Publications by authors named "George E Barreto"

242 Publications

Exploring the Role of Monoamine Oxidase Activity in Aging and Alzheimer's Disease.

Curr Pharm Des 2021 Jun 11. Epub 2021 Jun 11.

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

Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that exert a crucial role in the metabolism of neurotransmitters of the central nervous system. The impaired function of MAOs is associated with copious brain diseases. The alteration of monoamine metabolism is a characteristics feature of aging. MAO plays a crucial role in the pathogenesis of Alzheimer's disease (AD) - a progressive neurodegenerative disorder associated with an excessive accumulation of amyloid-beta (Aβ) peptide and neurofibrillary tangles (NFTs). Activated MAO has played a critical role in the development of amyloid plaques from Aβ, as well as the formation of the NFTs. In the brain, MAO mediated metabolism of monoamines is the foremost source of reactive oxygen species formation. The elevated level of MAO-B expression in astroglia has been reported in the AD brains adjacent to amyloid plaques. Increased MAO-B activity in the cortical and hippocampal regions is associated with AD. This review describes the pathogenic mechanism of MAOs in aging as well as the development and propagation of Alzheimer's pathology.
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http://dx.doi.org/10.2174/1381612827666210612051713DOI Listing
June 2021

Estrogenic Plants: to Prevent Neurodegeneration and Memory Loss and Other Symptoms in Women After Menopause.

Front Pharmacol 2021 20;12:644103. Epub 2021 May 20.

Facultad de Ciencias de la Salud, Universidad San Sebastian, Concepcion, Chile.

In mammals, sexual hormones such as estrogens play an essential role in maintaining brain homeostasis and function. Estrogen deficit in the brain induces many undesirable symptoms such as learning and memory impairment, sleep and mood disorders, hot flushes, and fatigue. These symptoms are frequent in women who reached menopausal age or have had ovariectomy and in men and women subjected to anti-estrogen therapy. Hormone replacement therapy alleviates menopause symptoms; however, it can increase cardiovascular and cancer diseases. In the search for therapeutic alternatives, medicinal plants and specific synthetic and natural molecules with estrogenic effects have attracted widespread attention between the public and the scientific community. Various plants have been used for centuries to alleviate menstrual and menopause symptoms, such as Cranberry, Ginger, Hops, Milk Thistle, Red clover, Salvia officinalis, Soy, Black cohosh, Turnera diffusa, Ushuva, and Vitex. This review aims to highlight current evidence about estrogenic medicinal plants and their pharmacological effects on cognitive deficits induced by estrogen deficiency during menopause and aging.
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http://dx.doi.org/10.3389/fphar.2021.644103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172769PMC
May 2021

The complex roles of efferocytosis in cancer development, metastasis, and treatment.

Biomed Pharmacother 2021 May 29;140:111776. Epub 2021 May 29.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

When tumor cells are killed by targeted therapy, radiotherapy, or chemotherapy, they trigger their primary tumor by releasing pro-inflammatory cytokines. Microenvironmental interactions can also promote tumor heterogeneity and development. In this line, several immune cells within the tumor microenvironment, including macrophages, dendritic cells, regulatory T-cells, and CD8 and CD4 T cells, are involved in the clearance of apoptotic tumor cells through a process called efferocytosis. Although the efficiency of apoptotic tumor cell efferocytosis is positive under physiological conditions, there are controversies regarding its usefulness in treatment-induced apoptotic tumor cells (ATCs). Efferocytosis can show the limitation of cytotoxic treatments, such as chemotherapy and radiotherapy. Since cytotoxic treatments lead to extensive cell mortality, efferocytosis, and macrophage polarization toward an M2 phenotype, the immune response may get involved in tumor recurrence and metastasis. Tumor cells can use the anti-inflammatory effect of apoptotic tumor cell efferocytosis to induce an immunosuppressive condition that is tumor-tolerant. Since M2 polarization and efferocytosis are tumor-promoting processes, the receptors on macrophages act as potential targets for cancer therapy. Moreover, researchers have shown that efferocytosis-related molecules/pathways are potential targets for cancer therapy. These include phosphatidylserine and calreticulin, Tyro3, Axl, and Mer tyrosine kinase (MerTK), receptors of tyrosine kinase, indoleamine-2,3-dioxygenase 1, annexin V, CD47, TGF-β, IL-10, and macrophage phenotype switch are combined with conventional therapy, which can be more effective in cancer treatment. Thus, we set out to investigate the advantages and disadvantages of efferocytosis in treatment-induced apoptotic tumor cells.
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http://dx.doi.org/10.1016/j.biopha.2021.111776DOI Listing
May 2021

Network pharmacology identifies IL6 as an important hub and target of tibolone for drug repurposing in traumatic brain injury.

Biomed Pharmacother 2021 May 28;140:111769. Epub 2021 May 28.

Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Limerick, Ireland. Electronic address:

Traumatic brain injury (TBI) is characterized by a complex network of signals mediating inflammatory, proliferative and apoptotic processes during its acute and chronic phases. Current therapies mitigate damage and are mainly for palliative care and there are currently no effective therapies for secondary damage. This suggests a need to discover a compound with a greater spectrum of action that can control various pathological aspects of TBI. Here we used a network pharmacology approach to explore the benefits of tibolone, an estrogen and androgen receptor agonist with broader actions in cells, as a possible repurposing drug for TBI therapy. Using different databases we retrieved the targets significantly associated to TBI and tibolone, obtaining 2700 and 652, respectively. The top 10 GO enriched terms were mostly related to cell proliferation, apoptosis and inflammation. Following protein-protein functional analysis, the top connected proteins were related to kinase activity (MAPK1/14/3, AKT1 PIK3R1), apoptosis (TP53, CASP3), growth factors (EGFR), estrogen signalling (ESR1) and inflammation (IL6, TNF), with IL6 as an important signalling hub belonging to the top GO categories. Thus, we identified IL6 as a cellular node which we then validated using molecular mechanics-generalized born surface area (MMGBSA) and docking to explore which tibolone metabolite might interact with this protein. Both 3α and 3β-OH tibolone seemed to bind better to IL6 at important sites responsible for its binding to IL6R. In conclusion, our study demonstrates key hubs involved in TBI pathology which indicates IL6 as a target molecule of tibolone as drug repurposing for TBI therapy.
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http://dx.doi.org/10.1016/j.biopha.2021.111769DOI Listing
May 2021

Efonidipine Exerts Cerebroprotective Effect by Down-regulation of TGF-β/SMAD-2-Dependent Signaling Pathway in Diabetic Rats.

J Mol Neurosci 2021 May 30. Epub 2021 May 30.

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

Calcium overload and hyperglycemia are risks of stroke onset in diabetics. Our study was designed to elucidate the beneficial role of calcium channel blockers by targeting voltage-gated calcium channels in diabetes-associated cerebrovascular complications. Diabetes was induced using the neonatal streptozotocin rat model. After confirmation of diabetes, middle cerebral artery occlusion (MCAO) was carried out. The pre-treatment with 1 mg/kg/day efonidipine was administered for the period of 4 weeks. After 24 h of ischemic induction surgery, the neurological score was determined, and blood was collected for determination of biochemical parameters. Treatment with efonidipine showed a significant reduction in post-ischemic brain infract volume, brain hemisphere weight difference, neurological score, Na-K ATPase activity, serum CK-MB, and LDH levels in normoglycemic and hyperglycemic MCAO-induced animals. While no significant changes in glucose and lipid levels were observed by treatment, efonidipine significantly decreased the levels of malondialdehyde, acetylcholine esterase, and nitrite levels and increased the levels of antioxidant markers in both normoglycemic and hyperglycemic MCAO animals. TGF-β and VEGF were found to be down-regulated after treatment with efonidipine in gene expression study. In conclusion, the study data supports the cerebroprotective role of efonidipine in diabetic animals possibly through TGF-β/SMAD-2 signaling pathway.
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http://dx.doi.org/10.1007/s12031-021-01857-zDOI Listing
May 2021

In silico interactions of statins with cell death-inducing DNA fragmentation factor-like effector A (CIDEA).

Chem Biol Interact 2021 May 19:109528. Epub 2021 May 19.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Statins are the low-density lipoproteins (LDL)-cholesterol-lowering drugs of first choice and are used to prevent the increased risk of cardiovascular and cerebrovascular diseases. Although some of their effects are well known, little is known about their ability to regulate other lipid-related proteins which control apoptotic mechanisms. The aim of this study was to explore whether statins can bind to cell death-inducing DNA fragmentation factor-like effector A (CIDEA), which might be a possible pleiotropic mechanism of action of these drugs on the modulation of apoptosis and lipid metabolism. The structures of statins were subjected to molecular docking and dynamics with the human CIDEA protein to investigate the interaction pattern and identify which residues are important. The docking results indicated that atorvastatin and rosuvastatin showed the best interaction energy (-8.51 and -8.04 kcal/mol, respectively) followed by fluvastatin (-7.39), pitavastatin (-6.5), lovastatin (-6.23), pravastatin (-6.04) and simvastatin (-5.29). Atorvastatin and rosuvastatin were further subjected to molecular dynamics at 50 ns with CIDEA and the results suggested that rosuvastatin-CIDEA complex had lower root-mean square deviation and root-mean square fluctuation when compared with atorvastatin-CIDEA. Since two arginine residues -ARG19 and ARG22-were identified to be common for the interaction with CIDEA, a single-point mutation was induced in these residues to determine whether they are important for binding interaction. Mutation of these two residues seems to affect mostly the interaction of atorvastatin with CIDEA, suggesting that they are important for the binding and therefore indicate another possible metabolic mechanism of the pleiotropic effects of this statin.
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http://dx.doi.org/10.1016/j.cbi.2021.109528DOI Listing
May 2021

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes.

Biofactors 2021 Apr 24. Epub 2021 Apr 24.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.
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http://dx.doi.org/10.1002/biof.1735DOI 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.
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http://dx.doi.org/10.1007/978-3-030-64872-5_29DOI Listing
April 2021

Protective Effects of Intravenous Magnesium Sulfate in Stroke Patients Receiving Amiodarone: A Randomized Controlled Trial.

Adv Exp Med Biol 2021 ;1308:579-588

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Anti-arrhythmic agents, like amiodarone, interfere at different stages of the ischemic stroke. However, amiodarone was accompanied with immunological pulmonary complications and adverse neurological effects. We hypothesize that magnesium sulfate in combination with amiodarone holds promise for stroke treatment. Thirty-six patients with confirmed diagnosis of ischemic stroke and atrial fibrillation who received bolus amiodarone were randomly assigned to magnesium sulfate every 24 h or similar volume of normal saline (as placebo) for 5 days. Various severity test scores were used to evaluate the symptoms. Routing biochemistry were also measured at days 1 and 5. Treatment with MgSO4 results in a significant reduction in serum levels of NGAL, Hb, T.Bill, IL-6, IL-8, SNSE, S100B, EGF, PAF, CRP and IgG. Also, MgSO4 treatment significantly improved the RASS, Candida, SOFA, NIHSS and APACHE scores. Moreover, reduction of IL-6, IL-8, SNSE, EGF and APACHE score and increase in RASS score were significantly higher in MgSO4 group compared with placebo. Intravenous administration of MgSO4 in amiodarone-treated stroke patients improved the inflammatory, immunological and neurological indicators and reduced disability in ICU-admitted AIS patients, suggesting that this treatment scheme may prevent amiodarone-induced complications in these patients.
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http://dx.doi.org/10.1007/978-3-030-64872-5_28DOI Listing
April 2021

Beneficial Medicinal Plants for Memory and Cognitive Functions Based on Traditional Persian Medicine.

Adv Exp Med Biol 2021 ;1308:283-290

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Alzheimer's disease (AD) is one of the most important causes of dementia, especially in the elderlies. Due to the failures of recent clinical trials in finding effective medications, it appears the use of complementary therapies such as Traditional Persian Medicine (TPM) and the rich sources of effective herbs as well as their constituents for improving memory function could be beneficial. The aim of this study was to evaluate the recommended natural remedies in the TPM and examine their pharmacological properties. For this purpose, the data were collected by searching the recommended prescriptions of the seminal TPM textbooks. Then, the names of the most freuqently mentioned plants were extracted from the natural remedies and evaluated for their pharmacological properties. The sources included recently published articles cited in the major scientific databases. A total of 262 plants were identified in 96 evaluated prescriptions; 20 plants were identified with the most frequency of report (i.e. more than 10 times). Their neuroprotective effects, antioxidant features, and anti-AD properties were discussed. Based on our results, TPM has introduced many effective treatments for AD. Hence, more clinical studies are warranted to verify their efficacy and safety.
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http://dx.doi.org/10.1007/978-3-030-64872-5_20DOI Listing
April 2021

Crocin Improves Oxidative Stress in Testicular Tissues of Streptozotocin-Induced Diabetic Rats.

Adv Exp Med Biol 2021 ;1308:273-281

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Crocin has been shown to have potent antioxidant properties, but its potential antioxidative effects on testicular tissue during uncontrolled diabetes is unknown. Wistar rats were randomly divided into four separate groups; normal, normal-treated, diabetic and diabetic treated (n = 6 per group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Two treated groups of animals (diabetic and non-diabetic) received Crocin daily for 56 days (40 mg/kg/intraperitoneally). At the end of the 56th day, animals were sacrificed and blood and testicular tissue obtained. The level of nitrate, malondialdehyde, glutathione, and the activities of superoxide dismutase and catalase enzymes were determined. Crocin therapy moderated the increased oxidative stress in testicular tissue induced by diabetes with a significant reduction in nitrate and malondialdehyde, whilst reducing superoxide dismutase and catalase enzyme activities in diabetes (p < 0.001), though glutathione was unaffected. Treatment by Crocin in normal rats also modestly improved parameters of oxidative stress (p < 0.05). Crocin has a protective effect on diabetes induced oxidative stress in testicular tissue in an animal model, though it is unclear if this is a direct antioxidant effect.
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http://dx.doi.org/10.1007/978-3-030-64872-5_19DOI Listing
April 2021

Curcumin Can Bind and Interact with CRP: An in silico Study.

Adv Exp Med Biol 2021 ;1308:91-100

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Curcuminis a polyphenol with anti-inflammatory and antioxidative properties, found primarily in turmeric, a flowering plant of the ginger family. Among its numerous medical uses, curcumin has been used in the management of metabolic syndrome, and inflammatory conditions such as artrhritis, anxiety and hyperlipidemia. In this paper, we used molecular docking tools to assess the affinity of four curcumin derivatives (Curcumin, Cyclocurcumin, Demethoxycurcumin, Bisdemethoxycurcumin) as well as the endogenous ligand phosphorylcholine to C-reactive protein (CRP), a sensitive marker of systemic inflammation. Our results showed that curcumin interacts through H bond with CRP at GLN 150 and ASP 140. Similar H bond interactions were found for each of the four curcumin derivatives with CRP. Moreover, a molecular dynamic simulation were performed to further establish the interaction between CRP and the ligands in atomic details using the Nanoscale Molecular Dynamics (NAMD) and CHARMM27 force field. Importantly, our results suggest the possible interaction between curcumin and curcurmin related molecules with CRP, thus showing an important regulatory function with plausible applications in inflammatory and oxidative processes in diseases.
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http://dx.doi.org/10.1007/978-3-030-64872-5_7DOI Listing
April 2021

siRNA Therapeutics: Future Promise for Neurodegenerative Diseases.

Curr Neuropharmacol 2021 04 1. Epub 2021 Apr 1.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Neurodegenerative diseases (ND), as a group of central nervous system (CNS) disorders, are among the most prominent medical problems in the 21st century. They are often associated with considerable disability, motor dysfunction and dementia and are more common in the aged population. ND imposes a psychologic, economic and social burden on the patients and their families. Currently, there is no effective treatment for ND. Since many of ND results from the gain of function of a mutant allele, small interference RNA (siRNA) can be a potential therapeutic agent for ND management. Based on the RNA interference (RNAi) approach, siRNA is a powerful tool for modulating gene expression through gene silencing. However, there are some obstacles in the clinical application of siRNA, including unfavorable immune response, off-target effects, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system. Since there are some issues related to siRNA delivery routes, in this review, we focus on the application of siRNA in the management of ND treatment from 2000 to 2020.
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http://dx.doi.org/10.2174/1570159X19666210402104054DOI Listing
April 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.
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http://dx.doi.org/10.1155/2021/4572471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960032PMC
May 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.
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http://dx.doi.org/10.3390/ijms22052258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956497PMC
February 2021

Astrocytes and Inflammasome: A Possible Crosstalk in Neurological Diseases.

Curr Med Chem 2021 Feb 28. Epub 2021 Feb 28.

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad. Iran.

Inflammasome research has primarily focused on neurological tissue, particularly on damaged tissue. Most current neurological literature involves in vivo and in vitro studies utilizing astroglia, as astroglia express the cytoskeletal glial fibrillary acidic protein (GFAP) which is used as a hallmark of neuropathological disorders. Research suggests that astrocytes respond to all forms of neurological damage or disease through reactive astrogliosis. Additionally, there is a consensus among scientists that inflammasomes play an important role in neuroinflammation. This review focuses on the latest developments in inflammasome biology, describing the current understanding of how inflammasomes can be triggered in the brain and summarizing the literature on the relevance of inflammasome NLR in prevalent neurological diseases.
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http://dx.doi.org/10.2174/0929867328666210301105422DOI Listing
February 2021

Therapeutic potential of trehalose in neurodegenerative diseases: the knowns and unknowns.

Neural Regen Res 2021 Oct;16(10):2026-2027

Applied Biomedical Research Center; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; School of Pharmacy Mashhad University of Medical Sciences, Mashhad, Iran.

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http://dx.doi.org/10.4103/1673-5374.308085DOI Listing
October 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 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.
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http://dx.doi.org/10.1007/s00894-021-04679-3DOI Listing
January 2021

Common genes and pathways involved in the response to stressful stimuli by astrocytes: A meta-analysis of genome-wide expression studies.

Genomics 2021 Mar 21;113(2):669-680. Epub 2021 Jan 21.

Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia.

Astrocytes play pivotal roles in the brain and they become reactive under stress conditions. Here, we carried out, for the first time, an integrative meta-analysis of genome-wide expression profiling of astrocytes from human and mouse exposed to different stressful stimuli (hypoxia, infections by virus and bacteria, cytokines, ethanol, among others). We identified common differentially expressed genes and pathways in human and murine astrocytes. Our results showed that astrocytes induce expression of genes associated with stress response and immune system regulation when they are exposed to stressful stimuli, whereas genes related to neurogenesis are found as downregulated. Several of the identified genes showed to be important hubs in the protein-protein interaction analysis (TRAF2, CDC37 and PAX6). This work demonstrates that despite astrocytes are highly heterogeneous and complex, there are common gene expression signatures that can be triggered under distinct detrimental stimuli, which opens an opportunity for exploring other possible markers of reactivity.
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http://dx.doi.org/10.1016/j.ygeno.2021.01.008DOI Listing
March 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.

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

Apoptotic neurons and amyloid-beta clearance by phagocytosis in Alzheimer's disease: Pathological mechanisms and therapeutic outlooks.

Eur J Pharmacol 2021 Mar 16;895:173873. Epub 2021 Jan 16.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland. Electronic address:

Neuronal survival and axonal renewal following central nervous system damage and in neurodegenerative illnesses, such as Alzheimer's disease (AD), can be enhanced by fast clearance of neuronal apoptotic debris, as well as the removal of amyloid beta (Aβ) by phagocytic cells through the process of efferocytosis. This process quickly inhibits the release of proinflammatory and antigenic autoimmune constituents, enhancing the formation of a microenvironment vital for neuronal survival and axonal regeneration. Therefore, the detrimental features associated with microglial phagocytosis uncoupling, such as the accumulation of apoptotic cells, inflammation and phagoptosis, could exacerbate the pathology in brain disease. Some mechanisms of efferocytosis could be targeted by several promising agents, such as curcumin, URMC-099 and Y-P30, which have emerged as potential treatments for AD. This review aims to investigate and update the current research regarding the signaling molecules and pathways involved in efferocytosis and how these could be targeted as a potential therapy in AD.
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http://dx.doi.org/10.1016/j.ejphar.2021.173873DOI Listing
March 2021

Brain lipidomics as a rising field in neurodegenerative contexts: Perspectives with Machine Learning approaches.

Front Neuroendocrinol 2021 Apr 12;61:100899. Epub 2021 Jan 12.

Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia. Electronic address:

Lipids are essential for cellular functioning considering their role in membrane composition, signaling, and energy metabolism. The brain is the second most abundant organ in terms of lipid concentration and diversity only after adipose tissue. However, in the central system (CNS) lipid dysregulation has been linked to the etiology, progression, and severity of neurodegenerative diseases such as Alzheimeŕs, Parkinson, and Multiple Sclerosis. Advances in the human genome and subsequent sequencing technologies allowed us the study of lipidomics as a promising approach to diagnosis and treatment of neurodegeneration. Lipidomics advances rapidly increased the amount and quality of data allowing the integration with other omic types as well as implementing novel bioinformatic and quantitative tools such as machine learning (ML). Integration of lipidomics data with ML, as a powerful quantitative predictive approach, led to improvements in diagnostic biomarker prediction, clinical data integration, network, and systems approaches for neural behavior, novel etiology markers for inflammation, and neurodegeneration progression and even Mass Spectrometry image analysis. In this sense, by exploiting lipidomics data with ML is possible to improve the identification of new biomarkers or unveil new molecular mechanisms associated with lipid impairment across neurodegeneration. In this review, we present the lipidomic neurobiology state-of-the-art highlighting its potential applications to study neurodegenerative conditions. Also, we present theoretical background, applications, and advances in the integration of lipidomics with ML. This review opens the door to new approaches in this rising field.
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http://dx.doi.org/10.1016/j.yfrne.2021.100899DOI Listing
April 2021

Recent advancements in liposome-based strategies for effective drug delivery to the brain.

Curr Med Chem 2020 12 18. Epub 2020 Dec 18.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Disorders of the central nervous system (CNS) and tumors of the brain are challenging to treat, and they rank amongst the most common causes of death worldwide. The delivery of drugs to the brain is problematic because the blood-brain barrier (BBB) effectively arrests the transport of large molecules (including drugs) from the blood to the CNS. Nanoparticle (NP)-mediated drug delivery has received much interest as a technique to overcome this difficulty. In particular, liposome NPs are promising candidates to carry and deliver drugs across the BBB and into the CNS. Liposomes are easy to prepare, highly biodegradable, and biocompatible. Liposomes can be easily modified with various ligands to enable efficient and targeted drug delivery. Liposomes can promote increased cellular uptake of drugs and can reduce the extent to which efflux transporters can remove drugs. Liposomes can be loaded with a wide range of drugs and biologically active substances. In this review, we will summarize recent advances in research relating to liposome-based strategies to enable drug delivery across the BBB.
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http://dx.doi.org/10.2174/0929867328666201218121728DOI 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.

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

The potential of mitochondrial modulation by neuroglobin in treatment of neurological disorders.

Free Radic Biol Med 2021 01 6;162:471-477. Epub 2020 Nov 6.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Halal Research Center of IRI, FDA, Tehran, Iran. Electronic address:

Neuroglobin is the third member of the globin family to be identified in 2000 in neurons of both human and mouse nervous systems. Neuroglobin is an oxygen-binding globin found in neurons within the central nervous system as well as in peripheral neurons, that produces a protective effect against hypoxic/ischemic damage induced by promoting oxygen availability within the mitochondria. Numerous investigations have demonstrated that impaired neuroglobin functioning is implicated in the pathogenesis of multiple neurodegenerative disorders. Several in vitro and animal studies have reported the potential of neuroglobin upregulation in improving the neuroprotection through modulation of mitochondrial functions, such as ATP production, clearing reactive oxygen species (ROS), promoting the dynamics of mitochondria, and controlling apoptosis. Neuroglobin acts as a stress-inducible globin, which has been associated hypoxic/ischemic insults where it acts to protect the heart and brain, providing a wide range of applicability in the treatment of human disorders. This review article discusses normal physiological functions of neuroglobin in mitochondria-associated pathways, as well as outlining how dysregulation of neuroglobin is associated with the pathogenesis of neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.002DOI Listing
January 2021

Bioinformatic Study of Involved Mechanisms in Relapse and Drug Resistance of Tamoxifen-Treated Breast Cancer.

Anticancer Agents Med Chem 2020 Oct 29. Epub 2020 Oct 29.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran.

Background: Breast cancer is currently among the most common cause of mortality in women. Estrogen and its subsequent signaling pathways play an important role in the occurrence of breast cancer relapse. Tamoxifen is the most common breast cancer treatment option in ER+ patients, which acts as an adjuvant endocrinotherapy with X-ray and surgery. This approach is recommended as the first line treatment and has increased the survival rate of breast cancer patients and reduced the relapse cases. However, we can observe resistance to tamoxifen and relapse cases in one-third of patients treated with this drug, which has become a major concern.

Objective: The precise mechanisms of relapse and resistance to tamoxifen have not yet been identified and were explored in this study.

Methods: Microarray profiles of relapse and relapse-free patients were investigated to explain the processes leading to relapse and possibly to tamoxifen resistance.

Results: According to the preliminary analysis, 1460 genes showed increased expression and 1132 genes showed decreased expression. According to our default for inclusion (-2LogFC≥ + 2), 36 genes had increased expression (upregulated) and 33 genes had decreased expression (down-regulated).

Conclusion: It seems that the mechanisms of resistance and relapse are multifactorial, and tumor cells induce relapse and resistance to tamoxifen through mechanisms of cell proliferation, survival, invasion, angiogenesis, extracellular matrix secretion, pump and membrane changes and immune evasion.
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http://dx.doi.org/10.2174/1871520620666201029114253DOI Listing
October 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.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577398DOI Listing
December 2020

Nano-engineered nerolidol loaded lipid carrier delivery system attenuates cyclophosphamide neurotoxicity - Probable role of NLRP3 inflammasome and caspase-1.

Exp Neurol 2020 12 15;334:113464. Epub 2020 Sep 15.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

Neuroinflammation is one of the most common etiology in various neurological disorders and responsible for multi-array neurotoxic manifestations such as neurodegeneration, neurotransmitters alteration and cognitive dysfunction. NR (Nerolidol) is a natural bioactive molecule which possesses significant antioxidant and anti-inflammatory potential, but suffers from glitches of low solubility, low bioavailability and fast hepatic metabolism. In the current study, we fabricated nano-engineered lipid carrier of nerolidol (NR-NLC) for its effective delivery into the brain and explored its effect on neuroinflammation, neurotransmitters level and on dysfunctional behavioral attributes induced by CYC (cyclophosphamide). The binding affinity of nerolidol with NLRP3 and TLR-4 was performed which showed stong interaction between them. NR-NLC was prepared by the ultrasonication methods and particle size was determined by Zeta-sizer. Swiss Albino mice were divided into 5 groups (n = 6), assessed for behavioral dysfunction, and sacrificed on the fifteenth day following cyclophosphamide treatment. Brains were then removed and used for biochemical, histopathological, immunohistochemical and fluorescence microscopic analysis. Biochemical analysis showed increased levels of MDA, TNF-α, IL-6, IL-1β, acetylcholine esterase, BDNF, 5-HT and dopamine, and reduced levels of SOD, CAT, GSH, IL-10, along with significant behavioral dysfunction in cyclophosphamide-treated animals. Significant neuronal damage was also observed in the histological study. Immunohistochemical analysis demonstrated increased expression of NLRP3 and caspase-1. Fluorescence microscopic analysis showed significant availability of NR-NLC in the hippocampus and cortex region. In contrast, treatment with NR-NLC effectively mitigated the aforementioned neurotoxic manifestation as compared to NR suspension. Our results showed potent neuroprotective effect of NR-NLC via modulation of oxidative stress, NLRP3 inflammasome, caspase-1 and neurotransmitter status.
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http://dx.doi.org/10.1016/j.expneurol.2020.113464DOI Listing
December 2020