Erythropoietin Protects against Retinal Damage in A Rat Model of Optic Neuropathy via Glial Suppression

Objective: Traumatic optic neuropathy (TON) causes partial or complete blindness because death of irreplaceableretinal ganglion cells (RGCs). Neuroprotective functions of erythropoietin (EPO) in the nervous system have beenconsidered by many studies investigating effectiveness of this cytokine in various retinal disease models. It has beenfound that changes in retinal neurons under conditions of glial cells are effective in vision loss, therefore, the presentstudy hypothesized that EPO neuroprotective effect could be mediated through glial cells in TON model.Materials and Methods: In this experiment study, 72 rats were assessed in the following groups: intact and optic nervecrush which received either the 4000 IU EPO or saline. Visual evoked potential and optomotor response and RGCnumber were assessed and regenerated axons evaluated by anterograde test. Cytokines gene expression changeswere compared by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Density of astrocytes cells,assessed by fluorescence intensity, in addition, possible cytotoxic effect of EPO was measured on mouse astrocyteculture in vitro.Results: In vitro data showed that EPO was not toxic for mouse astrocytes. Intravenous injection of EPO improvedvision, in terms of visual behavioral tests. RGCs protection was more than two times in EPO, compared to the vehiclegroup. More regenerated axons were determined by anterograde tracing in the EPO group compared to the vehicle.Moreover, GFAP immunostaining showed while the intensity of reactive astrocytes was increased in injured retina,systemic EPO decreased it. In the treatment group, expression of GFAP was down-regulated, while CNTF was upregulatedas assessed by qRT-PCR in the 60th day post-crush.Conclusion: Our study showed that systemic administration of EPO can protect degenerating RGCs. Indeed,exogenous EPO exerted neuroprotective and neurotrophic functions by reducing reactive astrocytic gliosis. Therefore,reduction of gliosis by EPO may be considered as therapeutic targets for TON

Levels of Blood Biomarkers among Patients with Myocardial Infarction in Comparison to Control Group

BACKGROUND: Myocardial infarction (MI) as a term for a heart attack happens due to reduced blood flow to heart myocardium and lack of oxygen supply caused by plaques inthe interior walls of coronary arteries. With respect to the importance of MI etiology, we aimed to study the relationship of MI and blood examination variables.METHODS: This study was conducted in Mazandaran Heart Center as a hospital-based case-control Comprising 894 participants including 465 cases and 429 controls, individually matched by sex and age. Considered blood markers were analyzed using routine laboratory methods and equipment.RESULTS: Of all participants, 64.3% of the cases and 51.0% of the controls were males with a mean age of 61.2 (±13.8) in cases and 62.4 (±14.) in controls. We could not find any differences between cases and controls for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and alkaline-phosphatase (ALP) (P>0.05). However, levels of creatine-kinase-muscle/brain (CK-MB) (P<0.0001), fasting-blood-sugar (FBS) (P<0.0001), aspartateaminotransferase (AST) (P<0.0001), alanine-transferase (ALT) (P<0.0001) and erythrocyte sedimentation rate (ESR) (P=0.001) were significantly higher in cases compared to the controls (P<0.05). Multivariable analyses revealed that the risk of MI was associated with high levels of AST (adjusted OR=24.3, 95%CI=3.5±165.6, P=0.001) and LDL (adjusted OR=7.4, 95%CI=1.0±51.8, P=0.001).CONCLUSION: Our investigation indicated that the levels of CK-MB, FBS, AST, ALT and ESR were significantly higher in patients with MI. Besides, our findings showed that the risk of MI in cases with high levels of AST and LDL was about 24 and 7 times more than the control group respectively

Compensation for Environmental Damages according to the Draft Principles on the Allocation of Loss in the Case of Transboundary Harm Arising out of Hazardous Activities Adopted by International Law Commission (2006)

Compensation of transboundary environmental damages, especially in the case of hazardous activities is one of the complex issues of international environmental law. Sometimes in spite of taking all preventive measures, some authorized and legitimate activities of States that are generally dangerous can cause irreparable damages to other subjects of international law and especially to the environment. For as much as these activities are not prohibited, the traditional systems of civil responsibility are not effective when dealing with the compensation of environmental damages. Therefore, the development and codification of particular system of compensation for environmental damages is inevitable. The result of international community's effort in this context is the approval of draft of International Law Commission titled Draft Principles on the Allocation of Loss in the Case of Transboundary Harm Arising out of Hazardous Activities, with Commentaries 2006” declaring that the State is responsible and obliged to prevent and the operator of hazardous activity is obliged for compensation of the damages under circumstances to commit such act

The Effects of Rosmarinic Acid on Hippocampal Oxidative Stress Markers in LPS-induced Neuroinflammation Rats: Rosmarinic Acid and Hippocampal Oxidative Stress

Neuroinflammation (NI) plays a pivotal role in the pathogenesis of several neurodegenerative diseases. It has been believed that alleviating NI can be a valuable approach in controlling the progress of neurodegenerative diseases. The generation of reactive oxygen and nitrogen species could trigger and deteriorate NI. According to previous studies, rosmarinic acid (RA) could exhibit neuroprotective potential. Therefore, this study aimed to evaluate the effect of RA on hippocampal oxidative stress markers in lipopolysaccharide (LPS)-induced NI in rat brain. A total of 24 adult male Wistar rats were randomly allocated into four equal groups (n=6 each) and NI was induced in three of them by intracerebroventricular (ICV) injection of LPS (50 μg/20μl; 10 μl into each ventricle). RA (2.5-5 mg/kg i.p.) was injected 30 min before the LPS injection and continued once per day up to 48 h. On day 3, animals were sacrificed and their hippocampi were dissected. Then, hippocampal concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NOx) were determined. RA prevented hippocampal MDA elevation in a dose-dependent-manner and increased SOD activity but did not affect NOx content. In conclusion, the results of the present study demonstrated that systemic administration of RA could effectively ameliorate oxidative stress induced by LPS in rat’s brain. This potential might be one of the underlying mechanisms through which RA mitigates NI

Electronic polarization effects on membrane translocation of anti-cancer drugs

Free-energy calculations are crucial for investigating biomolecular interactions. However, in theoretical studies, the neglect of electronic polarization can reduce predictive capabilities, specifically for free-energy calculations. To effectively mimick polarization, we explore a Charge Switching (CS) model, aiming to narrow the gap between computational and experimental results. The model requires quantum-level partial charge calculations of the molecule in different environments, combined with atomistic MD simulations. Studying three different anti-cancer drug molecules with three different phospholipid membranes, we show that the method significantly improves agreement with available experimental data. In contrast, using conventional fixed charge atomistic methods, qualitative discrepancies with experiments are observed, and we show that neglecting polarization may lead to an unphysical free energy sign inversion. While the CS method is here applied to anti-cancer drug-membrane translocation, it could be used more generally to study processes considering solvent effects

A modified Jarzynski free-energy estimator to eliminate non-conservative forces and its application in nanoparticle-membrane interactions

Computational methods to understand interactions in bio-complex systems are however limited to time-scales typically much shorter than in Nature. For example, on the nanoscale level, interactions between nanoparticles (NPs)/molecules/peptides and membranes are central in complex biomolecular processes such as membrane-coated NPs or cellular uptake. This can be remedied by the application of e.g. Jarzynski's equality where thermodynamic properties are extracted from non-equilibrium simulations. Although, the out of equilibrium work leads to non-conservative forces. We here propose a correction Pair Forces method, that removes these forces. Our proposed method is based on the calculation of pulling forces in backward and forward directions for the Jarzynski free-energy estimator using steered molecular dynamics simulation. Our results show that this leads to much improvement for NP-membrane translocation free energies. Although here we have demonstrated the application of the method in molecular dynamics simulation, it could be applied for experimental approaches

Molecular interaction of fibrinogen with zeolite nanoparticles

Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ 377–394 ), located in D-domain, showed the highest level of exposure compared to other sequences/residues

Mechanistic Understanding of the Interactions between Nano-Objects with Different Surface Properties and α-Synuclein

Aggregation of the natively unfolded protein α-synuclein (α-syn) is key to the development of Parkinson's disease (PD). Some nanoparticles (NPs) can inhibit this process and in turn be used for treatment of PD. Using simulation strategies, we show here that α-syn self-assembly is electrostatically driven. Dimerization by head-to-head monomer contact is triggered by dipole-dipole interactions and subsequently stabilized by van der Waals interactions and hydrogen bonds. Therefore, we hypothesized that charged nano-objects could interfere with this process and thus prevent α-syn fibrillation. In our simulations, positively and negatively charged graphene sheets or superparamagnetic iron oxide NPs first interacted with α-syn's N/C terminally charged residues and then with hydrophobic residues in the non-amyloid-β component (61-95) region. In the experimental setup, we demonstrated that the charged nano-objects have the capacity not only to strongly inhibit α-syn fibrillation (both nucleation and elongation) but also to disaggregate the mature fibrils. Through the α-syn fibrillation process, the charged nano-objects induced the formation of off-pathway oligomers

Conformation- and phosphorylation-dependent electron tunnelling across self-assembled monolayers of tau peptides

We report on charge transport across self-assembled monolayers (SAMs) of short tau peptides by probing the electron tunneling rates and quantum mechanical simulation. We measured the electron tunneling rates across SAMs of carboxyl-terminated linker molecules (C6H12O2S) and short cis-tau (CT) and trans-tau (TT) peptides, supported on template-stripped gold (AuTS) bottom electrode, with Eutectic Gallium-Indium (EGaIn)(EGaIn) top electrode. Measurements of the current density across thousands of AuTS/linker/tau//Ga2O3/EGaIn single-molecule junctions show that the tunneling current across CT peptide is one order of magnitude lower than that of TT peptide. Quantum mechanical simulation demonstrated a wider energy bandgap of the CT peptide, as compared to the TT peptide, which causes a reduction in its electron tunneling current. Our findings also revealed the critical role of phosphorylation in altering the charge transport characteristics of short peptides; more specifically, we found that the presence of phosphate groups can reduce the energy band gap in tau peptides and alter their electrical properties. Our results suggest that conformational and phosphorylation of short peptides (e.g., tau) can significantly change their charge transport characteristics and energy levels