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• The effect of age and dopamine application on working memory and LTP was studied in young and mature adult mice. • Maturation from young adult to mature adult had no effect on working memory. • Working memory increased following administration of dopamine only in mature adult subjects. • There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. • Applying dopamine on slices from mature adults increased LTP magnitude compared slices from young adults. Normal aging in mammals is accompanied by a decline in learning and memory. Dopamine plays a vital role in regulating cognitive functions, but it declines with age: During non-pathological aging, dopamine levels, receptors, and transporters decrease. Regarding the role of the dopaminergic system's changes in old age, we examined the effect of age and applied dopamine on working memory, synaptic transmission, and long-term potentiation (LTP) induction and maintenance in young adult and mature adult mice. We employed the Y-maze spontaneous alteration test to evaluate working memory. Maturation had no observed effect on working memory performance. Interestingly, working memory performance increased following intracerebroventricular administration of dopamine only in mature adult mice. We employed evoked field potential recording (in vitro) to assess the effects of age and maturation on the long-term potentiation (LTP) induction and maintenance. There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. However, the application of dopamine on mature adult murine slices increased LTP magnitude compared to slices from young adults. According to the obtained results, it may be concluded that hippocampal neural excitability increased in mature adult subjects, and application of dopamine abolished the difference in neural excitability among young mature and adult mature groups; which was accompanied with increment of working memory and synaptic potentiation in mature adult animals. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. [ABSTRACT FROM AUTHOR]

The relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) is so strong that scientists called it "brain diabetes". According to several studies, the critical factor in this relationship is brain insulin resistance. Due to the rapid global spread of both diseases, overcoming this cross-talk has a significant impact on societies. Long non-coding RNAs (lncRNAs), on the other hand, have a substantial impact on complex diseases due to their ability to influence gene expression via a variety of mechanisms. Consequently, the regulation of lncRNA expression in chronic diseases permits the development of innovative therapeutic techniques. However, developing a new drug requires considerable time and money. Recently repurposing existing drugs has gained popularity due to the use of low-risk compounds, which may result in cost and time savings. in this study, we identified drug repurposing candidates capable of controlling the expression of common lncRNAs in the cross-talk between DM and AD. We also utilized drugs that interfered with this cross-talk. To do this, high degree common lncRNAs were extracted from microRNA-lncRNA bipartite network. The drugs that interact with the specified lncRNAs were then collected from multiple data sources. These drugs, referred to as set D, were classified in to positive (D+) and negative (D−) groups based on their effects on the expression of the interacting lncRNAs. A feature selection algorithm was used to select six important features for D. Using a random forest classifier, these features were capable of classifying D+ and D− with an accuracy of 82.5%. Finally, the same six features were extracted for the most recently Food and Drug Administration (FDA) approved drugs in order to identify those with the highest likelihood of belonging to D+ or D−. The most significant FDA-approved positive drugs, chromium nicotinate and tapentadol, were presented as repurposing candidates, while cefepime and dihydro-alpha-ergocryptine were recommended as significant adverse drugs. Moreover, two natural compounds, curcumin and quercetin, were recommended to prevent this cross-talk. According to the previous studies, less attention has been paid to the role of lncRNAs in this cross-talk. Our research not only did identify important lncRNAs, but it also suggested potential repurposed drugs to control them. [ABSTRACT FROM AUTHOR]

The Wnt pathway is the most important cascade in the nervous system; evidence has indicated that deregulation of the Wnt pathway induced pathogenic hallmarks of neurodegenerative diseases. Glycogen synthase kinase‐3β (GSK‐3β) as the main member of the Wnt pathway increases tau inclusions, the main marker in the neurodegenerative diseases. Phosphorylated tau is observed in the pre‐tangle of the neurons in the early stage of neurodegenerative diseases. The researchers always try to improve pharmacological approaches of new therapeutic strategies to the treatment of neurodegenerative diseases that are required to represent a significant entry point by understanding the theoretical interactions of the molecular pathways. In this review, we have discussed the recent knowledge about the canonical and non‐canonical Wnt signalling pathway, GSK‐3β, Wnt/β‐catenin antagonists, tau phosphorylation, and their important roles in the neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive brain disorder characterized by the ongoing decline of brain functions. Studies have revealed the detrimental effects of hyperphosphorylated tau (p-tau) protein fibrils in AD pathogenesis, highlighting the importance of this factor in the early-stage detection of AD conditions. We designed an electrochemical immunosensor for quantitative detection of the cis conformation of the p-tau protein (cis-p-tau) employing platinum nanoparticles (Pt NPs) supported on zeolitic imidazolate frameworks (ZIF) for modifying the glassy carbon electrode (GCE) surface. Under optimum conditions, the immunosensor selectively and sensitively detected cis-p-tau within the broad linear range of 1 fg mL−1 to 10 ng mL−1 and the low limit of detection (LOD) of 1 fg mL−1 with desired reproducibility and stability. Furthermore, the fabricated immunosensor's performance was examined for the cis-p-tau analysis in the serum of AD patients, indicating its accuracy and feasibility for real-sample analysis. Notably, this is the first application of Pt@ZIF-8 nanocomposite in fabricating a valid immunosensor for selective cis-p-tau detection, even in the presence of trans-p-tau. It is worth mentioning that the enzyme-linked immunosorbent assay (ELISA) reference technique is not able to evaluate pico- or femtomolar concentrations of cis-p-tau, making the fabricated immunosensor superior for early-stage measurement and screening of AD. [ABSTRACT FROM AUTHOR]

Diabetes mellitus may cause tau protein hyperphosphorylation and neurodegeneration, but the exact mechanism by which diabetic conditions induce tau pathology remains unclear. Tau protein hyperphosphorylation is considered a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau‐directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed different techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in in vivo and in vitro models. We showed that diabetes‐related stresses and glucose metabolism deficiency could induce cis P‐tau (an early driver of the tau pathology) accumulation in the midbrain and corpus callosum of the diabetic mice models and cells treated with 2‐deoxy‐D‐glucose, respectively. We found that the active phosphorylated level of P38 was increased in the treated cells and diabetic mice models. We observed that oxidative stress activated P38, which directly and indirectly drove tau pathology in the GABAergic and glutamatergic neurons of the midbrain of the diabetic mice after 96 h, which accumulated in the other neighboring brain areas after 2 months. Notably, P38 inhibition suppressed tau pathogenicity and risk‐taking behaviors in the animal models after 96 h. The data establish P38 as a central mediator of diabetes mellitus‐induced tau pathology. Our findings provide mechanistic insight into the consequences of this metabolic disorder on the nervous system. [ABSTRACT FROM AUTHOR]

Background: One of the environmental factors leading to Alzheimer's disease (AD) is traumatic brain injury (TBI). Meanwhile, tau protein hyperphosphorylation is known as one of the mechanisms of AD development. In the present study, the effect of Rosa damascena and Ginkgo biloba aqueous extracts on tau hyperphosphorylation was studied on SH-SY5Y cell lines and mouse TBI models. Methods: Tau protein hyperphosphorylation was induced in SH-SY5Y cells using 10 μM retinoic acid (RA). Then, cells were treated with 500 and 1000 μg/ml aqueous extracts of Rosa damascena and Ginkgo biloba. Cell viability was studied by MTT test and tau protein hyperphosphorylation was studied by western blot and immunostaining techniques. Also, after the induction of TBI by pneumatic cylinder, mice were treated with 500 and 1000 μg/ml aqueous extracts of Rosa damascena and Ginkgo biloba, and the animals were tested for beam balance and walk tests to measure balance and muscle stiffness. Finally, tau protein hyperphosphorylation in the brain was investigated using an immunostaining technique. Results: Both aqueous extracts of Rosa damascena and Ginkgo biloba were able to improve SH-SY5Y viability. Also, a decrease in phosphorylated tau protein was observed in cells treated with aqueous extracts of Rosa damascena and Ginkgo biloba. Performance improvements in beam balance and walk tests in TBI mice treated with 1000 μg/ml Rosa damascena and Ginkgo biloba aqueous extracts were seen. Also, tau protein phosphorylation was significantly decreased in the brain of TBI rats treated with those aqueous extracts. Conclusion: aqueous extracts of Rosa damascena and Ginkgo biloba have neuroprotective effects and are beneficial in reducing TBI-induced tau protein hyperphosphorylation, and they can prevent tau pathology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets. [ABSTRACT FROM AUTHOR]

• Tauopathies are neurodegenerative diseases specified by pathological tau deposits. • Phosphorylation of tau in tauopathy is analyzed by Phos-tag phosphoaffinity SDS-PAGE. • Tauopathies show disease-specific phosphorylation profiles of tau. • Site-specific phosphorylation is different among tauopathies. • Neurotoxic cis conformation of tau at pT231 is increased in AD and AGD patients. Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aβ oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aβ1–42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aβ accumulation. Furthermore, adult male rats received Aβ1–42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aβ1–42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aβ administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aβ oligomers in the cortex and CA1 only. Our findings indicate that Aβ1–42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α‐Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α‐synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Also, we studied dopaminergic neurons of cytokine Interferon‐β knock‐out. Moreover, we examined rats treated with 6‐hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post‐mortem brains. We found the α‐synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α‐synuclein with prion‐like nature in various brain areas. We optionally removed P‐tau or P‐α‐synuclein from cytokine interferon‐β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α‐synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder. [ABSTRACT FROM AUTHOR]

Background: Retinal and/or optic nerve injury is one of the leading causes of blindness due to retinal ganglion cell (RGC) degeneration. There have been extensive efforts to suppress this neurodegeneration. Various somatic tissue-derived mesenchymal stem cells (MSCs) demonstrated significant neuroprotective and axogenic effects on RGCs. An alternative source of MSCs could be human embryonic stem cells (ES-MSCs), which proliferate faster, express lower levels of inflammatory cytokines, and are capable of immune modulation. It has been demonstrated that MSCs secrete factors or extracellular vesicles that may heal the injury. However, possible therapeutic effects and underlying mechanism of human ES-MSC extracellular vesicles (EVs) on optic nerve injury have not been assessed. Methods: EVs were isolated from human ES-MSCs. Then, ES-MSC EV was applied to an optic nerve crush (ONC) mouse model. Immunohistofluorescence, retro- and anterograde tracing of RGCs, Western blot, tauopathy in RGCs, and function assessments were performed during 2-month post-treatment to evaluate ONC improvement and underlying mechanism of human ES-MSC EV in in vivo. Results: We found that the ES-MSC EV significantly improved Brn3a+ RGCs survival and retro- and anterograde tracing of RGCs, while preventing retinal nerve fiber layer (RNFL) degenerative thinning compared to the vehicle group. The EVs also significantly promoted GAP43+ axon counts in the optic nerve and improved cognitive visual behavior. Furthermore, cis p-tau, a central mediator of neurodegeneration in the injured RGCs, is detectable after the ONC at the early stages demonstrated tauopathy in RGCs. Notably, after EV treatment cis p-tau was downregulated. Conclusions: Our findings propose that human ES-MSC EVs, as an off-the-shelf and cell-free product, may have profound clinical implications in treating injured RGCs and degenerative ocular disease. Moreover, the possible mechanisms of human ES-MSC EV are related to the rescue of tauopathy process of RGC degeneration. [ABSTRACT FROM AUTHOR]

Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr–Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM. DM is a major metabolic disorder that may result in neurodegeneration. Disrupted insulin signaling pathway or glucose metabolism deficiency can induce τ hyperphosphorylation. τ is a microtubule-associated protein. It is moderately phosphorylated under physiological conditions but its hyperphosphorylation reflects pathogenicity and is a major pathological hallmark of neurodegeneration. Phosphorylated τ at Thr231 exists in the two distinct cis and trans conformations. cis p-τ is neurotoxic and drives neurodegeneration. cis p-τ is accumulated in cultured neurons upon oxidative stress as well as nutrition depletion. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major risk factor for disabilities globally with no effective treatment thus far. Recently, homogenous population of clonal mesenchymal stem cells (cMSC) and their derived extracellular vesicles (cMSC-EVs) have been proposed as a promising TBI treatment strategy. We herein investigated possible therapeutic effect of cMSC-EVs in TBI treatment and the underlying mechanisms considering cis p-tau as an early hallmark of TBI. We examined the EVs morphology, size distribution, marker expression, and uptake. Moreover, the EVs neuroprotective effects were studied in both in-vitro and in-vivo model. We also examined the anti- cis p-tau antibody-loading characteristics of the EVs. We treated TBI mouse model with EVs; prepared from cMSC-conditioned media. TBI mice were given cMSC-EVs intravenously and their cognitive functions were analyzed two months of the treatment. We employed immunoblot analysis to study the underlying molecular mechanisms. We observed a profound cMSC-EVs uptake by primary cultured neurons. We found a remarkable neuroprotective effect of cMSC-EVs upon nutritional deprivation stress. Furthermore, cMSC-EVs were effectively loaded with an anti- cis p-tau antibody. There was a significant improvement in cognitive function in TBI animal models treated with cMSC-EVs compared to the saline-treated group. There was a decreased cis p-tau and cleaved caspase3 as well as increased p-PI3K in all treated animals. The results revealed that cMSC-EVs efficiently improved animal behaviors after TBI by reducing cistauosis and apoptosis. Moreover, the EVs can be employed as an effective strategy for antibody delivery during passive immunotherapy. • Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) improved behavioral recovery after traumatic brain injury. • MSC-EVs reduced cistauosis and apoptosis after traumatic brain injury. • MSC-EVs ameliorated traumatic brain injury as effective as anti-cis p-tau antibody. [ABSTRACT FROM AUTHOR]

Abstract Herein, the thermodynamic parameters of tau upon interaction with NiO NPs were determined by fluorescence spectroscopy. Also, molecular docking studies were run to explore the binding affinities of NiO NPs clusters with different sizes of 30 Å and 50 Å toward tau. Also, cytotoxic activity of NiO NPs against SH-SY5Y was determined by MTT, LDH, caspase-9/3 activity, and expression of apoptotic Bax and Bcl-2 genes assays. DLS study showed that NiO solution had a good colloidal stability. Fluorescence study revealed that K SV values were 2.95 ± 0.35 × 104, 3.31 ± 0.59 × 104 and 3.92 ± 0.65 × 104 at 298 K, 310 K and 315 K, respectively. Also, ∆ G° (kJ/mol), ∆ H° (kJ/mol) and T∆ S° (kJ/mol) values were − 13.27 ± 1.57, 1.98 ± 0.14, 15.25 ± 2.01, respectively at 298 K. Theoretical studies depicted that affinity of 5O3T segment toward NiO NP (30 Å) is higher than NiO NP (50 Å) and the proportion of Lys residues are higher in the docked pose of NiO NP (30 Å)/5O3T complex than NP (50 Å)/5O3T complex. Moreover, NiO NPs demonstrated a significant increase in the mortality of SH-SY5Y cells in an apoptotic manner. This study determined that NiO NPs may mediate the formation of electrostatic interactions with tau and induction of undesired harmful effects on neurons. [ABSTRACT FROM AUTHOR]

Abstract Nickel oxide nanoparticles (NiO NPs) have been used in the biological and medical sciences. However, their toxic effects against biological systems such as nervous system have not been well studied. Therefore, the adverse effect of NiO NPs on tau structure was investigated by fluorescence and CD spectroscopic methods as well as TEM study. Also, molecular dynamic study was run to extend the experimental data. Cytotoxic activity of NiO NPs against SH-SY5Y cell was determined by trypan blue exclusion, cell morphology, ROS, and apoptosis assays. ANS, Nile red, ThT assays and electron micrograph investigation revealed that NiO NPs can increase the hydrophobic portions of tau and induce the formation of amorphous tau aggregates. Far and near CD spectroscopic methods revealed that NiO NPs can change the secondary and tertiary structure of tau, respectively. Theoretical studies depicted that NiO NPs lead to folding of tau structure. In the cellular view, NiO NPs induced significant mortality and morphological effects against SH-SY5Y cells. NiO NPs also provided a significant impact on generating intracellular ROS and apoptosis induction. This study determined that NiO NPs could mediate the induction of some undesired effects on the nervous system. Highlights • NiO NPs increased the hydrophobic portions of tau. • NiO NPs induced the formation of amorphous tau aggregates. • NiO NPs induced significant mortality and morphological effects against SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Abstract Manganese oxide nanoparticles (Mn 2 O 3 NPs) have been widely used in the medical and biological applications. However, few studies have been undertaken to investigate the cytotoxicity of Mn 2 O 3 NPs against nervous system. Herein, we studied the toxicity of Mn 2 O 3 NPs against tau protein and neuroblastoma cells (SH-SY5Y) in vitro. Circular dichroism (CD) spectroscopy, fluorescence spectroscopy, molecular docking, and molecular dynamic studies were used to explore the conformational changes of protein. The cell-based experiments, such as viability, activation of caspases-3/9, apoptosis, and gene (Bax and Bcl-2) expression assays were performed in vitro. Spectroscopic methods and molecular dynamic studies revealed that Mn 2 O 3 NPs can fold the structure of tau toward a more packed structure. The Mn 2 O 3 NPs also decreased the cell viability in a dose-dependent manner. Indeed, caspase-3 and caspase-9 activation, Bax/Bcl-2 ratio elevation and apoptosis induction were observed after exposure of SH-SY5Y to Mn 2 O 3 NPs. In conclusion, tau folding and cytotoxicity against SH-SY5Y cells may be involved in adverse effects induced by Mn 2 O 3 NPs. [ABSTRACT FROM AUTHOR]

Abstract The application of nanomaterials in the healthy system may induce some neurodegenerative diseases initiated by tau folding and neuronal cell death. Herein, aluminium oxide nanoparticles (Al 2 O 3 NPs) were synthesized and characterized by XRD, TEM, DLS and zeta potential investigations. Afterwards, the interaction of Al 2 O 3 NPs with tau protein was investigated by fluorescence and CD spectroscopic methods. The molecular docking and molecular dynamic were also run to explore the binding site and conformational changes of tau after interaction with Al 2 O 3 cluster. Moreover, the MTT, LDH, caspase-9/-3 and flow cytometry assays were done to explore the Al 2 O 3 NPs-induced cytotoxicity against SH-SY5Y cells. It was revealed that Al 2 O 3 NPs bind to tau protein and form a static complex and fold the structure of tau toward a more packed structure. Molecular docking and molecular dynamic investigations revealed that NPs bind to the hydrophilic residues of the tau segments and promote some marginal structural folding of tau segment. The cellular assays displayed that Al 2 O 3 NPs can elicit cell mortality through membrane leakage, caspase-9/-3 activations, and induction of both apoptosis and necrosis. This data may indicate that NPs can induce some adverse effects on the biological systems. [ABSTRACT FROM AUTHOR]

The unique proline isomerase Pin1 is pivotal for protecting against age-dependent neurodegeneration in Alzheimer's disease (AD), with its inhibition providing a molecular link between tangle and plaque pathologies. Pin1 is oxidatively modified in human AD brains, but little is known about its regulatory mechanisms and pathological significance of such Pin1 modification. In this paper, our determination of crystal structures of oxidized Pin1 reveals a series of Pin1 oxidative modifications on Cys113 in a sequential fashion. Cys113 oxidization is further confirmed by generating antibodies specifically recognizing oxidized Cys113 of Pin1. Furthermore, Pin1 oxidation on Cys113 inactivates its catalytic activity in vitro , and Ala point substitution of Cys113 inactivates the ability of Pin1 to isomerize tau as well as to promote protein turnover of tau and APP. Moreover, redox regulation affects Pin1 subcellular localization and Pin1-mediated neuronal survival in response to hypoxia treatment. Importantly, Cys113-oxidized Pin1 is significantly increased in human AD brain comparing to age-matched controls. These results not only identify a novel Pin1 oxidation site to be the critical catalytic residue Cys113, but also provide a novel oxidative regulation mechanism for inhibiting Pin1 activity in AD. These results suggest that preventing Pin1 oxidization might help to reduce the risk of AD. [ABSTRACT FROM AUTHOR]

Purpose: Age-related macular degeneration (AMD) as the leading cause of central visual loss in the developed countries has extensive pathologic similarities with Alzheimer's disease (AD). Saitohin rs62063857 Q7 R polymorphism is associated with increased risk of AD though we decided to evaluate the possible association of this polymorphism with advanced AMD. Materials and Methods: 152 advanced AMD patients (134 wet AMD and 18 geographic atrophy) and 75 healthy controls included in this study. Cases and controls went through a standard ophthalmologic examination by a retinal specialist. Saitohin gene rs62063857 polymorphism determined by using PCR technique and restriction enzyme HinFI. To evaluate the differences between groups we used t-test, Chi-Squared and one-tailed Fisher exact test. Results: Distribution of genotypes was not significantly different between total AMD or wet AMD patients compared to that of controls (total AMD RR+QR: OR = 1.51, CI = 0.82–2.79, P =.12; wet AMD RR+QR: OR = 1.39, CI = 0.74–2.59, P =.19). The RR+QR genotypes were significantly higher in dry AMD group compared to that of controls (RR+QR: OR = 2.75, CI = 0.96–7.9, P =.05). Conclusion: Our results showed that although STH Q7 R polymorphism was not associated with wet AMD susceptibility it was significantly associated with geographic atrophy. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) have been widely used as anticancer and antibacterial agents. However, before their use in biomedical applications, some in vitro assays should be carried out to investigate their interaction with biological systems. The copper oxide NPs (CuO NPs) were synthesized by hydrothermal method and their interaction with human serum albumin (HSA), leukemia K562 cells and three strains of bacteria was explored by spectroscopic, docking, cellular, and antibacterial investigations. The TEM, DLS, XRD, FTIR, Raman, and UV–visible techniques revealed that synthesized CuO NPs provide a crystalline structure corresponding to CuO nanoclusters with good colloidal stability. Biothermodynamic studies showed that CuO NPs formed a static complex with HSA molecules through hydrogen bonds which was further confirmed by docking analysis. UV–Vis spectroscopy results exhibited that the melting temperature (Tm) of HSA was slightly changed in the presence of CuO NPs. Cellular studies displayed that CuO NPs selectively resulted in the mortality of K562 cells through cell membrane leakage, caspase-9 and -3 activation, and apoptosis. Finally, antibacterial assays depicted that CuO NPs can induce an inhibitory effect in the case of both Gram-negative and Gram-positive bacteria. In conclusion, this study may provide useful data regarding the protein binding and biomedical applications of NPs. • CuO NPs were synthesized by hydrothermal method. • CuO NPs formed a static complex with HSA molecules through hydrogen bonds. • Tm of HSA was slightly changed in the presence of CuO NPs. • CuO NPs selectively result in the mortality of K562 cells. • CuO NPs induced antibacterial effects aganist both Gram-negative and Gram-positive bacteria. [ABSTRACT FROM AUTHOR]

The interaction of nanoparticles with protein and cells may provide important information regarding their biomedical implementations. Herein, after synthesis of tin oxide (SnO 2) nanoparticles by hydrothermal method, their interaction with human serum albumin (HSA) was evaluated by multispectroscopic and molecular docking (MD) approaches. Furthermore, the selective antiproliferative impact of SnO 2 nanoparticles against leukemia K562 cells was assessed by different cellular assays, whereas lymphocytes were used as control cells. TEM, DLS, zeta potential and XRD techniques showed that crystalline SnO 2 nanoparticles have a size of less than 50 nm with a good colloidal stability. Fluorescence and CD spectroscopy analysis indicated that the HSA undergoes some slight conformational changes after interaction with SnO 2 nanoparticles, whereas the secondary structure of HSA remains intact. Moreover, MD outcomes revealed that the charged residues of HSA preferentially bind to SnO 2 nanoclusters in the binding pocket. Antiproliferative examinations displayed that SnO 2 nanoparticles can selectively cause the mortality of K562 cells through induction of cell membrane leakage, activation of caspase-9, -8, -3, down regulation of Bcl-2 mRNA, the elevation of ROS level, S phase arrest, and apoptosis. In conclusion, this data may indicate that SnO 2 nanoparticles can be used as promising particles to be integrated into therapeutic platforms. • Investigation of HSA structural changes in the presence of tin oxide NPs. • Selective anticancer effect of tin oxide NPs against K562 cells [ABSTRACT FROM AUTHOR]

The NiO NPs were synthesized by hydrothermal method and their interaction with Hb was investigated by employing fluorescence, UV–vis absorption techniques as well as docking studies. Also, the cytotoxic impacts of NiO NPs against human lymphocytes were examined by different cellular assays. The TEM, DLS and XRD investigations showed that the size of crystalline NiO NPs is less than 50 nm with a high colloidal stability. Analysis of the fluorescence quenching of Hb incubated with different concentrations of NiO NPs suggested that both static and dynamic quenching are involved in the spontaneous (∆G = −22.00 kJ/mol) formation of Hb-NiO NP complex through hydrogen bonding and van der Waals interactions (∆H = −46.16 kJ/mol, T∆S = −24.16 kJ/mol). Molecular docking also showed that NiO nanoclusters with different sizes bind to hydrophilic residues of Hb with different binding affinities. The UV–vis absorption further demonstrated that the Tm shifted to lower values in the presence of high concentrations of NiO NPs. Moreover, the cellular assay displayed that NiO NPs resulted in enhancement of cell mortality, LDH release, caspase-3 activity, ROS level, cell cycle arrest, and apoptosis/necrosis. These data can provide essential details in elucidating the nature of the reaction between NPs and the biological system. • The NiO NPs were synthesized by hydrothermal method. • Both static and dynamic quenching are involved in the interaction of NiO NPs and Hb. • NiO nanoclusters with different sizes bind to hydrophilic residues of Hb. • Tm shifted to lower values in the presence of higher concentrations of NiO NPs. • NiO NPs resulted in induction of apoptosis in lymphocytes. [ABSTRACT FROM AUTHOR]

In this study, we formulated silymarin-HSA nanoplex and assayed its ability to reduce LPS-induced toxicity in vitro and in vivo. Silymarin molecules were encapsulated into HSA nanoplex and the loading efficiency and characterization of fabricated nanoplex were performed by using HPLC, TEM, SEM, DLS, FTIR analysis, and theoretical studies. Afterwards, their protective effect against LPS (20 µg/ml) -induced toxicity in SH-SY5Y cells was investigated by MTT, ROS, and apoptosis assays. For in vivo experiments, rats were pre-treated with either silymarin or silymarin -HSA nanoplex (200 mg/kg) orally for 3 days and at third day received LPS by IP at a dose of 0.5 mg/kg, 150 min before scarification followed by SOD and CAT activity assay. The formulation of silymarin-HSA nanoplex showed a spherical shape with an average diameter between 50 nm and 150 nm, hydrodynamic radius of 188.3 nm, zeta potential of −26.6 mV, and a drug loading of 97.3%. In LPS-treated cells, pretreatments with silymarin-HSA noncomplex recovered the cell viability and decreased the ROS level and corresponding apoptosis more significantly than free silymarin. In rats, it was also depicted that, silymarin-HSA noncomplex can increase the SOD and CAT activity in brain tissue at LPS-triggered oxidative stress model more significantly than the free counterpart. Therefore, nanoformulation of silymarin improved its capability to reduce LPS-induced oxidative stress by restoring cell viability and elevation of SOD and CAT activity in vitro and in vivo , respectively. In conclusion, formulation of silymarin may hold a great promise in the development of antioxidant agents. [ABSTRACT FROM AUTHOR]