Publications by authors named "Ghulam Md Ashraf"

212 Publications

Deciphering the Interacting Mechanisms of Circadian Disruption and Alzheimer's Disease.

Neurochem Res 2021 Apr 19. Epub 2021 Apr 19.

Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Alzheimer's disease (AD) is one of the crucial causative factors for progressive dementia. Neuropathologically, AD is characterized by the extracellular accumulation of amyloid beta plaques and intracellular neurofibrillary tangles in cortical and limbic regions of the human brain. The circadian system is one of the many affected physiological processes in AD, the dysfunction of which may reflect in the irregularity of the sleep/wake cycle. The interplay of circadian and sleep disturbances inducing AD progression is bidirectional. Sleep-associated pathological alterations are frequently evident in AD. Understanding the interrelation between circadian disruption and AD may allow for earlier identification of AD pathogenesis as well as better suited approaches and potential therapies to combat dementia. In this article, we examine the existing literature related to the molecular mechanisms of the circadian clock and interacting mechanisms of circadian disruption and AD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-021-03325-xDOI Listing
April 2021

In Silico Identification of Novel Interactions for FABP5 (Fatty Acid-Binding Protein 5) with Nutraceuticals: Possible Repurposing Approach.

Adv Exp Med Biol 2021 ;1308:589-599

Department of Biological Sciences, University of Limerick, Limerick, Ireland.

Fatty Acid Binding-Protein 5 (FABP5) is a cytoplasmic protein, which binds long-chain fatty acids and other hydrophobic ligands. This protein is implicated in several physiological processes including mitochondrial β-oxidation and transport of fatty acids, membrane phospholipid synthesis, lipid metabolism, inflammation and pain. In the present study, we used molecular docking tools to determine the possible interaction of FABP5 with six selected compounds retrieved form Drugbank. Our results showed that FABP5 binding pocket included 31 polar and non-polar amino acids, and these residues may be related to phosphorylation, acetylation, ubiquitylation, and mono-methylation. Docking results showed that the most energetically favorable compounds are NADH (-9.12 kcal/mol), 5'-O-({[(Phosphonatooxy)phosphinato]oxy}phosphinato)adenosine (-8.62 kcal/mol), lutein (-8.25 kcal/mol), (2S)-2-[(4-{[(2-Amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioate (-7.17 kcal/mol), Pteroyl-L-glutamate (-6.86 kcal/mol) and (1S,3R,5E,7Z)-9,10-Secocholesta-5,7,10-triene-1,3,25-triol (-6.79 kcal/mol). Common interacting residues of FABP5 with nutraceuticals included SER16, LYS24, LYS34, LYS40 and LYS17. Further, we used the SwissADME server to determine the physicochemical and pharmacokinetic characteristics and to predict the ADME parameters of the selected nutraceuticals after molecular analysis by docking with the FABP5 protein. Amongst all compounds, pteroyl-L-glutamate is the only one meeting the Lipinski's rule of five criteria, demonstrating its potential pharmacological use. Finally, our results also suggest the importance of FABP5 in mediating the anti-inflammatory activity of the nutraceutical compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-030-64872-5_29DOI Listing
April 2021

Synaptotagmin-1: A Multi-Functional Protein that Mediates Vesicle Docking, Priming, and Fusion.

Curr Protein Pept Sci 2021 Mar 25. Epub 2021 Mar 25.

King Fahd Medical Research Center, King Abdul-Aziz University, Jeddah. Saudi Arabia.

The fusion of secretory vesicles with the plasma membrane depends on the assembly of v-SNAREs (VAMP2/synaptobrevin2) and t-SNAREs (SNAP25/syntaxin1) into the SNARE complex. Vesicles go through several upstream steps, referred to as docking and priming, to gain fusion competence. The vesicular protein synaptotagmin-1 (Syt-1) is the principal Ca2+ sensor for fusion in several central nervous system neurons and neuroendocrine cells and part of the docking complex for secretory granules. Syt-1 binds to the acceptor complex such as synaxin1, SNAP-25 on the plasma membrane to facilitate secretory vesicle docking, and upon Ca2+-influx promotes vesicle fusion. This review assesses the role of the Syt-1 protein involved in the secretory vesicle docking, priming, and fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389203722666210325110231DOI Listing
March 2021

Reconsidering and Reforming the Amyloid Cascade Hypothesis.

Curr Protein Pept Sci 2021 Mar 22. Epub 2021 Mar 22.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah. Saudi Arabia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389203722666210322151627DOI Listing
March 2021

Dissecting Sex-Related Cognition between Alzheimer's Disease and Diabetes: From Molecular Mechanisms to Potential Therapeutic Strategies.

Oxid Med Cell Longev 2021 5;2021:4572471. Epub 2021 Mar 5.

Department of Biological Sciences, University of Limerick, Limerick, Ireland.

The brain is a sexually dimorphic organ that implies different functions and structures depending on sex. Current pharmacological approaches against different neurological diseases act distinctly in male and female brains. In all neurodegenerative diseases, including Alzheimer's disease (AD), sex-related outcomes regarding pathogenesis, prevalence, and response to treatments indicate that sex differences are important for precise diagnosis and therapeutic strategy. Pathogenesis of AD includes vascular dementia, and in most cases, this is accompanied by metabolic complications with similar features as those assembled in diabetes. This review discusses how AD-associated dementia and diabetes affect cognition in relation to sex difference, as both diseases share similar pathological mechanisms. We highlight potential protective strategies to mitigate amyloid-beta (A) pathogenesis, emphasizing how these drugs act in the male and female brains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/4572471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960032PMC
March 2021

Impaired Quality Control of Mitochondria Underlying the Pathogenesis of Alzheimer's Disease.

Curr Drug Targets 2021 Mar 8. Epub 2021 Mar 8.

Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah. Saudi Arabia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389450122666210309105326DOI Listing
March 2021

Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges.

Int J Mol Sci 2021 Feb 24;22(5). Epub 2021 Feb 24.

Faculty of Medicine, Al-Azhar University, Damietta 34511, Egypt.

Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor's aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22052258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956497PMC
February 2021

Hutchinson-Gilford Progeria Syndrome: An Overview of the Molecular Mechanism, Pathophysiology and Therapeutic Approach.

Curr Gene Ther 2021 Mar 2. Epub 2021 Mar 2.

Department of Pharmacy, Southeast University, Dhaka. Bangladesh.

Lamin A/C encoded by LMNA gene is an important component for the maintenance of the nuclear structure. Mutation in the lamin A/C leads to a group of inherited disorders is known as laminopathies. In the human body, there are several mutations in the LMNA gene have been identified. It can affect diverse organs or tissues or can be systemic, causing different diseases. In this review, we mainly focused on one of the most severe laminopathies, Hutchinson-Gilford progeria syndrome (HGPS). HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. Here, we also presented the currently available data on the molecular mechanism, pathophysiology, available treatment, and future approaches of this deadly disease. Due to the production of progerin an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, impairment in gene regulation which ultimately results in aging in the early stage of life. Now some treatment options are available for this disease but a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566523221666210303100805DOI Listing
March 2021

MicroRNA and mRNA profiling of cerebral cortex in a transgenic mouse model of Alzheimer's disease by RNA sequencing.

Neural Regen Res 2021 Oct;16(10):2099-2108

Organic Chemistry and Function Laboratory, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

In a previous study, we found that long non-coding genes in Alzheimer's disease (AD) are a result of endogenous gene disorders caused by the recruitment of microRNA (miRNA) and mRNA, and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD. In this study, we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level. To this aim, we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD. Overall, 129 mRNAs and 68 miRNAs were aberrantly expressed. Among these, eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets. The main enriched signaling pathways involved mitogen-activated kinase protein, phosphatidylinositol 3-kinase-protein kinase B, mechanistic target of rapamycin kinase, forkhead box O, and autophagy. An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed. These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies, early diagnosis, and prevention of AD. The present results provide a novel perspective on the role of miRNAs and mRNAs in AD. This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing, China (approval No. IMB-201909-D6) on September 6, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/1673-5374.308104DOI Listing
October 2021

Gene Therapy for Neuroprotection and Neurorestoration-Part III.

Curr Gene Ther 2021 ;21(1)

Department of Pharmacy, Southeast University, Dhaka, Bangladesh.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/156652322101210209103113DOI Listing
January 2021

Exploring the New Horizon of AdipoQ in Obesity-Related Alzheimer's Dementia.

Front Physiol 2020 27;11:567678. Epub 2021 Jan 27.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh.

Alzheimer's disease (AD) is the most common form of dementia, which causes abnormalities in learning, thinking, memory, as well as behavior. Generally, symptoms of AD develop gradually and aggravate over time, and consequently severely interfere with daily activities. Furthermore, obesity is one of the common risk factors for dementia. Dysregulation of adipokine and adipocyte dysfunction are assumed to be accountable for the high risk of obesity in people that develop many related disorders such as AD. Moreover, it has been observed that the dysfunction of adipose is connected with changes in brain metabolism, brain atrophy, cognitive decline, impaired mood, neuroinflammation, impaired insulin signaling, and neuronal dysfunction in people with obesity. Conversely, the pathological mechanisms, as well as the molecular players which are involved in this association, have been unclear until now. In this article, we discuss the impact of adiponectin (AdipoQ) on obesity-related Alzheimer's dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.567678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873563PMC
January 2021

Emerging Promise of Nanoparticle-Based Treatment for Parkinson's Disease.

Curr Drug Metab 2021 Feb 1. Epub 2021 Feb 1.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah. Saudi Arabia.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that exerts a huge burden on our society. The occurrence of this neurodegenerative disease has been aggregating day-by-day. This disease can be a serious concern if the patients are left untreated. However, conventional treatment has many side-effects and less bioavailability in the brain. Therefore, the necessary measurement is required to solve the limitations. Nanotechnology has been introduced to us to deliver smart solutions to these circumstances. Nanotechnology has developed to provide efficient therapies that have reduced side-effects and have increased bioavailability in the brain. This review emphasizes the emerging promise of nanoparticle-based treatment, drug delivery, and other therapeutic approaches. Besides, the advantages of different approaches on nanotechnology platforms are far better over conventional therapy in the treatment of Parkinson's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389200222666210202110129DOI Listing
February 2021

Identification of new BACE1 inhibitors for treating Alzheimer's disease.

J Mol Model 2021 Jan 30;27(2):58. Epub 2021 Jan 30.

Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia.

Alzheimer's disease (AD) is a type of brain disorder, wherein a person experiences gradual memory loss, state of confusion, hallucination, agitation, and personality change. AD is marked by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) and synaptic losses. Increased cases of AD in recent times created a dire need to discover or identify chemical compounds that can cease the development of AD. This study focuses on finding potential drug molecule(s) active against β-secretase, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Clustering analysis followed by phylogenetic studies on microarray datasets retrieved from GEO browser showed that BACE1 gene has genetic relatedness with the RCAN1 gene. A ligand library comprising 60 natural compounds retrieved from literature and 25 synthetic compounds collected from DrugBank were screened. Further, 350 analogues of potential parent compounds were added to the library for the docking purposes. Molecular docking studies identified 11-oxotigogenin as the best ligand molecule. The compound showed the binding affinity of - 11.1 Kcal/mole and forms three hydrogen bonds with Trp124, Ile174, and Arg176. The protein-ligand complex was subjected to 25 ns molecular dynamics simulation and the potential energy of the complex was found to be - 1.24579e+06 Kcal/mole. In this study, 11-oxotigogenin has shown promising results against BACE1, which is a leading cause of AD, hence warrants for in vitro and in vivo validation of the same. In addition, in silico identification of 11-oxotigogenin as a potential anti-AD compound paves the way for designing of chemical scaffolds to discover more potent BACE1 inhibitors.Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00894-021-04679-3DOI Listing
January 2021

Neurotoxic Aβ: Linking Extracellular and Intracellular Aβ in Alzheimer's Disease.

Curr Protein Pept Sci 2021 Jan 22. Epub 2021 Jan 22.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah. Saudi Arabia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389203722666210122144437DOI Listing
January 2021

Exploring the Anti-Neuroinflammatory Potential of Steroid and Terpenoid-Derived Phytochemicals to Combat Alzheimer's Disease.

Curr Pharm Des 2021 Jan 1. Epub 2021 Jan 1.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah. Saudi Arabia.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that significantly affects cognitive functions in a way that causes loss of memory, thinking, and behavior. Multiple studies revealed that neuroinflammation associated with AD is linked with the amyloid-beta deposition in the brain. Elevated levels of expression of cytokines, microglial activation, nuclear factor kappa B, and reactive oxygen species play roles in ADrelated inflammatory processes. Indeed, effective therapeutic approaches are urgently required to develop therapeutic agents to prevent and treat AD. So far, many anti-AD drug candidates have failed in the clinical stages and currently available drugs only provide symptomatic treatment. In recent times, pharmacologically active phytochemicals have been found to possess promising anti-neuroinflammatory effects; therefore these natural products can be useful in the AD treatment. In this review, we have comprehensively discussed the role of neuroinflammation and the molecular processes altered by multiple steroid and terpenoid-derived phytochemicals in various AD-related neuroinflammatory pathways. Indeed, steroid and terpenoid-derived phytochemicals show important therapeutic activities, which can be useful in ameliorating and treating AD-related neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612826666210101152352DOI Listing
January 2021

Neuroproteomics on the Rise (Part I).

Curr Protein Pept Sci 2020;21(12):1144-1145

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/138920372112201210094133DOI Listing
April 2021

Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches.

Semin Cancer Biol 2020 Dec 25. Epub 2020 Dec 25.

Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Glioblastoma multiforme (GBM) is the most common form of brain cancer and one of the most aggressive cancers found in humans. Most of the signs and symptoms of GBM can be mild and slowly aggravated, although other symptoms might demonstrate it as an acute ailment. However, the precise mechanisms of the development of GBM remain unknown. Due to the improvement of molecular pathology, current researches have reported that glioma progression is strongly connected with different types of epigenetic phenomena, such as histone modifications, DNA methylation, chromatin remodeling, and aberrant microRNA. Furthermore, the genes and the proteins that control these alterations have become novel targets for treating glioma because of the reversibility of epigenetic modifications. In some cases, gene mutations including P16, TP53, and EGFR, have been observed in GBM. In contrast, monosomies, including removals of chromosome 10, particularly q23 and q25-26, are considered the standard markers for determining the development and aggressiveness of GBM. Recently, amid the epigenetic therapies, histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors have been used for treating tumors, either single or combined. Specifically, HDACIs are served as a good choice and deliver a novel pathway to treat GBM. In this review, we focus on the epigenetics of GBM and the consequence of its mutations. We also highlight various treatment approaches, namely gene editing, epigenetic drugs, and microRNAs to combat GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2020.12.015DOI Listing
December 2020

Novel Nano-formulations of Ellagic Acid are Promising in Restoring Oxidative Homeostasis in Rat Brains with Alzheimer's Disease.

Curr Drug Metab 2020 Dec 16. Epub 2020 Dec 16.

Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University (KAU). Saudi Arabia.

Background: Aluminum toxicity induces neurodegenerative changes in brain and results in Alzheimer's disease (AD).

Objective: Here the aim was to evaluate the antioxidant therapeutic effects of ellagic acid (EA) and EA-loaded nanoparticles (EA-NP) in an aluminum chloride-induced AD rat model.

Methods: The nanoparticles' loading of EA was 0.84/1 w/w. The in vitro release kinetics of EA from EA NP in fetal bovine serum showed 60% release in the first 1-5 hours followed by sustained release at 60-70% over 6-24 hours. Six groups were implemented; group 1 served as the control, group 2 received EA, group 3 received EA-NP, group 4 was the AD rat model administered AlCl3 (50 mg/kg) for 4 weeks, groups 5 (AD+EA) and 6 (AD+ EA-NP) were treated with EA and EA-NP respectively for 2 weeks after AlCl3 was stopped. The neurotoxicity in rat brain was examined by measuring the brain antioxidant biomarkers catalase, glutathione, and total antioxidant activity and lipid peroxidation (thiobarbituric acid, TBA). Histopathological studies using hematoxylin and eosin, cresyl violet, silver stains, and the novel object recognition test were examined.

Results: Data revealed significant increase of antioxidant biomarkers and decreased TBA in the EA-NP group. The pathological hallmarks of AD-vacuolation of the neurons, chromatolysis, neurofibrillary tangles, and the senile plaques in brains of AD rat model were decreased and restoration of Nissl granules was noted. The calculated discrimination index in behavioral test increased more in cases treated with EA-NP.

Conclusion: The treatment of AD with EA-NP was more effective than EA in alleviating the oxidative neurotoxic effects in AD rat brains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389200221666201216170851DOI Listing
December 2020

Current Trends for Rationalizing Brain Targeting Nanoparticles in Neurological Disorders (Part-I).

Curr Drug Metab 2020;21(9):648

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Shivdan Singh Institute of Technology and Management (SSITM), India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/138920022108201113094659DOI Listing
January 2020

Biomolecular alterations in acute traumatic brain injury (TBI) using Fourier transform infrared (FTIR) imaging spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Mar 13;248:119189. Epub 2020 Nov 13.

Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar. Electronic address:

Acute injury is one of the substantial stage post-traumatic brain injury (TBI) occurring at the moment of impact. Decreased metabolism, unregulated cerebral blood flow and direct tissue damage are triggered by acute injury. Understating the biochemical alterations associated with acute TBI is critical for brain plasticity and recovery. The objective of this study was to investigate the biochemical and molecular changes in hippocampus, corpus callosum and thalamus brain regions post-acute TBI in rats. Fourier Transform Infrared (FTIR) imaging spectroscopy were used to collect chemical images from control and 3 hrs post-TBI (Marmarou model was used for the TBI induction) rat brains and adjacent sections were treated by hematoxylin and eosin (H&E) staining to correlate with the disruption in tissue morphology and injured brain biochemistry. Our results revealed that the total lipid and total protein content decreased significantly in the hippocampus, corpus callosum and thalamus after brain injury. Reduction in lipid acyl chains (-CH) associated with an increase in methyl (-CH) and unsaturated lipids olefin = CH concentrations is observed. Furthermore, there is a decrease in the lipid order (disorder), which leads to an increase in acyl chain fluidity in injured rats. The results suggest acute TBI damages brain tissues mechanically rather than chemical alterations. This will help in assessing successful therapeutic strategy in order to mitigate tissue damage in acute TBI period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.saa.2020.119189DOI Listing
March 2021

Nano-Neurotherapeutics (NNTs): An Emergent and Multifaceted Tool for CNS Disorders.

Curr Drug Metab 2020 Nov 24. Epub 2020 Nov 24.

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah. Saudi Arabia.

Impressive research steps have been taken for the treatment of neurological disorders in the last few decades. Still effective treatments of brain related disorders are very less due to problems associated with crossing the blood brain barrier (BBB), non-specific therapies, and delay in functional recovery of central nervous system (CNS) after treatment. Striving for novel treatment options for neurological disorders, nanotechnology-derived materials, and devices have gained the ground due to inherent features of derivatization/encapsulation with drugs as per the neurological ailments and pharmacological targets. Facile developments/syntheses of the nanomaterials-drug conjugates have also been the driving force for researchers to get into this field. Moreover, the tunable size and hydro/lipophilicity of these nanomaterials are the added advantages that make these materials more acceptable for CNS disorders. These nano-neurotherapeutics (NNTs) systems provide the platform for diagnosis, theranostics, treatments, restoration of CNS disorders, and encourage the translation of NNTs from "bench to bedside". Still, these techniques are in primary stages of medical development. This review describes the latest advancements and future scenarios of developmental and clinical aspects of polymeric NNTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389200221666201124123939DOI Listing
November 2020

Molecular Genetics of Early- and Late-Onset Alzheimer's Disease.

Curr Gene Ther 2021 ;21(1):43-52

Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic factors. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood, with three gene variants such as APP, PSEN1, and PSEN2 leading to the disease. Some common alleles, including APOE, are effectively associated with LOAD identified, but the genetics of LOAD is not clear to date. It has been accounted that about 5-10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and the APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease-triggering genes yet. Although several genes have been identified by using the technology of next-generation sequencing in EOAD families, including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants are identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of the ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetic facets which will assist in understanding the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article, based on current knowledge, represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism that might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566523220666201123112822DOI Listing
January 2021

Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-κB to Halt Alzheimer's Disease.

Curr Pharm Des 2021 ;27(3):402-414

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies have been found yet. Over the last few decades, research on AD has mainly highlighted pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus shows a promising candidate for inflammation- based AD therapy. Recent data reveal that phytochemicals, mainly polyphenol compounds, exhibit potential neuroprotective functions and these may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-κB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-κB to combat AD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612826666201118092422DOI Listing
January 2021

Standardizing the Effective Correlated Dosage of Olanzapine and Empagliflozin in Female Wistar Rats.

Curr Gene Ther 2021 ;21(1):53-59

Department of Psychiatry and Neurology, Harvard Medical School and McLean Hospital, Belmont, MA 02478, United States.

Aim: The primary aim of this study was to standardize the correlated effective dosage of the antidiabetic drug empagliflozin (EMPA) and the antipsychotic drug olanzapine (Ola).

Background: Atypical antipsychotics are associated with BWG and metabolic disturbances for which many approaches have been used to minimize these issues, including antidiabetic drugs. The antidiabetic drugs have been quite effective in reversing BWG induced by the administration of antipsychotic drugs in patients who have psychosis, schizophrenia and bipolar disorder.

Objective: The objective of this study was to standardize the correlated effective dosage of EMPA and Ola.

Methods: The study was carried out for 28 days to represent the chronic effect of Ola on female Wistar rats. Rats were divided into three groups based on the dose they received: control (vehicle), Ola-4 and Ola-8 (4 and 8 mg/kg/OD, respectively), and EMPA-10 and EMPA-20 (10 and 20 mg/kg/OD, respectively).

Results: Both doses of Ola produced a significant increase in the percentage of BWG, however, Ola-4 produced a higher BWG. Also, both the doses of EMPA were able to reverse the effect of Ola-induced BWG; however, EMPA-20 produced a higher reversal in BWG and normalized the rat's body weight.

Conclusion: We conclude that Ola-4 and EMPA-20 were the most effective dosage for experimental purposes in female Wistar rats. The findings of this study standardized the effective correlated dosage of olanzapine and empagliflozin in female Wistar rats that will help understand the underlying molecular and behavioral mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566523220999201111195047DOI Listing
January 2021

Challenges of Gene Therapy for Neurodegenerative Disorders.

Curr Gene Ther 2021 ;21(1):3-10

Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566523220999201105150442DOI Listing
January 2021

Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies.

Curr Gene Ther 2020 ;20(3):223-235

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications.

Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes.

Materials And Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity.

Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate.

Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566523220999200726225457DOI Listing
January 2020

Gene Therapy for Neuroprotection and Neurorestoration (Part II).

Curr Gene Ther 2020 ;20(3):163

Department of Pharmacy, Southeast University, Dhaka, Bangladesh.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/156652322003200901112821DOI Listing
January 2020

The neutrophil-to-lymphocyte ratio in Alzheimer's disease: Current understanding and potential applications.

J Neuroimmunol 2020 12 18;349:577398. Epub 2020 Sep 18.

Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting millions of people, and its prevalence is expected to continue to grow in the older age population. It is characterized by cognitive impairment and dementia on the long term leading to a wide spectrum of social and financial burdens. Due to these burdens, there is a need to have a better understanding of the disease pathophysiology as well as to come up with more readily available and cost-effective screening tools to provide an acceptable estimate of the disease risk/diagnosis in the early years of the disease before dementia develops as it is in these early years that lifestyle modifications can be more effective in protecting against and delaying the frank cognitive impairment associated with AD. Recently, there has been a more detailed, yet incomplete, comprehension of the inflammatory component of the AD pathophysiology. The inflammatory response in AD entails hyperactivation of neutrophils with noticeable changes in their subsets and increased migration of lymphocytes into the central nervous system (CNS) across the compromised blood-brain barrier (BBB). These changes in the counts of the different immune cells in AD allowed for pursuing a new cost-effective, and more widely accessible diagnostic tool, which is the neutrophil-to-lymphocyte ratio (NLR). In this review, we aimed to discuss the inflammatory response in AD, and how this response is reflected in the counts of different immune cells, mainly neutrophils and lymphocytes which can be implemented in the utility of NLR as a diagnostic tool in AD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2020.577398DOI Listing
December 2020

Molecular Insight into the Crosstalk of UPS Components and Alzheimer's Disease.

Curr Protein Pept Sci 2020 ;21(12):1193-1201

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

The ubiquitin (Ub)-proteasome system (UPS) targets various cellular proteins for degradation. It has been found that defects in the UPS play a crucial role in the pathogenesis of Alzheimer's disease (AD), as the existence of Ub immunoreactivity in AD-linked neuronal inclusions, including neurofibrillary tangles, is observed in all types of AD cases. Current investigations have shown that components of the UPS can be connected with the early stage of AD, which is characterized by synaptic dysfunction, and to the late phases of the disease, marked by neurodegeneration. Although the significance of UPS in the pathogenesis of AD has been emphasized, targeted treatment at the main components of these pathways has a great perspective in advancing new therapeutic interventions for AD. In this review, we emphasize the relationship between UPS and AD pathology. We also represent the recent therapeutic advancements targeting UPS components in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389203721666200923153406DOI Listing
January 2020

Multi-Target Drug Candidates for Multifactorial Alzheimer's Disease: AChE and NMDAR as Molecular Targets.

Mol Neurobiol 2021 Jan 15;58(1):281-303. Epub 2020 Sep 15.

Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.

Alzheimer's disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer's symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-020-02116-9DOI Listing
January 2021