Alpha pyrrolidinovalerophenone (α-PVP) administration impairs spatial learning and memory in rats through brain mitochondrial dysfunction.

Novel psychoactive substances (NPS) consumption has increased in recent years, thus NPS-induced cognitive decline is a current source of concern. Alpha-pyrrolidinovalerophenone (α-PVP), as a member of NPS, is consumed throughout regions like Washington, D.C., Eastern Europe, and Central Asia. Mitochondrial dysfunction plays an essential role in NPS-induced cognitive impairment. Meanwhile, no investigations have been conducted regarding the α-PVP impact on spatial learning/memory and associated mechanisms. Consequently, our study investigated the α-PVP effect on spatial learning/memory and brain mitochondrial function. Wistar rats received different α-PVP doses (5, 10, and 20 mg/kg) intraperitoneally for 10 sequential days; 24 h after the last dose, spatial learning/memory was evaluated by the Morris Water Maze (MWM). Furthermore, brain mitochondrial protein yield and mitochondrial function variables (Mitochondrial swelling, succinate dehydrogenase (SDH) activity, lipid peroxidation, Mitochondrial Membrane Potential (MMP), Reactive oxygen species (ROS) level, brain ADP/ATP proportion, cytochrome c release, Mitochondrial Outer Membrane (MOM) damage) were examined. α-PVP higher dose (20 mg/kg) significantly impaired spatial learning/memory, mitochondrial protein yield, and brain mitochondrial function (caused reduced SDH activity, increased mitochondrial swelling, elevated ROS generation, increased lipid peroxidation, collapsed MMP, increased cytochrome c release, elevated brain ADP/ATP proportion, and MOM damage). Moreover, the lower dose of α-PVP (5 mg/kg) did not alter spatial learning/memory and brain mitochondrial function. These findings provide the first evidence regarding impaired spatial learning/memory following repeated administration of α-PVP and the possible role of brain mitochondrial dysfunction in these cognitive impairments.

177Lu-labeled cyclic RGD peptide as an imaging and targeted radionuclide therapeutic agent in non-small cell lung cancer: Biological evaluation and preclinical study.

Non-small cell lung carcinoma (NSCLC) is among the most lethal lung cancers responsible for 80-85% of death. αvß3 integrin receptor subtype has been identified as a lung cancer biomarker since its expression correlates with tumor progression and metastasis. The extracellular domain of the receptor forms a binding site for RGD-based sequences. Therefore, specific targeting of αvß3 integrin receptors by these short peptides can be an excellent candidate for cancer imaging and therapy. In this research, the radiolabeling of DOTA-E(cRGDfK)2 with 177Lu was efficiently implemented. The Log P value, in vivo, in vitro, metabolic stability, cellular uptake and specific binding of the radiopeptide was determined. The tumor targeting capacity and the therapeutic potential of the radiotracer was studied in A549 tumor-bearing mice. Imaging studies at different time intervals were performed by SPECT/CT. Radiochemical purity of more than 99% and Log P of -3.878 was obtained for 177Lu-labelled peptide. Radiotracer showed favorable in vivo, in vitro and metabolic stability. The radiopeptide dissociation constant (Kd) was 15.07 nM. Radiopeptide specific binding was more than 95%. Biodistribution studies showed high accumulation of the radiopeptide in tumor and rapid excretion by urinary route. Maximum tumor uptake was at 4 h post-injection. Following administration of this radiopeptide to mice, not only tumor growth was suppressed, but significant tumor shrinkage was also observed. In conclusion, this radiopeptide can be employed for staging, follow-up imaging and as peptide receptor radionuclide therapeutic agent allowing efficient therapy for NSCLC and other cancers overexpressing αvß3 integrin receptors.

Design, preparation and biological evaluation of a 177Lu-labeled somatostatin receptor antagonist for targeted therapy of neuroendocrine tumors.

Somatostatin receptor-targeted radionuclide therapy has become an effective treatment in patients with neuroendocrine tumors. Recently, investigations on the development of antagonistic peptides are increasing with possible superior biological properties as opposed to the agonists. Herein, we have reported the development of a new somatostatin receptor peptide ligand labeled with 177Lu to achieve a therapeutic ligand for tumor treatment. The interactions of selected and drown ligands using Avogadro software were docked on somatostatin receptor by Dink algorithm. The best docked peptide-chelator conjugate (DOTA-p-Cl-Phe-Cyclo(d-Cys-l-BzThi-d-Aph-Lys-Thr-Cys)-d-Tyr-NH2) (DOTA-Peptide 2) was synthesized using the Fmoc solid-phase method. DOTA-Peptide 2 was radiolabeled with the 177Lu Trichloride (177LuCl3) solution at 95 °C for 30 min and radiochemical purity (RCP) of 177Lu-DOTA-Peptide 2 solution was monitored by radio-HPLC and radio-TLC procedures. The new radiolabeled peptide was evaluated for stability, receptor binding, internalization, biodistribution and single-photon emission computed tomography (SPECT) imaging using C6 glioma cells and C6 tumor-bearing rats. DOTA-Peptide 2 was obtained with 98% purity and efficiently labeled with 177Lu (RCP > 99%). 177Lu-DOTA-Peptide 2 showed a high value of stability in acetate buffer (91.4% at 312 h) and human plasma (>97% at 24 h). Radioconjugate exhibited low internalization (<5%) and high affinity for somatostatin receptors (Kd = 12.06 nM, Bmax = 0.20 pmol/106 cells) using saturation binding assay. Effective tumor uptake of 7.3% ID/g (percentage of injected dose per gram of tumor) at 4 h post-injection and fast clearance of radiopeptide from blood and other organs led to a high tumor-to-normal organ ratios. SPECT/CT imaging clearly showed the activity localization in tumor. The favorable antagonistic properties of 177Lu-DOTA-Peptide 2 on the somatostatin receptors can make it a suitable candidate for peptide receptor radionuclide therapy (PRRT). In the future study, the therapeutic application of this radiopeptide will be evaluated.

Synthesis, biological evaluation and preclinical study of a novel 99mTc-peptide: A targeting probe of amyloid-ß plaques as a possible diagnostic agent for Alzheimer's disease.

With respect to the main role of amyloid-ß (Aß) plaques as one of the pathological hallmarks in the brain of Alzheimer's patients, the development of new imaging probes for targeted detection of Aß plaques has attracted considerable interests. In this study, a novel cyclopentadienyl tricarbonyl Technetium-99 m (99mTc) agent with peptide scaffold, 99mTc-Cp-GABA-D-(FPLIAIMA)-NH2, for binding to the Aß plaques was designed and successfully synthesized using the Fmoc solid-phase peptide synthesis method. This radiopeptide revealed a good affinity for Aß42 aggregations (Kd = 20 µM) in binding affinity study and this result was confirmed by binding to Aß plaques in brain sections of human Alzheimer's disease (AD) and rat models using in vitro autoradiography, fluorescent staining, and planar scintigraphy. Biodistribution studies of radiopeptide in AD and normal rats demonstrated a moderate initial brain uptake about 0.38 and 0.35% (ID/g) 2 min post-injection, respectively. Whereas, AD rats showed a notable retention time in the brain (0.23% ID/g at 30 min) in comparison with fast clearance in normal rat brains. Normal rats following treatment with cyclosporine A as a p-glycoprotein inhibitor showed a significant increase in the radiopeptide brain accumulation compared to non-treated ones. There was a good correlation between data gathered from single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Therefore, these findings showed that this novel radiopeptide could be a potential SPECT imaging agent for early detection of Aß plaques in the brain of patients with AD.

Design, synthesis, radiolabeling and biological evaluation of new urea-based peptides targeting prostate specific membrane antigen.

Early diagnosis of Prostate cancer (PCa) plays a vital role in successful treatment increasing the survival rate of patients. Prostate Specific Membrane Antigen (PSMA) is over-expressed in almost all types of PCa. The goal of present study is to introduce new 99mTc-labeled peptides as a PSMA inhibitor for specific detection of PCa at early stages. Based on published PSMA-targeting compounds, a set of peptides bearing the well-known Glu-Urea-Lys pharmacophore and new non-urea containing pharmacophore were designed and assessed by in silico docking studies. The selected peptides were synthesized and radiolabeled with 99mTc. The in-vitro tests (log P, stability in normal saline and fresh human plasma, and affinity toward PSMA-positive LNCaP cell line) and in-vivo characterizations of radiopeptides (biodistribution and Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging in normal and tumour-bearing mice) were performed. The peptides 1-3 containing Glu-Urea-Lys and Glu-GABA-Asp as pharmacophores were efficiently interacted with crystal structure of PSMA and showed the highest binding energies range from -8 to -11.2 kcal/mol. Regarding the saturation binding test, 99mTc-labeled peptide 1 had the highest binding affinity (Kd = 13.58 nM) to PSMA-positive cells. SPECT-CT imaging and biodistribution studies showed high kidneys and tumour uptake 1 h post-injection of radiopeptide 1 and 2 (%ID/g tumour = 3.62 ± 0.78 and 1.8 ± 0.32, respectively). 99mTc-peptide 1 (Glu-urea-Lys-Gly-Ala-Asp-Naphthylalanine-HYNIC-99mTc) exhibited the highest binding affinity, high radiochemical purity, the most stability and high specific accumulation in prostate tumour lesions. 99mTc-peptide 1 being of comparable efficacy and pharmacokinetic properties with the well-known PET tracer (68Ga-PSMA-11) seems to be applied as a promising SPECT imaging agent to early diagnose of PCa and consequently increase survival rate of patients.

Synthesis and characterization of novel 99mTc-DGC nano-complexes for improvement of heart diagnostic.

In this research, early diagnosis of cardiovascular diseases can reduce their mortality and burden. In our study, we developed a new nano-agent, 99mTc-Dendrimer Glyco Conjugate (99mTc-DGC), and assessed its safety and capability for myocardial viability scan. To develop 99mTc-DGC, we first synthesized the dendrimer and then, glucose has been conjugated. Afterwards, we measured toxicity of the product on normal cells by XTT and apoptosis/necrosis methods. We compared the myocardial viability scan (measured by SPECT and dynamic planar imaging) in two rabbit models, with and without infarction. We also assessed the biodistribution of 99mTc-DGC in rats with no infarction. DGC synthesis was confirmed by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR), liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS) and static light scattering techniques (SLS). Then radiochemical purity (RCP) was done to present the stability and potential of DGC to complex formation with 99mTc. In vitro cytotoxicity showed nontoxic concentration up to 8 mg/mL. Single Photon Emission Computed Tomography (SPECT) and dynamic planar imaging clearly showed the accumulation of 99mTc-DGC in myocardial. Biodistribution result showed the 2.60% accumulation of 99mTc-DGC in myocardial after 2 h. Our findings indicated 99mTc-DGC to be safe and can accurately diagnose myocardial infarctions at early stages. Human studies to further assess such effects are critical.

Protective role of thymoquinone against paraquat-induced hepatotoxicity in mice.

Paraquat is a common and effective herbicide; although its poisoning could lead to severe oxidative organ damages and its main target organs are the lungs, kidneys, heart, and liver. Thymoquinone is the active ingredient of Nigella sativa which is traditionally used in herbal medicine; recent studies have shown that thymoquinone could inhibit oxidative stress. This study explores protective effects of thymoquinone on paraquat-induced hepatotoxicity in mice. Accordingly, adult male mice were randomly divided into nine groups for three continuous days intraperitoneal injection treatment: (1) control; (2) solvent; (3) 20 mg/kg vitamin E; (4) 20 mg/kg thymoquinone; (5) 20 mg/kg paraquat and Groups 6, 7, 8, and 9 received 20 mg/kg of vitamin E and 5, 10, and 20 mg/kg of thymoquinone, respectively. The last four groups, received 20 mg/kg paraquat just 24 h after pretreatments. We assessed serum liver enzymes activities, liver histopathology changes, oxidative (lipid peroxidation) and antioxidative (ferric reducing antioxidant power) potential, superoxide dismutase (SOD) and catalase activity, and total thiol groups content after administration of the poison and treatments. Pretreatment with 10 mg/kg thymoquinone inhibited, safely, the elevations in levels of liver function tests (LFTs) and lipid peroxidation, restored the activity of SOD, and ameliorated the histopathological alterations induced by paraquat. Eventually, our results indicate that thymoquinone performs its hepatoprotective role in mice by prevention of SOD suppression mediated by paraquat.

Evaluation of the Hepatoprotective Effect of the Lumpy Bracket Medicinal Mushroom Trametes gibbosa (Agaricomycetes) on CCl4-Induced Liver Injury in Rats.

Mushrooms have been used as medicine by humans for more than 5000 years. They have had a successful role in treating immune deficiencies. Nowadays, some extracts and compounds obtained from medicinal mushrooms have increased a great prospect of treating many disorders by having a great role in modulation of immune system, cancer inhibiting, cardio-vascular health, antiviral, antibacterial, antioxidant and protective effects against hepatitis and diabetes. In this study, we evaluated the antioxidant effect of methanol and hot water extract of the Trametes gibbosa (Pers.) Fr. mushroom and hepatoprotective effect of the extract with the most radical scavenging potency. To assess the antioxidant properties of different extracts of the mushroom, DPPH method was used. For assessing the hepatoprotective properties, a seven-day experiment was designed, and liver toxicity was induced by carbon tetrachloride [intraperitoneal (ip) for 7 consecutive days, 0.5 mL/kg body weight (BW)]. Rats were simultaneously fed with aqueous extract of the mushroom with the dose of 250, 500, and 1000 mg/kg BW and silymarin (100 mg/kg BW) as positive control. At the end of the experiment, blood serums of the rats were collected for quantification of major liver factors (e.g., aspartate aminotransferase, alanine aminotransferase, alanine phosphatase, bilirubin, etc.). Tissue samples were obtained for pathological examination. Based on the results, the aqueous extract showed more potent radical scavenging activity (half-maximal inhibitory concentration = 414.33 µg/mL, compared with 936.92 µg/mL for methanolic extract). Indeed, hepatoprotective properties of the aqueous extract of the mushroom (500 and 1000 mg/kg BW) were comparable with those of silymarin and even showed superior protective effects in histopathological examination. It seems that with further complementary studies, T. gibbosa could be considered a potential candidate for hepatoprotection.

Liraglutide alleviated alpha-pyrrolidinovalerophenone (α-PVP) induced cognitive deficits in rats by modifying brain mitochondrial impairment.

The use of NPS compounds is increasing, and impairment in spatial learning and memory is a growing concern. Alpha-pyrrolidinovalerophenone (α-PVP) consumption, as a commonly used NPS, can impair spatial learning and memory via the brain mitochondrial dysfunction mechanism. Liraglutide isone of the most well-known Glucagon-Like Peptide 1 (GLP-1) agonists that is used as an anti-diabetic and anti-obesity drug. According to current research, Liraglutide likely ameliorates cognitive impairment in neurodegenerative conditions and substance use disorders. Hence, the purpose of this study is examining the effect of Liraglutide on α-PVP-induced spatial learning and memory problems due to brain mitochondrial dysfunction. Wistar rats (8 in each group) received α-PVP (20 mg/kg/d for 10 consecutive days, intraperitoneally (I.P.)). Then, Liraglutide was administered at 47 and 94 µg/kg/d, I.P., for 4 weeks following the α-PVP administration. The Morris Water Maze (MWM) task evaluated spatial learning and memory 24 h after Liraglutide treatment. Bedside, brain mitochondrial activity parameters, including reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), cytochrome c release, mitochondrial outer membrane damage and swelling, and brain ADP/ATP ratio, were studied. Our results showed that Liraglutide ameliorated α-PVP-induced spatial learning and memory impairments through alleviating brain mitochondrial dysfunction (which is indicated by increasing ROS formation, collapsed MMP, mitochondrial outer membrane damage, cytochrome c release, mitochondrial swelling, and increased brain ADP/ATP ratio). This study could be used as a starting point for future studies about the possible role of Liraglutide in ameliorating mitochondrial dysfunction leading to substance use disorder- induced cognitive impairment.

Sublethal exposures of diazinon alters glucose homostasis in Wistar rats: Biochemical and molecular evidences of oxidative stress in adipose tissues.

Disorder of glucose homeostasis is one of the most important complications following exposure to organophosphorous (OPs) pesticides. Regarding the importance of adipose tissue in regulating blood glucose and the role of oxidative stress in toxicity of OPs and in the continue of our previous works, in the present study we focused on tumor necrosis factor alpha (TNFα), glucose transporter type 4 (GLUT4), and nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB) in a sublethal model of toxicity by diazinon as a common OPs. Following time-course study of various doses of diazinon in impairing blood glucose, dose of 70mg/kg/day was found the optimum. Animals were treated for 4 weeks and after gavage of glucose (2g/kg), the glucose change was evaluated at time-points of 0, 30, 60, 120 and 180min to identify oral glucose tolerance test (GTT). In addition, serum insulin was measured in fasting condition. In adipose tissue, oxidative stress markers including reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and TNFα were evaluated. The mRNA expression of GLUT4, Nf-κB and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were also determined by real time reverse transcription polymerase chain reaction (RT-PCR). Diazinon at dose of 70mg/kg/day impaired GTT and diminished insulin level while augmented ROS, NADPH oxidase, and TNFα. The GLUT4 mRNA expression was amplified by diazinon while unlikely, the expression of Nf-κB gene did not change. On the basis of biochemical and molecular findings, it is concluded that diazinon impairs glucose homeostasis through oxidative stress and related proinflammatory markers in a way to result in a reduced function of insulin inside adipose tissue. Although, diazinon interfered with pancreatic influence on the adipose tissue most probably via stimulation of muscarinic receptors, current data are not sufficient to introduce adipose tissue as a target organ to OPs toxicity. Considering the potential of OPs to accumulate in adipose tissue, it seems a good candidate organ for future studies. Although, hyperglycemia was not induced by diazinon but increased AUC0-180min leads us to the point that diazinon induces kind of instability in glucose homostasis and diabetes.

Acute and subacute toxicity of novel biogenic selenium nanoparticles in mice.

CONTEXT: In the present investigation, acute and subacute toxicity of the biogenic Se nanoparticles (Se NPs) has been reported. OBJECTIVE: To characterize the Se NPs produced by a bacterium species and to evaluate their toxicity and impact on clinical chemistry and hematological parameters of NMRI mice. MATERIALS AND METHODS: The Se NPs were prepared by Bacillus sp. MSh-1 in a culture medium containing SeO(2) (1.26 mM) and their physiochemical properties investigated using TEM, XRD and FT-IR. The LD(50) of Se NPs and SeO(2) were determined and the subacute toxicity evaluated by orally administration of 0, 2.5, 5, 10 and 20 mg kg(-1) of Se NPs to male mice for 14 consecutive days. Parameters of blood cells, AST, ALT, ALP, creatinine, BUN, cholesterol, bilirubin, triglyceride and CPK were experimentally measured. RESULTS: The XRD and TEM analyses showed that the spherical NPs were amorphous, in the size range of 80-220 nm. The toxicological evaluation showed that the LD(50) values of SeO(2) and Se NPs were 7.3 and 198.1 mg kg(-1), respectively. No biochemical changes were observed from the administration of 2.5, 5 and 10 mg kg(-1) of Se NPs, but a dose of 20 mg kg(-1) was accompanied with signs of toxicity including lower body weight and changes in clinical chemistry and hematological parameters. CONCLUSION: The biogenic Se NPs were less toxic than synthetic Se NPs and much less (26-fold) toxic than the SeO(2), which demonstrates the important role of Bacillus sp. MSh-1 in conversion of a highly toxic Se compound to the less toxic Se NPs.

Evaluation of acute and sub-chronic oral toxicities of Neoneaster in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Jaundice is a condition caused by the elevation of bilirubin level in the blood. Due to the neurological and neurodevelopmental sequalae of jaundice in newborns, the high cost of the treatment, and the side effects of the currently used therapies, novel therapeutically approaches are needed. Purgative manna (Shir-e-Khesht) has been used in Persian traditional medicine to reduce serum bilirubin levels of neonates. Neoneaster® is a natural health product formulated by a unique method from the manna of Cotoneaster nummularius Fisch. & C.A.Mey. for treating neonatal jaundice and managing constipation. The main component of Neoneaster®, mannitol, is an osmotic laxative which could increase intestinal transit and reduce the re-absorption of bilirubin in the enterohepatic cycle. AIM OF THE STUDY: We conducted this study to investigate acute and sub-chronic oral toxicities of Neoneaster in Wistar rats. MATERIALS AND METHODS: In the acute oral toxicity test, based on OECD 423 we administered Neoneaster to the Wistar rats at doses of 5, 50, 300, and 2000 mg/kg(OECD, 2002). Toxicological effects, including mortality and behavioral changes, were recorded for 14 days and compared to the control group. We also carried out histopathological assessments of the tissues of liver, heart, kidney, and spleen after this period. To evaluate sub-chronic toxicity, while administering 2000 mg/kg of Neoneaster daily to the Wistar rats, we recorded for changes in mortality and behavior for 45 days and compared these to the values of the control group. We also carried out biochemical, hematological, and histopathological assessments after this period. RESULTS: In both acute and sub-chronic oral toxicity tests, no mortalities, behavioral abnormalities, and histological signs of toxicity was observed in any of the administered doses in comparison to the control group. The percentage of weight gains in acute toxicity test and the weight gain in sub-chronic test were not significant (P>0/05). There were also no significant differences in hematological and biochemical markers (P>0/05). Based on our finding, Neoneaster can be classified as category 5 in the Globally Harmonized Chemical Classification and Labeling System (GHS) as its Lethal Dose 50 (LD50) is higher than 2000 mg/kg. CONCLUSIONS: This study suggests that Neoneaster is safe and can be classified as category 5 in the GHS system.

Hybrid ultrasound-activated nanoparticles based on graphene quantum dots for cancer treatment.

Theranostic liposomes have recently found a broad range of applications in nanomedicine due to stability, the high solubility of biomacromolecules, bioavailability, efficacy, and low adverse effects. However, the limitations of liposomes concerning the short systemic circulation in the body, limited controllability of the release rate, and the inability of in vivo imaging remain challenging. Herein, the development of novel hybrid ultrasound-activated piezoelectric nanoparticles based on a hybrid liposome nanocarrier composed of poly(vinylidene fluoride-trifluoroethylene), graphene quantum dots (GQDs), and Silibinin (a hydrophobic drug) is presented. The hybrid nanoparticles are an acoustically sensitive drug delivery platform that releases the biomacromolecules in a specific tissue area (through surface labeling with PD-1 antibody) in a non-invasive and controlled manner. We show that the developed hybrid nanoparticles (with an average outer diameter of âˆ¼ 230 ± 20 nm) enable piezoelectric-stimulated drug delivery combined with simultaneous fluorescent imaging of cancer cells in vivo. Significant enhancement (>80 % up to 240 h) and tunable drug release from the nanocarrier through enhanced diffusion from the liposome membrane are demonstrated. Cytotoxicity assays using MCF-7, 4T1, and NIH3T3 cell lines exhibit no confrontational influence of nanoparticles on cell viability up to 125 µg/ml. The PD-1 antibody on the surface of the hybrid nanocarrier allows for selective delivery to breast cancer tumors and low biodistribution to other tissues. Our results affirm that the developed ultrasound-activated piezoelectric nanoparticles have great potential as multifunctional platforms with sustainable release profiles for the delivery of hydrophobic drugs to breast cancer, especially when the ability for adequate labeling and cell monitoring is valued.

Influence of reducing agents on in situ synthesis of gold nanoparticles and scaffold conductivity with emphasis on neural differentiation.

BACKGROUND: Recorded advancements in nerve tissue regeneration have still not provided satisfactory results, and complete physiological recovery is not assured. The engineering of nanofibrous scaffolds provides a suitable platform for stem cell transplantation by controlling cell proliferation and differentiation to replace lost cells. In this study, a conductive scaffold was fabricated by in situ synthesis of gold nanoparticles (Au-NPs) on electrospun polycaprolactone/chitosan nanofibrous scaffolds and its effect on neural differentiation of mesenchymal stem cells was investigated. METHOD: The conductive scaffold was prepared using polycaprolactone/chitosan solution containing soluble Au ions by electrospinning approach. In situ synthesis of Au-NPs was conducted using two reducing agents, Tetrakis(hydroxymethyl)phosphonium chloride (THPC) as an organophosphorus compound and formaldehyde, and also different reduction times. Morphology and distribution of the Au-NPs on the nanofibrous scaffolds were assessed using field emission scanning electron microscopy (FE-SEM) and energy dispersed X-ray spectroscopy (EDX). The hydrophilicity and biocompatibility of the scaffolds were determined by water contact angle and MTT assays respectively. The characterization of the scaffolds was proceeded by testing the porosity, tensile strength and electrical conductivity. Also, the scaffold's ability to support neural differentiation of mesenchymal stem cells was evaluated by immune-staining/blotting of Beta tubulin III. RESULTS & CONCLUSION: FE-SEM and EDX results demonstrated the uniform distribution of Au-NPs on electrospun nanofibers made of a combination of polycaprolactone and chitosan (PCL/CS). We found that electrical conductivity of the scaffolds fabricated using THPC for 4 days and formaldehyde for 7 days was in the range of electrical conductivity of the scaffolds suitable for nerve regeneration. Contact angle measurements showed the effect of Au-NPs on the hydrophilic properties of the scaffolds, where the scaffold showed the porosity of 50% in the presence of Au-NPs. Au-NPs decoration on the scaffold decreased the mechanical properties with the ultimate strength of 14 (MPa). In vitro assessment demonstrated the potential of the fabricated conductive scaffold to enhance the attachment and proliferation of fibroblast cells, and differentiation potential of mesenchymal stem cells toward neuron-like cells. This designed scaffold holds promise as a future carrier and delivery platform in nerve tissue engineering.

The Situation of Small Molecules Targeting Key Proteins in combatting SARS-CoV-2: Synthesis, Metabolic Pathway, Mechanism of Action, and Potential Therapeutic Applications.

Due to the high mortality rate of the 2019 coronavirus disease (COVID-19) pandemic, there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, and mechanism of action of the existing drugs with potential therapeutic applications for COVID-19. Furthermore, we summarized the molecular docking stimulation of the medications related to key protein targets. These already established drugs could be further developed, and after their testing through clinical trials, they could be used as suitable therapeutic options for patients suffering from COVID-19.

Opioidergic and nitrergic systems mediate the anticonvulsant effect of mefloquine and chloroquine on seizures induced by pentylenetetrazol and maximal electroshock in mice.

This study was designed to investigate the involvement of opioidergic/nitrergic systems in the anticonvulsant effect of mefloquine, compared with chloroquine, in mice. Seizures were induced by pentylenetetrazol and maximal electroshock. Mice were randomly subjected to receive mefloquine or chloroquine thirty minutes in advance. The role of opioidergic/nitrergic systems was shown by co­administration of pharmacological intervention and nitrite levels measurement in mice hippocampi. Results indicated that mefloquine (40 mg/kg) and chloroquine (5 mg/kg) significantly decreased the occurrence of tonic hindlimb extension. Also, mefloquine 120 mg/kg and chloroquine 5 mg/kg significantly increased seizure latency and decreased mortality rate. Mefloquine decreased seizure frequency too. Besides, mefloquine (20 mg/kg) and chloroquine (5, 10 mg/kg) significantly increased seizure threshold. Interestingly, L­NAME, 7­NI and naltrexone pre­treatment reversed the anticonvulsant effects of both mefloquine (20 mg/kg) and chloroquine (5 mg/kg). Moreover, co­administration of minimal­effective doses of morphine with mefloquine/chloroquine (both 1 mg/kg) potentiated anticonvulsant effects, which was reversed by naltrexone and endorsed the involvement of opioid receptors. Also, nitrite levels in mice hippocampi remarkably increased after treatment with both mefloquine (20 mg/kg) and chloroquine (5 mg/kg). To conclude, mefloquine could protect the central nervous system against seizures in PTZ/MES­induced models through opioidergic/nitrergic pathways, with similarity to chloroquine effects.

Benefit of nanocarrier of magnetic magnesium in rat malathion-induced toxicity and cardiac failure using non-invasive monitoring of electrocardiogram and blood pressure.

Medical management in acute organophosphate (OP) poisoning is not always successful because of tissue hypoxia which results in a reduction of heart contractility and cell damage. This study reports improvement of malathion (MAL)-induced cardiac failure by a nanocarrier of magnetic isotope of Mg (PMC16). A rat model of acute MAL poisoning was set up. PMC16 nanoparticle at doses of 0.05, 0.1, 0.2 LD50 = 896 mg/kg) were administered intravenously (iv) 30 minutes after a single intraperitoneal (ip) injection of MAL (0.25 LD50= 207 mg/kg). Atropine (AT; 40 mg/kg, ip) plus pralidoxime (PAM; 40 mg/kg, ip) and magnesium sulfate (MgSO4; 600 mg/kg, iv) were used as standard therapy or controls. Anesthetized animals were monitored for heart rate, electrocardiogram, blood pressure, and blood oxidative stress biomarkers like cellular lipid peroxidation, total thiol molecules, antioxidant power, gamma glutamil transpeptidase, and acetylcholinesterase (AChE) as a marker of OP toxicity. Results indicated that after MAL administration, heart rate and BP decreased and R-R duration increased. PMC16 markedly restored BP at all doses as compared with MgSO4. PMC16 at the dose of 0.05 LD50 significantly increased BP in comparison to AT + PAM. PMC16 restored heart rate at dose of 0.2 LD50 and reduced lipid peroxidation at dose of 0.05 LD50 as compared to MgSO4. PMC16 also improved total antioxidant power at all doses when compared to AT + PAM and reduced GGT activity at dose of 0.2 LD50 but did not affect total thiol molecules. MgSO4 could improve MAL-induced reduction of total antioxidant power. After 24 h, PMC16 significantly improved MAL-suppressed AChE activity at doses of 0.05 and 0.1 LD50. PMC16 at all doses significantly recovered MAL-induced arrhythmia when compared to standard therapies. It is concluded that PMC16 is able to control OP-induced cardiac failure and toxicity.

Bisphenol-A in biological samples of breast cancer mastectomy and mammoplasty patients and correlation with levels measured in urine and tissue.

Endocrine disrupting chemicals (EDCs) are organic compounds that have estrogenic activity and can interfere with the endocrine system. Bisphenol-A (BPA) is one of these compounds which possess a potential risk for breast cancer. The aim of this research was to evaluate BPA concentration in both the urine and breast adipose tissue samples of breast cancer mastectomy and mammoplasty patients and study correlations of BPA levels in breast adipose tissue with urine samples in the both groups. Urine and breast adipose tissue samples from 41 breast cancer mastectomy and 11 mammoplasty patients were taken. BPA concentrations were detected using an ELISA assay. Urinary BPA concentrations were significantly higher in cancerous patients (2.12 ± 1.48 ng/ml; P < 0.01) compared to non-cancerous (0.91 ± 0.42 ng/ml). Likewise, tissue BPA concentrations in cancerous patients (4.20 ± 2.40 ng/g tissue; P < 0.01) were significantly higher than non- cancerous (1.80 ± 1.05 ng/g tissue). Urinary BPA concentrations were positively correlated with breast adipose tissue BPA in the case group (P < 0.001, R = 0.896). We showed that BPA was present in urine and breast adipose tissue samples of the studied populations. With regard to higher BPA mean concentration in cancerous patients than non-cancerous individuals in this study, BPA might increase the risk of breast cancer incidence.

ß-Sitosterol Alters the Inflammatory Response in CLP Rat Model of Sepsis by Modulation of NFκB Signaling.

PURPOSE: Sepsis originates from the host inflammatory response, especially to bacterial infections, and is considered one of the main causes of death in intensive care units. Various agents have been developed to inhibit mediators of the inflammatory response; one prospective agent is ß-sitosterol (ßS), a phytosterol with a structure similar to cholesterol. This study is aimed at evaluating the effects of ßS on the biomarkers of inflammation and liver function in cecal ligation and puncture- (CLP-) induced septic rats. METHODS: Thirty male Wistar rats were divided equally into six groups as follows: sham, CLP, CLP+dexamethasone (DX, 0.2 mg/kg), CLP+ßS (1 mg/kg), CLP+imipenem (IMI, 20 mg/kg), and CLP+IMI (20 mg/kg)+ßS (1 mg/kg). Serum levels of IL-1ß, IL-6, IL-10, AST, ALT, and liver glutathione (GSH) were assessed by ELISA. Liver expression levels of TNF-α and NF-κBi mRNAs were evaluated by RT-qPCR. RESULTS: Serum concentrations of IL-1ß, IL-6, IL-10, ALT, and AST and mRNA levels of TNF-α and NF-κBi were all significantly higher in septic rats than in normal rats (p < 0.05). Liver GSH content was markedly lower in the CLP group than that in the sham group. ßS-treated rats had remarkably lower levels of IL-1ß, IL-6, IL-10, TNF-α, NF-κBi, AST, and ALT (51.79%, 62.63%, 41.46%, 54.35%, 94.37%, 95.30%, 34.87%, and 46.53% lower, respectively) and greater liver GSH content (35.71% greater) compared to the CLP group (p < 0.05). CONCLUSION: ßS may play a protective role in the septic process by mitigating inflammation. This effect is at least partly mediated by inhibition of the NF-κB signaling pathway. Thus, ßS can be considered as a supplementary treatment in septic patients.

Biosynthesis and recovery of selenium nanoparticles and the effects on matrix metalloproteinase-2 expression.

Today, green synthesis of nanoparticles is attracting increasing attention. In the present study, the Bacillus sp. MSh-1 was isolated from the Caspian Sea (located in the northern part of Iran) and identified by various identification tests and 16S ribosomal DNA analysis. The reduction time course study of selenium ion (Se(4+)) reduction by using this test strain was performed in a liquid culture broth. Then, the intracellular NPs (nanoparticles) were released by the liquid nitrogen disruption method and thoroughly purified using an n-octyl alcohol water extraction system. Characterization of the separated NPs on features such as particle shape, size and purity was carried out with different devices. The energy dispersive X-ray and X-ray diffraction patterns showed that the purified NPs consisted of only selenium and are amorphous respectively. In addition, the transmission electron micrograph showed that the separated NPs were spherical and 80-220 nm in size. Furthermore, the cytotoxicity effect of these extracted biogenic selenium (Se) NPs on the fibrosarcoma cell line (HT-1080) proliferation and the inhibitory effect of the Se NPs on MMP-2 (matrix metalloproteinase-2) expression were studied using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and gelatin zymography. Biogenic Se NPs showed a moderately inhibitory effect on MMP-2 expression.