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The growing world population and the increasing burden on the agricultural sector to meet the associated increased food demand are major concerns of the modern world. In addition to increasing the quantity of food, the focus is also on improving food quality in terms of its nutritional content. Sustainable agricultural approaches to maximize the use of limited land and water resources while reducing harmful chemicals have been studied extensively over the past decade. The advent of nanotechnology has provided a new direction in which nanoparticles with small sizes and unique properties are being used to improve crop production by enhancing crop quality, growth, and productivity, used as biofertilizers, and for biological pest control while maintaining soil health. Nanoparticles are now also being used in precision agriculture and food packaging. However, the ethical concerns associated with their use, given that humans are the primary consumers, as well as their toxicity to certain life forms, require proper evaluation of their application. Therefore, this review provides insight into the types and sources of nanoparticles, as well as the current status of approaches to their synthesis, environmental impact, and risk assessment of their use in the agriculture and food sectors. [ABSTRACT FROM AUTHOR]

Erlotinib is a reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that acts by inhibiting signaling pathways, resulting in the disruption of cancerous cell proliferation. Erlotinib is a promising anticancer agent mainly utilized in the mitigation of non-small cell lung cancer cells (NSCLC) and pancreatic tumor. Apart from NSCLC and pancreatic tumor, erlotinib has also been employed in different malignancies, including metastatic colorectal cancer, malignant glioma, breast cancer, gastrointestinal cancers, etc. Despite erlotinib's distinctive qualities as a targeted drug, its applications are still limited by poor solubility, variable oral bioavailability, a high daily dose requirement, large protein binding, and primitive or acquired therapeutic resistance. Nanotechnology is a favorable approach to increase therapeutic effectiveness of erlotinib. It is one of the newest scientific field directed toward the diagnosis and targeted treatment of cancer. This technology aids in the distinction between normal and malignant cells, which overlays the strategy for targeted delivery. This manuscript discussed the advances of erlotinib nanoformulations in the management of different cancers. Moreover, the manuscript also comprises various research outcomes of erlotinib nanoformulations with other therapeutic agents as combinational therapy. Erlotinib can be delivered to a precise target in the body utilizing different polymers, lipids, and metals. [ABSTRACT FROM AUTHOR]

In the quickly evolving world of healthcare today, new technologies are constantly altering the way we approach medical treatments. Biomedical implants are specialist devices designed to enhance physiological functions. Heart pacemakers and artificial joints are merely a few instances of how they could enhance, assist, or replace different bodily parts. These implants have significantly improved our health and enjoyment of life. In this discipline, nanoparticles are now creating new opportunities. These tiny particles are endowed with extraordinary properties that could improve implant functionality. They can decrease side effects, increase the effectiveness of therapy, and facilitate more harmonious interactions between implants and human bodies. We explored the connection between implants and nanoparticles and showed how both might enhance universal healthcare. This review provides a roadmap for where this technology is headed and how it can help us design safer, more effective implants that enhance people's lives by examining the most recent research and discoveries. It is an intriguing look at healthcare in the future that demonstrates how nanoparticles are reshaping the biomedical implant industry. [ABSTRACT FROM AUTHOR]

Background and purpose: Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers exist for phenotype classification, symptom severity, prognosis, and treatment guidance of MOG-IgG-associated disease (MOGAD). This study evaluated neurofilament light chain (NfL) and endothelial growth factor receptor (EGFR) mRNA expression levels in serum and cerebrospinal fluid (CSF) as potential biomarkers for MOGAD in Chinese children. Methods: This was a cross-sectional and single-center study. We enrolled 22 consecutive pediatric patients hospitalized with MOGAD and 20 control pediatric patients hospitalized for noninflammatory neurological diseases in Hebei Children's Hospital. Serum and CSF were collected from MOGAD patients within 3 days before immunotherapy. The mRNA levels of NfL and EGFR in serum and CSF were measured by real-time polymerase chain reaction (qPCR), and the EGFR/NfL ratio mRNA was calculated. These measurement values were then compared between disease groups and among MOGAD phenotypes. In addition, the correlations between the mRNAs of three markers (NfL, EGFR, EGFR/NfL ratio), extended disability status scale (EDSS) scores, and clinical phenotypes were analyzed. Results: Serum and CSF NfL mRNA levels were significantly higher of acute-stage MOGAD patients than those of control patients (p< 0.05 and p< 0.01, respectively), while the mRNA levels of serum EGFR and EGFR/NfL ratio were significantly lower of MOGAD patients than those of controls (p < 0.05, p < 0.0001). Serum NfL mRNA was significantly correlated with mRNA of serum EGFR (r =0.480, p < 0.05). Serum and CSF NfL mRNA levels in MOGAD patients with the ADEM-like phenotype were also significantly higher than those in control patients (p < 0.01, p < 0.01) and optic neuritis (ON) phenotype (p < 0.05, p < 0.05). Both mRNAs of NfL in CSF and EGFR/NfL ratio in serum were correlated with EDSS scores (p < 0.05, r = 0.424; p < 0.05, r= -0.521). Conclusion: The mRNA levels of elevated NfL in serum and CSF as well as lower EGFR and EGFR/NfL ratio in serum could help distinguish acute-phase MOGAD. Higher mRNA levels of NfL in serum and CSF of MOGAD patients help distinguish ADEM-like phenotype. In addition, serum EGFR/NfL mRNA ratio is indicative of disease severity in pediatric patients with MOGAD. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Lipid-based polymeric nanoparticles are the highly popular carrier systems for cancer drug therapy. But presently, detailed investigations have revealed their flaws as drug delivery carriers. Lipid polymer hybrid nanoparticles (LPHNPs) are advanced core–shell nanoconstructs with a polymeric core region enclosed by a lipidic layer, presumed to be derived from both liposomes and polymeric nanounits. This unique concept is of utmost importance as a combinable drug delivery platform in oncology due to its dual structured character. To add advantage and restrict one's limitation by other, LPHNPs have been designed so to gain number of advantages such as stability, high loading of cargo, increased biocompatibility, rate-limiting controlled release, and elevated drug half-lives as well as therapeutic effectiveness while minimizing their drawbacks. The outer shell, in particular, can be functionalized in a variety of ways with stimuli-responsive moieties and ligands to provide intelligent holding and for active targeting of antineoplastic medicines, transport of genes, and theragnostic. This review comprehensively provides insight into recent substantial advancements in developing strategies for treating various cancer using LPHNPs. The bioactivity assessment factors have also been highlighted with a discussion of LPHNPs future clinical prospects. [ABSTRACT FROM AUTHOR]

Polymer-lipid hybrid nanoparticles (PLHNs) have been widely used as a vehicle for carrying anticancer owing to its unique framework of polymer and lipid combining and giving the maximum advantages over the lipid and polymer nanoparticle drug delivery system. Surface modification of PLHNs aids in improved targeting and active delivery of the encapsulated drug. Therefore, surface modification of the PLHNs with the cell-penetrating peptide is explored by many researchers and is explained in this review. Cell-penetrating peptides (CPPs) are made up of few amino acid sequence and act by disrupting the cell membrane and transferring the cargos into the cell. Ideally, we can say that CPPs are peptide chains which are cell specific and are biocompatible, noninvasive type of delivery vehicle which can transport siRNA, protein, peptides, macromolecules, pDNA, etc. into the cell effectively. Therefore, this review focuses on the structure, type, and method of preparation of PLHNs also about the uptake mechanism of CPPs and concludes with the therapeutic application of PLHNs surface modified with the CPPs and their theranostics. [ABSTRACT FROM AUTHOR]

In this study, amphoteric hydroxyethyl starch/p([2(acryloyloxy)ethyl]trimethylammonium chloride-co-itaconic acid (HES/p(AETAC-co-IA) hydrogels containing both cationic and anionic groups in their structure were synthesized by the redox polymerization method. The synthesized hydrogels were modified with gold nanoparticles, and nanocomposite hydrogels were obtained. The characterizations of the nanocomposite HES/p(AETAC-co-IA)@Au hydrogels prepared for biomedical applications were carried out by SEM, TEM, FT-IR, TGA, and XRD techniques and swelling tests in simulated biological environments. Hydrogels designed as drug carrier cargo materials were loaded with sodium diclofenac (NaDcF) and ibuprofen drugs, and their release properties were studied. The release mechanisms and release kinetics of the two drugs were studied. The release kinetics determined for the drug NaDcF is consistent with the Higuchi model, while the release kinetics determined for ibuprofen is consistent with the first-order model. In addition, the antibacterial and antifungal properties of the hydrogels were tested. It was found that the HES/p(AETAC-co-IA)@Au hydrogel was effective against gram-positive Staphylococcus aureus, gram-negative Pseudomonas aeruginosa, and the fungal species Candida albicans. [ABSTRACT FROM AUTHOR]

Background: PP1γ is one of the isoforms of catalytic subunit of a Ser/Thr phosphatase PP1. The role of PP1γ in cellular regulation is largely unknown. The present study investigated the role of PP1γ in regulating neuronal insulin signaling and insulin resistance in neuronal cells. PP1 was inhibited in mouse neuroblastoma cells (N2a) and human neuroblastoma cells (SH-SY5Y). The expression of PP1α and PP1γ was determined in insulin resistant N2a, SH-SY5Y cells and in high-fat-diet-fed-diabetic mice whole-brain-lysates. PP1α and PP1γ were silenced by siRNA in N2a and SH-SY5Y cells and effect was tested on AKT isoforms, AS160 and GSK3 isoforms using western immunoblot, GLUT4 translocation by confocal microscopy and glucose uptake by fluorescence-based assay. Results: Results showed that, in one hand PP1γ, and not PP1α, regulates neuronal insulin signaling and insulin resistance by regulating phosphorylation of AKT2 via AKT2-AS160-GLUT4 axis. On the other hand, PP1γ regulates phosphorylation of GSK3β via AKT2 while phosphorylation of GSK3α via MLK3. Imbalance in this regulation results into AD-like phenotype. Conclusion: PP1γ acts as a linker, regulating two pathophysiological conditions, neuronal insulin resistance and AD. 9kZE1HTKkUH8PMrXCf3pWd Video Abstract [ABSTRACT FROM AUTHOR]

Thyroid hormones (TH) are vital for brain functions, while TH d eficiency, i.e. hypothyroidism, induces neurological impairment in children and adults. Cerebellar neuronal apoptosis and motor deficits are crucial events in hypo thyroidism; however, the underlying mechanism is less-known. Using a methimazole-tre ated hypothyroidism rat model, we investigated cerebellar autophagy, growth factor, and apoptotic mechanisms that participate in motor functions. We first identified that methimazole up-regulated cerebellar autophagy, marked by enhanced LC3B-II, Beclin-1, ATG7, ATG5-12, p-AMPKa/AMPKa, and p62 degradation as well as reduced p-AKT/AKT, p-mTOR/mTOR, and p-ULK1/ULK1 in developing and young adult rats. We probed u pstream effectors of this abnormal autophagy and detected a methimazole-induced redu ction in cerebellar phospho-epidermal growth factor receptor (p-EGFR)/EGFR and heparin-binding EGF-like growth factor (HB-EGF). Here, while a thyroxine-induced TH replenishment alleviated autophagy process and restored HB-EGF/EGFR, HB-EGF treatment regulated AKT-mTOR and autophagy signaling in the cerebellum. Moreover, neurons of the rat cerebellum demonstrated this reduced HB-EGF-dependent increased autophagy in hypothyroidism. We further checked whether the above events were related to cerebellar neuronal apoptosis and motor functions. We detected that comparable to thyroxine, treatment with HB-EGF or autophagy inhibitor, 3-MA, reduced methimazole-i nduced decrease in Nissl staining and increase in c-Caspase-3 and TUNEL-+ve apoptotic count of cerebellar neurons. Additionally, 3-MA, HB-EGF, and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for the motor performance of rats. Overall, our study enlightens HB-EGF/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine. [ABSTRACT FROM AUTHOR]

The present study was developed to explore whether microRNA (miR)-760 targets heparin-binding EGF-like growth factor (HBEGF) to control cartilage extracellular matrix degradation in osteoarthritis. Both miR-760 and HBEGF expression levels were analysed in human degenerative cartilage tissues and in interleukin (IL)-1β/tumour necrosis factor (TNF)-α-treated chondrocytes in vitro. A series of knockdown and overexpression assays were then used to gauge the functional importance of miR-760 and HBEGF in OA, with qPCR and western immunoblotting analyses. Bioinformatics assays were used to identify putative miR-760 target genes, with these predictions then being validated through RNA pulldown and luciferase reporter assays. A murine anterior cruciate ligament transection model of OA was then established to prove the in vivo relevance of these findings. These experiments revealed that human degenerative cartilage tissues exhibited significant increases in miR-760 expression with a concomitant drop in HBEGF levels. IL-1β/TNF-α-treated chondrocytes also exhibited significant increases in miR-760 expression with a concomitant drop in HBEGF expression. When chondrocytes were transfected with either miR-760 inhibitor or HBEGF overexpression constructs, this was sufficient to interfere with degradation of the extracellular matrix (ECM). Moreover, miR-760 was confirmed to control chondrocyte matrix homeostasis by targeting HBEGF, and the overexpression of HBEGF partially reversed the effects of miR-760 mimic treatment on the degradation of the cartilage ECM. When OA model mice were administered an intra-articular knee injection of an adenoviral vector encoding a miR-760 mimic construct, cartilage ECM degradation was aggravated. Conversely, the overexpression of HBEGF in OA model mice partially reversed the effects of miR-760 overexpression, restoring appropriate ECM homeostasis. In summary, these data indicated that the miR-760/HBEGF axis plays a central role in orchestrating the pathogenesis of OA, making it a candidate target for therapeutic efforts in OA. [ABSTRACT FROM AUTHOR]

The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (− 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential. Highlights: PEGylated lipid polymer hybrid nanoparticles exhibit a core–shell assembly with higher loading efficiency, biocompatibility, and enhanced steric stability. Hybrid nanoparticles using combination of drugs illustrated long-term serum stability. Ergotamine hybrid nanoparticles demonstrated higher uptake and sustained presence in brain. [ABSTRACT FROM AUTHOR]

Amphiphilic copolymers have long been utilized to turn hydrophobic anticancer drugs into nanoparticles administered to patients with cancer. A lack of stability in these monotherapies may be blamed for their poor clinical results in patients with cancer. We propose novel nanotherapies based on polymeric small prodrugs that preserve pharmacologic effectiveness while significantly reducing the toxicity of the fabricated drugs in animals to overcome this problem. Doxorubicin is attached to the end of the PLA fragments through a hydrolyzable ester bond utilizing methoxypolyethylene glycol-block-poly(d, l-lactic acid) (mPEG-PCL(2K)) with conjugates to mimic the self-assembly of colloidal nanotherapies. In a gastric cancer xenograft model, this nanotherapy displays a long-lasting suppression of tumor growth once a reasonable dosage is administered. Our findings imply that a toxic chemical and hydrophobic can be converted into therapeutic effective self-delivery nanotreatment. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a pregnancy-associated disease that may cause maternal and fetal morbidity and mortality. The dysregulation of microRNAs (miRNAs) and their potential functions has been an important direction for elucidating the mechanism of preeclampsia in recent years. The present study investigated whether miR-4443 was significantly increased in the placentas of severe preeclamptic patients, and the upregulation of miR-4443 inhibited the migration and invasion of HTR-8/SVneo cells according to transwell assays. Matrix metallopeptidase 2 (MMP2), which is involved in the degradation of extracellular matrix (ECM) components and harbors a miR-4443-binding site within its 3'-UTR as confirmed by a luciferase reporter assay, was identified to be directly inhibited by miR-4443. Moreover, siRNA targeting MMP2 imitated the effects of overexpressed miR-4443 on HTR-8/SVneo cell invasion and migration, whereas rescue experiments showed that MMP2 reversed this inhibitory function of miR-4443. Heparin-binding EGF-like growth factor (HB-EGF), as the downstream gene of MMP2, plays an important role in trophoblast invasion, and we confirmed that the expression of HB-EGF/EGFR pathway-related biomolecules was consistent with MMP2 influenced by upregulating and downregulating miR-4443 and that activated EGFR further transmitted intracellular downstream signaling via the MAPK pathway according to western blot assay. In conclusion, we demonstrated that miR-4443 suppresses the migration and invasion of trophoblasts, and its inhibitory effects are at least partially mediated by the suppression of MMP2. This inhibition might further affect the progression of preeclampsia through the HB-EGF/EGFR pathway, thus providing a new clue on the role of miR-4443 in the pathogenesis of preeclampsia. [ABSTRACT FROM AUTHOR]

Currently, tumor treatments are characterized by intelligence, diversity and personalization, but the therapeutic reagents used are often limited in clinical efficacy due to problems with water solubility, targeting, stability and multidrug resistance. To remedy these shortcomings, the application of multifunctional nanotechnology in the biomedical field has been widely studied. Synthetic melanin nanoparticles (MNPs) surfaces which contain highly reactive chemical groups such as carboxyl, hydroxyl and amine groups, can be used as a reaction platform on which to graft different functional components. In addition, MNPs easily adhere to substrate surface, and serve as a secondary reaction platform to modify it. The multifunctionality and intrinsic biocompatibility make melanin-like nanoparticles promising as a multifunctional and powerful nanoplatform for oncological applications. This paper first reviews the preparation methods, polymerization mechanisms and physicochemical properties of melanin including natural melanin and chemically synthesized melanin to guide scholars in MNP-based design. Then, recent advances in MNPs especially synthetic polydopamine (PDA) melanin for various medical oncological applications are systematically and thoroughly described, mainly focusing on bioimaging, photothermal therapy (PTT), and drug delivery for tumor therapy. Finally, based on the investigated literature, the current challenges and future directions for clinical translation are reasonably discussed, focusing on the innovative design of MNPs and further elucidation of pharmacokinetics. This paper is a timely and comprehensive and detailed study of the progress of MNPs in tumor therapy, especially PTT, and provides ideas for the design of personalized and customizable oncology nanomedicines to address the heterogeneity of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

The present research work describes development of dual drug‐loaded lipid–polymer hybrid nanoparticles (LPHNPs) of anticancer therapeutics for the management of colon cancer. The epidermal growth factor (EGF)‐functionalized LPHNPs coloaded with 5‐fluorouracil (FU) and sulforaphane (SFN) were prepared by one‐step nanoprecipitation method. Box–Behnken design was applied for optimizing the material attributes and process parameters. The optimized LPHNPs revealed particle size 198 nm, polydispersity index 0.3, zeta potential −25.3 mV, and drug loading efficiency 19–20.3% for 5‐FU and SFN, respectively. EGF functionalization on LPHNPs was confirmed from positive magnitude of zeta potential to 21.3 mV as compared with the plain LPHNPs. In vitro drug release performance indicated sustained and non‐Fickian mechanism release nature of the drugs from LPHNPs. Anticancer activity evaluation in HCT‐15 colon cancer cells showed significant reduction (p < 0.001) in the cell growth and cytotoxicity of the investigated drugs from various treatments in the order: EGF‐functionalized LPHNPs > plain LPHNPs > free drug suspensions. Overall, the research work corroborated improved treatment efficacy of EGF‐functionalized LPHNPs for delivering chemotherapeutic agents for the management of colon carcinoma. [ABSTRACT FROM AUTHOR]

Junctophilins (JPHs) comprise a family of structural proteins that connect the plasma membrane to intracellular organelles such as the endo/sarcoplasmic reticulum (ER/SR). Tethering of these membrane structures results in the formation of highly organized subcellular junctions that play important signaling roles in all excitable cell types. There are four JPH isoforms, expressed primarily in muscle and neuronal cell types. Each JPH protein consists of six membrane occupation and recognition nexus (MORN) motifs, a joining region connecting these to another set of two MORN motifs, a putative alpha-helical region, a divergent region exhibiting low homology between JPH isoforms, and a carboxy-terminal transmembrane region anchoring into the ER/SR membrane. JPH isoforms play essential roles in developing and maintaining subcellular membrane junctions. Conversely, inherited mutations in JPH2 cause hypertrophic or dilated cardiomyopathy, while trinucleotide expansions in the JPH3 gene cause Huntington Disease-Like 2. Loss of JPH1 protein levels can cause skeletal myopathy, while loss of cardiac JPH2 levels causes heart failure and atrial fibrillation, among other disease. This review will provide a comprehensive overview of the JPH gene family, phylogeny, and evolutionary analysis of JPH genes and other MORN domain proteins. JPH biogenesis, membrane tethering, and binding partners will be discussed, as well as functional roles of JPH isoforms in excitable cells. Finally, potential roles of JPH isoform deficits in human disease pathogenesis will be reviewed. [ABSTRACT FROM AUTHOR]

The mini‐emulsion polymerization of polystyrene–titanium dioxide (PS/TiO2) hybrid antibacterial material was carried out. Triethylene glycol dimethacrylate (TEGDMA) was used, as a crosslinking agent, to enhance the stability, the encapsulation efficiency of TiO2, the self‐organized structure of the nanoparticles and photocatalytic behavior. The particle size and morphology as well as the photocatalytic properties of the polymer hybrids were characterized by dynamic light scattering, field emission SEM and UV–visible spectroscopy. The results showed that the average particle size of PS/TiO2 hybrids was in the range 98–242 nm with a narrow size distribution. The results of field emission SEM demonstrated the raspberry‐like self‐organized hexagonal structure of the polymer hybrids in the presence of TEGDMA. The morphology and structure of the PS/TiO2 hybrid were observed using high resolution TEM. The results show that the PS and PS/TiO2 hybrids have a well‐defined structure. Energy‐dispersive X‐ray spectroscopy was used to confirm that PS/TiO2 hybrid contains elemental titanium. It was noticed that the elemental analysis of Ti and O was 8.03 wt% (2.9 at%) and 7.97 wt% (6.5 at%), respectively. It should be emphasized that the results of high resolution TEM and energy‐dispersive X‐ray spectroscopy are considered excellent proof for the formation of PS/TiO2 hybrid. The thermal properties of PS and the hybrids with TiO2 were explored by DSC. It was found that the presence of TEGDMA in the system may reduce the glass transition temperature (Tg) of the polymer hybrids. XRD confirmed the formation of PS/TiO2 hybrids and the antibacterial activity was also investigated. An escalation of intensity in the XRD pattern of the TiO2 signals in the PS/TiO2 hybrids was observed. The antibacterial activity study noted that the PS/TiO2 hybrid demonstrated excellent antifungal and antibacterial properties against a broad range of both Gram‐positive (Staphylococcus aureus) and Gram‐negative (Klebsiella pneumoniae) bacteria. The photocatalytic efficiency of PS/TiO2 was assessed by monitoring the discoloration of an organic dye (methylene blue) under UVA irradiation. It indicated that the photocatalysis of PS/TiO2 in the presence of TEGDMA was increased due to the association of TEGDMA in the self‐organization structure of the hybrid system. © 2021 Society of Industrial Chemistry. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is a chronic neurological disease in which demyelination and loss of axons lead to disruption of communication between neurons in the central nervous system. Cognitive impairment occurs in a significant proportion of patients with MS. Therefore, the aim of this study was to investigate the relationship between retinal nerve fiber layer (RNFL) thickness and corpus callosum atrophy in magnetic resonance imaging with memory disorders in patients with MS. Methods: This descriptive analytical study was performed on patients with a diagnosis of relapsing–remitting multiple sclerosis referred to the clinic of Ali Ibn Abi Talib Hospital in Zahedan, Iran. An information form that includes a Mini–Mental State Examination was first prepared, by which the patient's memory impairment is measured. After recording the data, the data were collected using an information form and finally analyzed by SPSS software version 22 using an independent t-test. Results: In this study, 80 patients with MS primary progressive multiple sclerosis were included in the study, of which 53 were female and 27 were male. The mean age of patients was 45.1 ± 5.9 years, which did not show a statistically significant difference (P = 0.536). The mean RNFL thickness in patients with memory impairment was significantly lower than that in patients without memory impairment. The mean corpus callosum thickness was found to be significantly lower in patients with memory impairment than in patients without memory impairment. Conclusion: All in all, the results of this study showed that the thickness of RNFL and the corpus callosum in patients with memory impairment was significantly lower than that in patients without memory impairment. [ABSTRACT FROM AUTHOR]

Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates aging and neurodegeneration with anomalous neuronal metabolism as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress, and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer's disease (AD).Objective: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM).Methods: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs.Results: Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed.Conclusion: This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the brain, along with profound alterations in phosphorylation-related events and regulatory pathways. The production of the neurotoxic Aβ peptide via amyloid precursor protein (APP) proteolysis is a crucial step in AD development. APP is highly expressed in the brain and is complexly metabolized by a series of sequential secretases, commonly denoted the α-, β-, and γ-cleavages. The toxicity of resulting fragments is a direct consequence of the first cleaving event. β-secretase (BACE1) induces amyloidogenic cleavages, while α-secretases (ADAM10 and ADAM17) result in less pathological peptides. Hence this first cleavage event is a prime therapeutic target for preventing or reverting initial biochemical events involved in AD. The subsequent cleavage by γ-secretase has a reduced impact on Aβ formation but affects the peptides’ aggregating capacity. An array of therapeutic strategies are being explored, among them targeting Retinoic Acid (RA) signalling, which has long been associated with neuronal health. Additionally, several studies have described altered RA levels in AD patients, reinforcing RA Receptor (RAR) signalling as a promising therapeutic strategy. In this review we provide a holistic approach focussing on the effects of isoform-specific RAR modulation with respect to APP secretases and discuss its advantages and drawbacks in subcellular AD related events. [ABSTRACT FROM AUTHOR]

Genetic medicines hold great promise for treatment of a number of diseases; however, the development of effective gene delivery carrier is still a challenge. The commonly used gene carrier liposomes and cationic polymers have limited their clinical application due to their respective disadvantages. Lipid–polymer hybrid nanoparticles (LHNPs) are novel drug delivery system that exhibit complementary characteristics of both polymeric nanoparticles and liposomes. In this account, we developed the α-cyclodextrin-conjugated generation-2 polyamidoamine dendrimers–lipids hybrid nanoparticles (CDG2-LHNPs) for gene delivery. The pDNA/CDG2-LHNPs was stable during 15 days of storage period both at 4 °C, 25 °C, and 37 °C, whereas the particle size of pDNA/CDG2 and pDNA/liposomes dramatically increased after storage at 4 °C for 8 h. CDG2-LHNPs showed significantly superior transfection efficiencies compared to either CDG2 or liposomes. The mechanism of high transfection efficiency of pDNA/CDG2-LHNPs was further explored using pharmacological inhibitors chlorpromazine, filipin, and cytochalasion D. The result demonstrated that cell uptake of pDNA/CDG2-LHNPs was mediated by clathrin-mediated endocytosis (CME), caveolae-mediated endocytosis (CvME), and macropinocytosis together. pDNA/CDG2-LHNPs were more likely be taken up by cells through CvME, which avoided lysosomal degradation to a large extent. Moreover, the liposome component of pDNA/CDG2-LHNPs increased its cell uptake efficiency, and the CDG2 polymer component increased its proton buffer capacity, so the hybrid nanoparticles taken up by CME could also successfully escape from the lysosome. CDG2-LHNPs with stability and high-transfection efficiency overcome the shortcomings of liposomes and polymers applied separately, and have great potential for gene drug delivery. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-β (Aβ) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-β protein precursor (AβPP) through the successive cleaving by β-site AβPP-cleavage enzyme 1 (BACE1) and γ-secretase. AβPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AβPP. In the recent years, about 10 phosphorylation sites of AβPP were identified, and they play complex roles in glycosylation modification and cleavage of AβPP. In this article, we introduced the transport and the cleavage pathways of AβPP, then summarized the phosphorylation and glycosylation sites of AβPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AβPP trafficking and cleavage in order to provide theoretical basis for AD research. [ABSTRACT FROM AUTHOR]

BRI2 is a type II transmembrane protein ubiquitously expressed whose physiological function remains poorly understood. Although several recent important advances have substantially impacted on our understanding of BRI2 biology and function, providing valuable information for further studies on BRI2. These findings have contributed to a better understanding of BRI2 biology and the underlying signaling pathways involved. In turn, these might provide novel insights with respect to neurodegeneration processes inherent to BRI2-related pathologies, namely Familial British and Danish dementias, Alzheimer's disease, ITM2B-related retinal dystrophy, and multiple sclerosis. In this review, we provided a state-of-the-art outline of BRI2 biology, both in physiological and pathological conditions, and discuss the proposed molecular underlying mechanisms. Overall, the BRI2 knowledge here reviewed is of extreme importance and may contribute to propose BRI2 and/or BRI2 proteolytic fragments as novel therapeutic targets for neurodegenerative diseases, such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Hybrid systems of nanoparticles and polymers have emerged as a new material in the biomedical field. To date, various kinds of hybrid systems have been introduced and applied to drug delivery, regenerative medicine, therapeutics, disease diagnosis, and medical implantation. Among them, the hybridization of nanostructured porous silicon nanoparticles (pSiNPs) and biocompatible polymers has been highlighted due to its unique biological and physicochemical properties. This review focuses on the recent advances in the hybrid systems of pSiNPs and biocompatible polymers from an engineering aspect and its biomedical applications. Representative hybrid formulations, (i) Polymer-coated pSiNPs, (ii) pSiNPs-embedded polymeric nanofibers, are outlined along with their preparation methods, biomedical applications, and future perspectives. We believe this review provides insight into a new hybrid system of pSiNPs and biocompatible polymers as a promising nano-platform for further biomedical applications. Recently developed and representative hybrid systems of porous silicon nanoparticles and biocompatible polymers and their biomedical applications are introduced. [ABSTRACT FROM AUTHOR]

Background: The relationship between visual impairment and cognitive performance in multiple sclerosis (MS) remains poorly understood. Objective: To determine associations between visual acuity and optical coherence tomography (OCT) measures with cognitive performance of MS patients and healthy controls (HCs). Methods: 141 MS patients (with and without MS optic neuritis; MSON) and 50 HCs underwent neuropsychological, visual, and OCT testing. California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test (BVMT-R), and Symbol Digit Modalities Test (SDMT) were used. Patients with test performance below − 1.5 standard deviations of the mean HCs scores were labeled as cognitive impairment. Visual ability was assessed with 100%, 2.5%, and 1.25% low-contrast letter acuity (LCLA) charts. OCT-derived peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume (MV), macular ganglion cell inner plexiform (mGCIP) thickness (as a sum of GC and IP layers), and macular inner nuclear layer (mINL) were computed. Results: 100% and 2.5% LCLA associated with SDMT in MS and HCs (p < 0.001; and p < 0.012, respectively). In MSON patients, visually demanding tests were explained by pRNFL and macular volume for SDMT (β = 0.172, p = 0.039 and β = 0.27, p = 0.001) and MV for BVMT-R (β = 0.21, p = 0.012). In non-MSON, only mINL was predictor of CVLT-II. pRNFL and MV predicted cognitive impairment with an accuracy of 72.2% (Negelkerke R2 = 0.234). These findings were driven by associations within the progressive MS subgroup. HC's SDMT performance was explained by mGCIP (β = 0.316, p = 0.001). Conclusions: Both LCLA and OCT-based measures (pRNFL and macular volume) were associated with MS cognitive performance. OCT-based measures were also significant predictors of cognitive status in MS patients. mGCIP associated with cognitive performance in HCs. [ABSTRACT FROM AUTHOR]

The nuclear envelope (NE) separates the nucleus from the cytoplasm in all eukaryotic cells. A disruption of the NE structure compromises normal gene regulation and leads to severe human disorders collectively classified as nuclear envelopathies and affecting skeletal muscle, heart, brain, skin, and bones. The ubiquitous NE component LAP1B is encoded by TOR1AIP1, and the use of an alternative start codon gives rise to the shorter LAP1C isoform. TOR1AIP1 mutations have been identified in patients with diverging clinical presentations such as muscular dystrophy, progressive dystonia with cerebellar atrophy, and a severe multi-systemic disorder, but the correlation between the mutational effect and the clinical spectrum remains to be determined. Here, we describe a novel TOR1AIP1 patient manifesting childhood-onset muscle weakness and contractures, and we provide clinical, histological, ultrastructural, and genetic data. We demonstrate that the identified TOR1AIP1 frameshift mutation leads to the selective loss of the LAP1B isoform, while the expression of LAP1C was preserved. Through comparative review of all previously reported TOR1AIP1 cases, we delineate a genotype/phenotype correlation and conclude that LAP1B-specific mutations cause a progressive skeletal muscle phenotype, while mutations involving a loss of both LAP1B and LAP1C isoforms induce a syndromic disorder affecting skeletal muscle, brain, eyes, ear, skin, and bones. [ABSTRACT FROM AUTHOR]

The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer's disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are well-described neurotrophic and neuromodulator EGFR ligands, both implicated in neurological disorders, including AD. Pro-HB-EGF arose as a putative novel APP interactor in a human brain cDNA library yeast two-hybrid screen. Based on their structural and functional similarities, we first aimed to verify if APP could bind to (HB-)EGF proforms. Here, we show that APP interacts with these two EGFR ligands, and further characterized the effects of APP-EGF interaction in ERK activation and neuritogenesis. Yeast co-transformation and co-immunoprecipitation assays confirmed APP interaction with HB-EGF. Co-immunoprecipitation also revealed that APP binds to cellular pro-EGF. Overexpression of HB-EGF in HeLa cells, or exposure of SH-SY5Y cells to EGF, both resulted in increased APP protein levels. EGF and APP were observed to synergistically activate the ERK pathway, crucial for neuronal differentiation. Immunofluorescence analysis of cellular neuritogenesis in APP overexpression and EGF exposure conditions confirmed a synergistic effect in promoting the number and the mean length of neurite-like processes. Synergistic ERK activation and neuritogenic effects were completely blocked by the EGFR inhibitor PD 168393, implying APP/EGF-induced activation of EGFR as part of the mechanism. This work shows novel APP protein interactors and provides a major insight into the APP/EGF-driven mechanisms underlying neurite outgrowth and neuronal differentiation, with potential relevance for AD and for adult neuroregeneration. [ABSTRACT FROM AUTHOR]

The purpose of this research is to predict the cognitive impairment and to determine its correlation with retinal thickness, mainly (RFNL and GCIPL) in cases of multiple sclerosis. 60 multiple sclerosis patients and 30 age and sex-matched healthy controls were included in this study. Cognitive functions were evaluated in all study participants by the Montreal Cognitive Assessment (MoCA). OCT imaging was done to determine the thickness. The correlation between the cognitive domains of MoCA and the thickness of the retinal nerve fiber layers was analyzed by Spearman correlation. ROC curve was constructed to determine the cut-off points for retinal thickness, and a binary logistic regression was performed to determine the independent predictive capacity of established cut-off points. Impaired cognition was found in 26 MS patients (43.3%). Cognitively impaired patients were significantly older (P < 0.05), had significantly longer disease duration (P < 0.05), had higher average EDSS scores (4.3 ± 1.22 vs 3.1 ± 1.45, P < 0.001), and occurred more in progressive types of MS (P < 0.001). A significant positive correlation was found between cognitive function and RNFL thickness and GCIPL (P < 0.001). The retinal thickness (RNFL and GCIPL) cut-off points established for the prediction of cognitive impairment in MS patients were 79 μm and 76 μm, respectively. The clear correlation between cognitive impairment and atrophy of inner retinal layers (RNFL and GCIPL) proposes that OCT is valuable in evaluating the neurodegeneration and prediction of early cognitive impairment in MS. EDSS: Expanded Disability Status Scale; HCs: Healthy controls; GCIPL: Ganglion cell–inner plexiform layer; ILM: Internal limiting membrane; INL: Inner nuclear layer; MoCA: Montreal Cognitive Assessment; MS: Multiple sclerosis; PPMS: Primary progressive multiple sclerosis; RNFL: Retinal nerve fiber layer; RRMS: Relapsing-remitting multiple sclerosis; SD: Standard deviations; SPMS: Secondary progressive multiple sclerosis; SPSS: Statistical Package for the Social Sciences. [ABSTRACT FROM AUTHOR]

The essential and distinct functions of Protein Phosphatase type 1 (PP1) catalytic subunit in eukaryotes are exclusively achieved through its interaction with a myriad of regulatory partners. In this work, we report the molecular and functional characterization of Gametocyte EXported Protein 15 (GEXP15), a Plasmodium specific protein, as a regulator of PP1. In vitro interaction studies demonstrated that GEXP15 physically interacts with PP1 through the RVxF binding motif in P. berghei. Functional assays showed that GEXP15 was able to increase PP1 activity and the mutation of the RVxF motif completely abolished this regulation. Immunoprecipitation assays of tagged GEXP15 or PP1 in P. berghei followed by immunoblot or mass spectrometry analyses confirmed their interaction and showed that they are present both in schizont and gametocyte stages in shared protein complexes involved in the spliceosome and proteasome pathways and known to play essential role in parasite development. Phenotypic analysis of viable GEXP15 deficient P. berghei blood parasites showed that they were unable to develop lethal infection in BALB/c mice or to establish experimental cerebral malaria in C57BL/6 mice. Further, although deficient parasites produced gametocytes they did not produce any oocysts/sporozoites indicating a high fitness cost in the mosquito. Global proteomic and phosphoproteomic analyses of GEXP15 deficient schizonts revealed a profound defect with a significant decrease in the abundance and an impact on phosphorylation status of proteins involved in regulation of gene expression or invasion. Moreover, depletion of GEXP15 seemed to impact mainly the abundance of some specific proteins of female gametocytes. Our study provides the first insight into the contribution of a PP1 regulator to Plasmodium virulence and suggests that GEXP15 affects both the asexual and sexual life cycle. [ABSTRACT FROM AUTHOR]

Cognitive impairment has been reported at all phases and all subtypes of multiple sclerosis. It remains a major cause of neurological disability in young and middle-aged adults suffering from the disease. The severity and type of cognitive impairment varies considerably among individuals and can be observed both in early and in later stages. The areas which have commonly shown more deficits are: information processing speed, complex attention, memory, and executive function. Even though an alteration in both the white matter and in the gray matter has been found in patients with multiple sclerosis and cognitive impairment, the underlying process still remains unknown. Standardized neurological examinations fail to detect emerging cognitive deficits and self-reported cognitive complaints by the patients can be confounded by other subjective symptoms. This review is a comprehensive and short update of the literature on cognitive dysfunctions, the possible confounders and the impact of quality of life in patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Ghrelin, an orexigenic gut-derived peptide, is gaining increasing attention due to its multifaceted role in a number of physiological functions, including reproduction. Ghrelin exists in circulation primarily as des-acylated and acylated ghrelin. Des-acyl ghrelin, until recently considered to be an inactive form of ghrelin, is now known to have independent physiological functionality. However, the relative contribution of acyl and des-acyl ghrelin to reproductive development and function is currently unknown. Here we used ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no measurable levels of endogenous acyl ghrelin and chronically high levels of des-acyl ghrelin, to characterize how the developmental and life-long absence of acyl ghrelin affects ovarian development and reproductive capacity. We combined the assessment of markers of reproductive maturity and the capacity to breed with measures of ovarian morphometry, as well as with ovarian RNA sequencing analysis. Our data show that while GOAT KO mice retain the capacity to breed in young adulthood, there is a diminished number of ovarian follicles (per mm3) in the juvenile and adult ovaries, due to a significant reduction in the number of small follicles, particularly the primordial follicles. We also show pronounced specific changes in the ovarian transcriptome in the juvenile GOAT KO ovary, indicative of a potential for premature ovarian development. Collectively, these findings indicate that an absence of acyl ghrelin does not prevent reproductive success but that appropriate levels of acyl and des-acyl ghrelin may be necessary for optimal ovarian maturation. [ABSTRACT FROM AUTHOR]

Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af-derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene which encodes the deubiquitinating enzyme, ATXN3. Several mechanisms have been proposed to explain the pathogenic role of mutant, polyQ-expanded ATXN3 in SCA3 including disease protein aggregation, impairment of ubiquitin-proteasomal degradation and transcriptional dysregulation. A better understanding of the normal functions of this protein may shed light on SCA3 disease pathogenesis. To assess the potential normal role of ATXN3 in regulating gene expression, we compared transcriptional profiles in WT versus Atxn3 null mouse embryonic fibroblasts. Differentially expressed genes in the absence of ATXN3 contribute to multiple signal transduction pathways, suggesting a status switch of signaling pathways including depressed Wnt and BMP4 pathways and elevated growth factor pathways such as Prolactin, TGF-β, and Ephrin pathways. The Eph receptor A3 (Efna3), a receptor protein-tyrosine kinase in the Ephrin pathway that is highly expressed in the nervous system, was the most differentially upregulated gene in Atxn3 null MEFs. This increased expression of Efna3 was recapitulated in Atxn3 knockout mouse brainstem, a selectively vulnerable brain region in SCA3. Overexpression of normal or expanded ATXN3 was sufficient to repress Efna3 expression, supporting a role for ATXN3 in regulating Ephrin signaling. We further show that, in the absence of ATXN3, Efna3 upregulation is associated with hyperacetylation of histones H3 and H4 at the Efna3 promoter, which in turn is induced by decreased levels of HDAC3 and NCoR in ATXN3 null cells. Together, these results reveal a normal role for ATXN3 in transcriptional regulation of multiple signaling pathways of potential relevance to disease processes in SCA3. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS). Objective: To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS. Methods: Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement. Results: The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p≤0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (β≤-0.34, p≤0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (β≤-0.29, p≤0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (ß≥0.29, p≤0.032). Anxiety was associated with lower white matter volume (ß = -0.25, p = 0.045). Conclusion: Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS. [ABSTRACT FROM AUTHOR]

In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective. [ABSTRACT FROM AUTHOR]