29][30] From the recent reports, Shyam et al described the linear polyethylene glycol polymer-based micelles nanocomposition frame of BACE1 in the brain via infusing the nanocomposition in mouse lateral ventricle. ...
Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain–blood barrier (BBB). Novel drugs, for instance, iAβ 5 , are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ 5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ 5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.
... According to the World Alzheimer Report 2018, 1 there are currently about 30 million people having AD worldwide. The numbers of patients with AD are expected to increase 3-fold by 2050. 1 Alzheimer disease has become the third leading cause of death for the elderly, only after cardiovascular and cerebrovascular diseases and malignant tumors. 2 Although the detailed pathogenesis of AD still remains unclear, several important clinical hallmarks, such as extracellular deposits of amyloid b (Ab) peptides as senile plaques, intraneuronal neurofibrillary tangles, and large-scale neuronal loss are implicated in the occurrence and development of AD. 3 Many hypotheses on the etiology of AD have been developed and tested, involving Ab, Tau, cholinergic neuron damage and oxidative stress, and inflammation. [4][5][6][7] However, therapies based on Ab cascade hypothesis and/or tau hypothesis have been examined in clinical trials without promising results. ...
Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC 50 = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure–activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.
... 4 A neurovascular unit (NVU) is a dynamic structure consisting of cerebral microvasculature, extracellular matrix, astrocyte end-feet, pericytes, neurocytes and their axons and other sustentacular cells (eg, microglia and oligodendrocytes), and so on. 5,6 Neurovascular unit is the basic unit that maintains the normal function of the central nervous system. Its major functions are regulating brain nutrient supply and biological signal transduction and protecting the brain by preventing harmful substances in the blood from entering the brain. ...
Although the effect of activated protein C (APC) on neuronal injury and neuroinflammatory responses has been extensively studied, the detailed mechanism underlying APC-protective effect in the blood–brain barrier (BBB) injury during ischemia is still not clear. In this study, the APC effect against neuroinflammatory responses was evaluated in the model of right middle cerebral artery occlusion in male Sprague-Dawley rats with 2 hours of ischemia and 22 hours of reperfusion. The results showed that APC can significantly improve the neurological function scoring and reduce the infarct volume and BBB permeability. Moreover, the expression of protein nuclear factor-kappa B (NF-κB), both in cytoplasm and nuclei, was reduced. The downstream of NF-κB activation, including tumor necrosis factor-α and interleukin-1β secretion, was inhibited. In all, APC exerts a neuroprotective effect in focal cerebral ischemia–reperfusion in rats by inhibiting the activation and nuclear translocation of NF-κB. It may indicate a therapeutic approach for ischemic brain injury.
... The blood-brain barrier (BBB), which comprises the cerebral microvascular endothelium together with astrocytes, pericytes, microglia, neurons, and the extracellular matrix, is the regulated interface between the central neural system and the peripheral cycle. [1][2][3][4] Disruption of the BBB is a critical event in the formation of brain edema during the early phase of ischemic brain injury. 5 In experimental studies, BBB opening is biphasic: the initial breakdown is most likely caused by oxidative stress and is followed by partial BBB recovery. ...
The disruption of blood–brain barrier (BBB) is a critical event in the formation of brain edema during early phases of ischemic brain injury. Poly(ADP-ribose) polymerase (PARP) activation, which contributes to BBB damage, has been reported in ischemia–reperfusion and traumatic brain injury. Here, we investigated the effect of 3-aminobenzamide (3-AB), a PARP-1 inhibitor, on the ultrastructure of BBB. Male Sprague Dawley rats were suffered from 90 minutes of middle cerebral artery occlusion, followed by 4.5 hours or 22.5 hours of reperfusion (R). The vehicle or 3-AB (10 mg/kg) was administered intraperitoneally (ip) 60 minutes after lacking of blood. Tissue Evans Blue (EB) levels, ultrastructures of astrocytes and microvessels, and areas of perivascular edema were examined in penumbra and core, at I 1.5 hours /R 4.5 hours and I 1.5 hours /R 22.5 hours, respectively. The severity of ultrastructural changes was graded with a scoring system in each group. We showed that 3-AB treatment significantly decreased tissue EB levels and ultrastructural scores, attenuated damages in astrocytes and microvessels, and reduced areas of perivascular edema. In conclusion, PARP inhibition may provide a novel therapeutic approach to ischemic brain injury.
... The prediction methodology category includes, but is not limited to, the following sub-categories: *text-mining; [22][23][24][25][26][27][28] *machine learning; [5,7,[29][30][31] *network-based; [32][33][34][35] *semantics; [36][37][38] *ligand-binding/ligand-protein docking/binding-site focused; [39][40][41][42] *protein targeting; [43][44][45] *transcriptional signature-focused. [46][47][48] The LRD approach of TR is in the text mining sub-category of prediction methodology-focused approaches. ...
... 34,35 The recent study suggested raised level of clusterin principally in profuse Aβ regions of AD brain. 36 However, it did not correspond to increased level of Aβ42 in particular. Even though initial research was controversial, recent large-scale studies acknowledged clusterin as a risk factor for evolving AD. 37 Augmented levels of clusterin have been associated not only with AD but are also observed in other neurodegenerative diseases, counting multiple sclerosis, ALS and Huntington's disease. ...
An exponential grade prevalence in neurological disorders strains substantial steps to be taken for their prevention and treatment. The neurodiagnostic biomarkers are gaining momentum presently in order to enhance the diagnostic accuracy of neurodegenerative disorder, to assess its advancement precisely and to monitor therapeutic efficiency of therapeutic interventions. Therefore, the primary focus of the present review is the recent development in this field of neurodiagnostic biomarkers, and the current stature of biomarker exploration in the context of various neurodegenerative disease. This review encompasses an updated and detail account of specific (β‐Amyloid, Tau and Phospho‐tau 181, Tar‐DNA binding protein‐43, Progranulin, a‐synuclein, Clusterin, etc.) and non‐specific (genetic, synaptic, inflammatory and coagulation) neurodiagnostic biomarkers and the recent advances in this growing field. This comprehensive review also suggests the utilization of neurodiagnostic markers in network approaches and personalized medication that will eventually improvise the existing diagnostic and therapeutic complexities of neurodiagnostic biomarkers.
... Comparing with traditional macroscopic culture methods, such as cell culture in dishes, well-plates, and flasks, microfluidic cell culture shows significant advantages [7,[57][58][59]. For example, a well-designed microfluidic cell culture can satisfy the needs of individual cell types and cellular co-cultures at the same time [60]. ...
Investigation of cell behavior under different environments and manual operations can give information in specific cellular processes. Among all cell-based analysis, single-cell study occupies a peculiar position, while it can avoid the interaction effect within cell groups and provide more precise information. Microfluidic devices have played an increasingly important role in the field of single-cell study owing to their advantages: high efficiency, easy operation, and low cost. In this review, the applications of polymer-based microfluidics on cell manipulation, cell treatment, and cell analysis at single-cell level are detailed summarized. Moreover, three mainly types of manufacturing methods, i.e., replication, photodefining, and soft lithography methods for polymer-based microfluidics are also discussed.
