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Azam Shamsian,1,2 Mohammad Reza Sepand,3 Marziye Javaheri Kachousangi,1,2 Tahereh Dara,4 Seyed Nasser Ostad,3 Fatemeh Atyabi,1,2 Mohammad Hossein Ghahremani1,3 1Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranCorrespondence: Mohammad Hossein GhahremaniDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, New Building, Room 2-318, Tehran 1417614411, IranTel/Fax +982166959102Email mhghahremani@tums.ac.irBackground: Among various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.Keywords: co-delivery, HDAC inhibitor, Wnt, cancer stem cell, protein corona

There are increasing concerns regarding the toxic effects of chlorpyrifos (CPF) on human health. Curcumin (CUR) is a yellow pigment isolated from turmeric ground rhizome of Curcuma longa Linn., which has been identified as an antioxidant agent. This study was designed to examine the protective effect of CUR and vitamin E (Vit E) on CPF-induced lung toxicity. Rats were divided into seven groups: control, CPF (13.5 mg/kg, orally), CPF + CUR (100 and 300 mg/kg, respectively, orally), CPF + α-tocopherol (Vit E, 150 mg/kg, intraperitoneally), CPF and CUR (100 and 300 mg/kg, respectively) in combination with α-tocopherol. The regimens were administered once daily for 28 days. At the end of the treatment period, lungs were collected for evaluation of oxidative factors and histopathological parameters. CUR and Vit E led to a decrease in lipid peroxidation in the lungs of the CPF-injected animals (48% and 51%, respectively). Glutathione peroxidase inhibited by CPF (91.9 nmol/min/mg protein) was induced again by CUR and Vit E (167.1 and 171.8 nmol/min/mg protein). CUR and Vit E caused a significant induction of superoxide dismutase (103.4 U/mg protein). Catalase activity almost returned to normalcy in CPF-intoxicated rats subjected to CUR + Vit E treatment (p < 0.001). Lung sections from CPF-treated rats displayed histopathological damages, while coadministration of CUR and Vit E resulted in apparently normal morphology with a significant decrease in injuries (p < 0.05). Our findings revealed that coadministration of Vit E and CUR to CPF-treated animals prevents the oxidative damages in the lung tissues. [ABSTRACT FROM PUBLISHER]

Aim: Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system. Oxidative stress via distinct pathobiological pathways plays a pivotal role in the formation and persistence of MS lesions. Acetyl-L-carnitine (ALC) facilitates the uptake of acetyl coenzyme-A into the mitochondria by a fatty acid oxidation process. ALC could be a therapeutic antioxidant in the myelin repair process. This study explored the potential neuroprotective effects of ALC in cuprizone (CPZ) intoxicated mice., Materials and Methods: Thirty male C57BL/6 mice were divided into three groups. The control animals received a normal diet. The CPZ and CPZ + ALC groups were fed with a 0.2% cuprizone diet for 12 weeks. In the CPZ + ALC group, animals received ALC (300 mg/kg/day) from the 10 th -12 th weeks. Animals were evaluated functionally by beam walking test (BWT) weekly. Eventually, the corpus callosum (CC) was extracted for histological, biochemical, and molecular studies., Results: BWT data showed ALC significantly improves balance and gait in the demyelinating mouse model. Histological staining represented ALC effectively increased remyelination in the CC. Biochemical evaluations demonstrated ALC decreased the malondialdehyde level with a parallel increase in the reduced glutathione and catalase activity levels in the CC. Molecular analysis revealed that ALC significantly increased the expression of oligodendrocyte transcription-2 (Olig-2) and Poly lipoproteins (Plp) genes in the CC., Conclusions: ALC improved balance and motor coordination in the demyelinated mouse model. It may be by reducing the levels of free radicals and increasing the expression of Olig-2 and Plp as myelin-related genes.

Background: More than 3 y into the coronavirus 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to undergo mutations. In this context, the Receptor Binding Domain (RBD) is the most antigenic region among the SARS-CoV-2 Spike protein and has emerged as a promising candidate for immunological development. We designed an IgG-based indirect enzyme-linked immunoassay (ELISA) kit based on recombinant RBD, which was produced from the laboratory to 10 L industry scales in Pichia pastoris., Methods: A recombinant-RBD comprising 283 residues (31 kDa) was constructed after epitope analyses. The target gene was initially cloned into an Escherichia coli TOP10 genotype and transformed into Pichia pastoris CBS7435 muts for protein production. Production was scaled up in a 10 L fermenter after a 1 L shake-flask cultivation. The product was ultrafiltered and purified using ion-exchange chromatography. IgG-positive human sera for SARS-CoV-2 were employed by an ELISA test to evaluate the antigenicity and specific binding of the produced protein., Results: Bioreactor cultivation yielded 4 g/l of the target protein after 160 h of fermentation, and ion-exchange chromatography indicated a purity > 95%. A human serum ELISA test was performed in 4 parts, and the ROC area under the curve (AUC) was > 0.96 for each part. The mean specificity and sensitivity of each part was 100% and 91.5%, respectively., Conclusion: A highly specific and sensitive IgG-based serologic kit was developed for improved diagnostic purposes in patients with COVID-19 after generating an RBD antigen in Pichia pastoris at laboratory and 10 L fermentation scales., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has a complex interaction with the immune system, including growing evidence of sex-specific differences in the immune response. Sex-disaggregated analyses of epidemiological data indicate that males experience more severe symptoms and suffer higher mortality from COVID-19 than females. Many behavioural risk factors and biological factors may contribute to the different immune response. This review examines the immune response to SARS-CoV-2 infection in the context of sex, with emphasis on potential biological mechanisms explaining differences in clinical outcomes. Understanding sex differences in the pathophysiology of SARS-CoV-2 infection will help promote the development of specific strategies to manage the disease., (© 2022 John Wiley & Sons Ltd.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated symptoms, named coronavirus disease 2019 (COVID-19), have rapidly spread worldwide, resulting in the declaration of a pandemic. When several countries began enacting quarantine and lockdown policies, the pandemic as it is now known truly began. While most patients have minimal symptoms, approximately 20% of verified subjects are suffering from serious medical consequences. Co-existing diseases, such as cardiovascular disease, cancer, diabetes, and others, have been shown to make patients more vulnerable to severe outcomes from COVID-19 by modulating host-viral interactions and immune responses, causing severe infection and mortality. In this review, we outline the putative signaling pathways at the interface of COVID-19 and several diseases, emphasizing the clinical and molecular implications of concurring diseases in COVID-19 clinical outcomes. As evidence is limited on co-existing diseases and COVID-19, most findings are preliminary, and further research is required for optimal management of patients with comorbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bigdelou, Sepand, Najafikhoshnoo, Negrete, Sharaf, Ho, Sullivan, Chauhan, Etter, Shekarian, Liang, Hutter, Esfandiarpour and Zanganeh.)

Questions and concerns regarding the efficacy and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines have plagued scientists since the BNT162b2 mRNA vaccine was introduced in late 2020. As a result, decisions about vaccine boosters based on breakthrough infection rates and the decline of antibody titers have commanded worldwide attention and research. COVID-19 patients have displayed continued severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-spike-protein-specific antibodies and neutralizing antibodies in longitudinal studies; in addition, cytokine activation has been detected at early steps following SARS-CoV-2 infection. Epitopes that are highly reactive and can mediate long-term antibody responses have been identified at the spike and ORF1ab proteins. The N-terminal domain of the S1 and S2 subunits is the location of important SARS-CoV-2 spike protein epitopes. High sequence identity between earlier and newer variants of SARS-CoV-2 and different degrees of sequence homology among endemic human coronaviruses have been observed. Understanding the extent and duration of protective immunity is consequential for determining the course of the COVID-19 pandemic. Further knowledge of memory responses to different variants of SARS-CoV-2 is needed to improve the design of the vaccine.

Despite numerous studies on the mechanisms of cigarette smoking toxicity over the past three decades, some aspects remain obscure. Recent developments have drawn attention to some hopeful indicators that allow us to advance our awareness of cigarette-induced cell death. Ferroptosis is considered a type of governed death of cells distinguished by the iron-dependent lipid hydroperoxide deposition to fatal concentrations. Ferroptosis has been linked with pathological settings such as neurodegenerative diseases, cancer, heart attack, hemorrhagic stroke, traumatic brain injury, ischemia-reperfusion injury, and renal dysfunction. This review tries to explain the causal role of ferroptosis cascade in cigarette smoke-mediated toxicity and cell death, highlighting associations on potential action mechanisms and proposing suggestions for its detoxifying and therapeutic interventions., (Copyright © 2021. Published by Elsevier Inc.)

Macrophages are a critical member of the innate immune system and can intensify tumor invasiveness and assist the growth of neoplastic cells. Moreover, they have the capability to reinforce immunosuppression and angiogenesis. Various investigations suggest that health-related issues, including inflammatory disorders and neoplastic diseases may be caused by environmental toxicant exposure. However, it is still unclear what role these environmental toxicants play in causing carcinogenesis by disturbing the mechanisms of migration, polarization, differentiation, and immune-stimulatory functions of macrophages. Accordingly, in this article, we will explore the interaction between environmental chemicals and inflammatory macrophage processes at the molecular level and their association with tumor progression and carcinogenesis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It is estimated that around 140 million people are drinking highly contaminated water with arsenic (As) as a natural earth's crust component. On the other hand, the prevalence of neurodegenerative disorders, especially Alzheimer's disease, is constantly increasing. The aim of the present study was to investigate the correlation between oral arsenic trioxide exposure and its impact on tau protein phosphorylation at Ser262. Fifty-four male mice were randomly divided into three groups and were freely accessed to food and contaminated water of 1 and 10 ppm arsenic trioxide for 3 months, except for control subjects. At the end of each month, As concentration and tau phosphorylation were checked with graphite furnace atomic absorption spectrometer and western blot analysis, respectively. Surprisingly, it was observed that the amount of measured brain arsenic in 10 ppm-exposed subjects was significantly increased after 3 months ( P -value ˂ 0.0001). The significant changes in tau phosphorylation were not seen in the 1 ppm-exposed subjects, and it was observed that Ser262 phosphorylation significantly increased after 2 and 3 months in the 10 ppm group ( P -value < 0.05). Our results demonstrated that arsenic accumulated in the brain time-dependently and increased Ser262 tau phosphorylation, which is very important in several tauopathies. In conclusion, it could be inferred that environmental arsenic exposure even at very low concentrations could be considered as a reason for increasing the risk of developing neurodegenerative disease., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Many tumors develop resistance to most of the apoptosis-based cancer therapies. In this sense targeting non-apoptotic forms of cell death including necroptosis, autophagy and ferroptosis may have therapeutic benefits in apoptosis-defective cancer cells. Nanomaterials have shown great advantages in cancer treatment owing to their unique characteristics. Besides, the capability of nanomaterials to induce different forms of cell death has gained widespread attention in cancer treatment. Reports in this field reflect the therapeutic potential of necroptotic cell death induced by nanomaterials in cancer. Also, autophagic cell death induced by nanomaterials alone and as a part of chemo-, radio- and photothermal therapy holds great promise as anticancer therapeutic option. Besides, ferroptosis induction by iron-based nanomaterials in drug delivery, immunotherapy, hyperthermia and imaging systems shows promising results in malignancies. Hence, this review is devoted to the latest efforts and the challenges in this field of research and its clinical merits., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Necroptosis is a regulated cell death that is governed by mixed lineage kinase domain-like, receptor-interacting serine-threonine kinase 3 and commonly displays with necrosis morphological characteristics. This study examined the molecular mechanisms involved in the chemical-induced necroptosis where a systematic evaluation of experimental studies addressing this issue is missing. We strictly reviewed all scientific reports related to our search terms including "necroptosis" or "programmed necrosis", "environmental chemicals" or "air pollutants" or "pesticides" or "nanoparticles" and "Medicines" from 2009 to 2019. Manuscripts that met the objective of this study were included for further evaluations. Studies showed that several pathological contexts like cancer, neurodegenerative disorders, and inflammatory diseases were related to necroptosis. Furthermore, multiple chemical-induced cytotoxic effects, such as DNA damage, mitochondrial dysregulation, oxidative damage, lipid peroxidation, endoplasmic reticulum disruption, and inflammation are also associated with necroptosis. The main environmental exposures that are related to necroptosis are air pollutants (airborne particulate matter, cadmium, and hydrogen sulfide), nanoparticles (gold, silver, and silica), pesticides (endosulfan, cypermethrin, chlorpyrifos, and paraquat), and tobacco smoke. To sum up, air pollutants, pesticides, and nanoparticles could potentially affect human health via disruption of cell growth and induction of necroptosis. Understanding the exact molecular pathogenesis of these environmental chemicals needs further comprehensive research to provide innovative concepts for the prevention approaches and introduce novel targets for the amelioration of a range of human health problems.

It is becoming increasingly accepted that various diseases have a capacity to alter the composition of plasma proteins. This alteration in protein composition may consequently change the targeting capacity of nanoparticles (NPs). In this study, the impact of a model targeting ligand's (i.e., Transferrin; Tf) concentration in human plasma on the targeting capacity of gold NPs (Au NPs), pre-conjugated with Tf, is investigated. Our findings demonstrate that the protein corona formation by both healthy and Tf depleted human plasma diminishes the targeting efficacy of Au NPs within human cancer cells despite a preservation of targeting ability by plasma with excess Tf (10-fold). Moreover, the plasma samples obtained from patients with various Tf levels (e.g., thalassemia major, sickle cell anemia, aplastic anemia, and iron deficiency anemia) have affected the accessibility of the targeting Tf in the corona layer and subsequently affected their targeting ability, which emphasizes the critical role of disease-specific protein corona on the efficacy of Au NPs. Ultimately, variations of protein concentration (e.g., due to disease occurrence and progress) in plasma affect its recruiting in corona formation, and in turn, affect the targeting and therapeutic efficacies of Au NPs.

Background: The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties., Objectives: The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity., Methods: Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p)., Results: After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats., Conclusions: EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.

Cuprizone (cup) model targets oligodendrocytes (OLGs) degeneration and is frequently used for the mechanistic understanding of de- and remyelination. Improperly, this classic model is time-consuming and the extent of brain lesions and behavioral deficits are changeable (both temporally and spatially) within a mouse strain. We aimed to offer an alternative, less time-consuming, and more reproducible cup model. Mice (C57BL/6) were treated with cup (400 mg kg -1  day -1 /gavage) for three consecutive weeks to induce OLGs degeneration with or without YM155 (1 mg kg -1  day -1 ) to examine the effects of this molecule in cup neurotoxicity. Co-administration of cup and YM155 (cuYM) accelerated the intrinsic apoptosis of mature OLGs (MOG positive cells) through the upregulation of caspase-9 and caspase-3. In addition to the stimulation of oxidative stress via reduction of glutathione peroxidase and induction of malondialdehyde, behavioral deficits in both Open-field and Rota-rod tests were worsened by cuYM. In the cuYM group, the expression of BIRC5, BIRC4 and NAIP was reduced, but no significant changes were observed in the abundance of the other inhibitor of apoptosis proteins (cIAP1 and cIAP2) in comparison with the cup group. Moreover, in silico analysis validated that YM155 directly interrupts the binding sites of certain transcription factors, such as krüppel-like family (Klf), specificity proteins (SPs), myeloid zinc fingers (MZFs), zinc finger proteins (ZNFPs), and transcription factor activating enhancer-binding proteins (TFAPs), on the promoters of target genes. In conclusion, this modified model promotes cup-induced redox and apoptosis signaling, elevates behavioral deficits, saves time, minimizes variations, and can be employed for early evaluation of novel neuroprotective agents in oligodendropathies.

Patients diagnosed with glioblastoma have poor prognosis. Conventional treatment strategies such as surgery, chemotherapy, and radiation therapy demonstrated limited clinical success and have considerable side effects on healthy tissues. A central challenge in treating brain tumors is the poor permeability of the blood-brain barrier (BBB) to therapeutics. Recently, various methods based on immunotherapy and nanotechnology have demonstrated potential in addressing these obstacles by enabling precise targeting of brain tumors to minimize adverse effects, while increasing targeted drug delivery across the BBB. In addition to treating the tumors, these approaches may be used in conjunction with imaging modalities, such as magnetic resonance imaging and positron emission tomography to enhance the prognosis procedures. This review aims to provide mechanistic understanding of immune system regulation in the central nervous system and the benefits of nanoparticles in the prognosis of brain tumors. This article is characterized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2019 Wiley Periodicals, Inc.)

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20 min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3 mg/kg) 20 min after induction of I/R, and (5) GR127935 (0.3 mg/kg) 15 min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3 mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

Benzo[α]pyrene (BaP) can have significant role in the development of breast cancer via aryl hydrocarbon receptor (AhR) activation. AhR activation has been studied in several functions such as survival, migration and invasion of cancer cells. In cancer, integrins contribute to the migration/invasion process and are regulated by nuclear factor of activated T cells (NFAT) and transforming growth factor (TGF) beta pathways. The aim of the present study was to examine the effect of BaP, an activator of AhR and cyclosporine A (CsA), as inhibitor of NFAT on migration and invasion of MDA-MB-231 cells. Furthermore, the effects of BaP and CsA were evaluated regarding the crosstalk of AhR, NFAT1 and TGF-β receptor 1 signaling. Treatment of MDA-MB-231 with BaP resulted in significantly more live cells in low doses; however, blocking NFAT with CsA decreased the viability of the cells. Activation of AhR by BaP induced invasion as well as migration in MDA-MB-231 cells, which was blocked by AhR antagonist. Unlike BaP, block of NFAT with CsA inhibited cell migration and cell invasion. In these cells, BaP significantly reduced AhR expression while this reduction was reversed by CH-223191; however, CsA treatment lowered the AhR expression only at low dose. The level of β4 integrin was significantly reduced by CsA at 1 and 2.5 μm. Protein levels of Snail and TGF-β receptor 1 were not significantly altered by BaP and CsA treatments. Considering these findings, the low AhR expression and high β4 integrin level following BaP and/or CsA treatments may contribute to the higher invasion/migration in MDA-MB-231 cells., (© 2018 John Wiley & Sons, Ltd.)

Augmentation of mitochondrial oxidative stress through activating a series of deadly events has implicated as the main culprit of arsenic toxicity and therapeutic approaches based on improving mitochondrial function hold a great promise for attenuating the arsenic-induced toxicity. Acetyl-L-carnitine (ALC) through balancing the coenzyme A (CoA)/acyl-CoA ratio plays an important role in mitochondrial metabolism and thereby can help protect hippocampal neurons from oxidative damage. In the present study, we aimed to explore the effect of arsenic interactions on the mitochondrial function in the hippocampus of rats. Rats were randomly divided into five groups of control (distilled water), sodium arsenite (NaAsO 2 , 20 mg/kg), and co-treatment of NaAsO 2 with various doses of ALC in three groups (100, 200, 300 mg/kg) and were treated orally for 21 consecutive days. Our results point out that arsenic exposure caused oxidative stress in rats' hippocampus, which led to the reactive oxygen species (ROS) generation, mitochondrial swelling, the collapse of the mitochondrial membrane potential, and release of cytochrome c. It also altered Bcl-2/Bax expression ratio and increased caspase-3 and caspase-9 activities. Furthermore, arsenic exposure via activation of NF-κB and microglia increased inflammation. ALC could concentration-dependently counteract the arsenic-induced oxidative stress, modulate the antioxidant defense capacity, and improve mitochondrial functions. In addition, ALC decreased the expression of both death-associated proteins and of inflammatory markers. These findings indicate that ALC improved the arsenic-induced hippocampal mitochondrial dysfunction which underlines the importance of ALC in providing a possible therapeutic strategy for the prevention of arsenic-induced neurodegeneration.

Alzheimer's disease (AD), a neurodegenerative disorder in elderly, is indicated with deposition of Amyloid β (Aβ) in the brain and accompanied with cognitive impairment. Bucladesine, a phosphodiesterase inhibitor, may ameliorate AD's cognitive dysfunctions through mimicking the action of cAMP and raising its intracellular level. Here, we investigated the effects of bucladesine on Aβ-induced memory and learning impairment in a Morris water maze (MWM) model. Rats were injected with bucladesine (1 μl/side from a 100 μM stock solution) and Aβ (1 μl/side from a 100 μM stock solution) intra-hippocampally and after 19 days were trained for 4 successive days. The oxidative stress was evaluated through measurement of thiobarbituric acid (TBARS), thiol groups, and ferric reducing antioxidant power (FRAP). Effect of Aβ and its combination with bucladesine on the mitochondrial function was assessed according to changes in the ROS generation, mitochondrial membrane potential (MMP), mitochondrial swelling, ATP/ADP ratio, mitochondrial outer membrane damage and cytochrome C release. Our results showed a significant elevation in TBARS level after administration of Aβ causing mitochondrial ROS generation, swelling, outer membrane damage, cytochrome C release and also lower thiol, FRAP, and MMP levels. Aβ-induced spatial memory impairment was prevented by pre-treatment with bucladesine and the changed mitochondrial and biochemical indices upon treatment dose were improved. Taken together, we have obtained satisfactory results suggesting protecting effects of bucladesine against the Aβ-mediated memory deficit and implying its plausible beneficial capacity as a therapeutic agent in oxidative stress-associated neurodegenerative diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l-carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5 mg/kg) and arsenic plus ALC (5 mg/kg; 100, 200, 300 mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24 h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-ĸB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mesenchymal stem cells (MSCs) have therapeutic potential for treatment of diabetes. However, in vitro behavior of MSCs in high glucose condition as well as presence of glucose lowering agents is not fully understood. Because MSCs have an important role in tissue repair, we examined the effects of metformin and celecoxib on viability of MSCs in different glucose conditions. MSCs, from umbilical cord blood, were cultured in normoglycemic (glucose 5.5 mM), midglycemic (glucose 10 mM), and hyperglycemic (glucose 25 mM) conditions, and the cell viability was evaluated by MTT assay. The cytotoxicity and secretion of GDF-15 were further tested in MSCs treated with metformin and celecoxib in various glucose concentrations. Our results showed that high glucose condition lowered viability of MSCs. Metformin treatment also inhibited proliferation of MSCs, but its toxicity was not changed in high glucose condition. Celecoxib induced cytotoxicity in MSCs, and the toxicity was increased in high glucose condition. Metformin and celecoxib induced release from MSCs; however, high glucose inhibited the metformin-induced GDF-15 release. These findings suggested that metformin did not increase the cytotoxicity of high glucose condition in MSCs. Moreover, celecoxib treatment in diabetic condition can reduce the viability of MSCs to proliferate and regenerate perhaps via change in release of GDF-15., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objectives: The aim of this study was to investigate the possible protective effect of ellagic acid (EA) against gentamicin (GEN)-induced nephrotoxicity using biochemical, molecular and histopathological approaches., Methods: Rats (n = 24) were divided into four groups: control, GEN (100 mg/kg, i.p.), EA (10 mg/kg, p.o.) and GEN plus EA. The regimes were administered for 10 successive days. 24 h after last treatment, kidney and blood samples were collected., Key Findings: Ellagic acid treatment significantly reduced plasma creatinine and urea levels, which were initially increased due to GEN administration. Also, EA significantly ameliorated oxidative stress markers including lipid peroxidation, catalase (CAT) and superoxide dismutase (SOD) enzyme activity as well as glutathione (GSH) content in kidney tissue. Activation of caspase-3 and increase in the ratio of Bcl-2/Bax expression observed in GEN-treated group were significantly ameliorated by EA treatment. EA also protected GEN-induced mitochondrial damages as indicated by decreasing the mitochondrial ROS content, preventing of mitochondrial membrane potential (MMP) loss, reducing mitochondrial swelling and decreasing cytochrome c release. In addition, histopathological findings revealed that EA ameliorates GEN-induced kidney injury., Conclusions: Our findings suggest that EA treatment attenuates GEN-induced nephrotoxicity, which may be ascribed to its antioxidant and anti-apoptotic properties., (© 2016 Royal Pharmaceutical Society.)

Background: Sepsis is a debilitating systemic disease and described as a severe and irregular systemic inflammatory reaction syndrome (SIRS) against infection. We employed CLP (Cecal Ligation and Puncture) model in rats to investigate anti-inflammatory and antioxidant effects of phloretin, as a natural antioxidant agent, and its protective effect on liver tissue damage caused by sepsis., Methods: Male Wistar albino rats were randomly divided into three groups: sham group, CLP induced sepsis group and phloretin treated CLP group. Sepsis was induced by CLP method. 50 mmol/kg Phloretin was administered intraperitoneally in two equal doses immediately after surgery., Results: It was observed that blood urea nitrogen (BUN) and tumor necrosis factor alpha (TNF-α) levels were dramatically increased in the CLP induced sepsis group (43.88 ± 1.905 mg/dl, 37.63 ± 1.92, respectively) when compared to the sham group. Moreover, tissue Glutathione (GSH) and liver nuclear factor ĸB (NF-ĸB p65) transcription factor values were higher in CLP induced sepsis group. This elevation was considerably reduced in the phloretin treated CLP group. No significant differences were observed in serum creatinine and creatinine phosphokinase levels., Conclusions: The present study suggested that phloretin, as a natural protective agent, act against tissue damages introduced following the experimental sepsis induced model, likely caused by free oxygen radicals.

Arsenic (As) is a widespread environmental contaminant present around the world in both organic and inorganic forms. Oxidative stress is postulated as the main mechanism for As-induced toxicity. This study was planned to examine the protective effect of acetyl-L-carnitine (ALC) on As-induced oxidative damage in male rats. Animals were randomly divided into four groups of control (saline), sodium arsenite (NaAsO2, 20 mg/kg), ALC (300 mg/kg), and NaAsO2 plus ALC. Animals were dosed orally for 28 successive days. Blood and tissue samples including kidney, brain, liver, heart, and lung were collected on the 28th day and evaluated for oxidative damage and histological changes. NaAsO2 exposure caused a significant lipid peroxidation as evidenced by elevation in thiobarbituric acid-reactive substances (TBARS). The activity of antioxidant enzymes such as glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), as well as sulfhydryl group content (SH group) was significantly suppressed in various organs following NaAsO2 treatment (P < 0.05). Furthermore, NaAsO2 administration increased serum values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and bilirubin. Our findings revealed that co-administration of ALC and NaAsO2 significantly suppressed the oxidative damage induced by NaAsO2. Tissue histological studies have confirmed the biochemical findings and provided evidence for the beneficial role of ALC. The results concluded that ALC attenuated NaAsO2-induced toxicity, and this protective effect may result from the ability of ALC in maintaining oxidant-antioxidant balance.

Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD.

Context: The application of bleomycin is limited due to its side effects including lung toxicity. Silymarin is a flavonoid complex isolated from milk thistle [Silybum marianum L. (Asteraceae)] which has been identified as an antioxidant and anti-inflammatory compound., Objective: This study evaluates the effect of silymarin on oxidative and inflammatory parameters in the lungs of mice exposed to bleomycin., Materials and Methods: BALB/c mice were divided into four groups of control, bleomycin (1.5 U/kg), bleomycin plus silymarin (50 and 100 mg/kg). After bleomycin administration, mice received 10 d intraperitoneal silymarin treatment. On 10th day, blood and lung samples were collected for measurement of oxidative and inflammatory factors., Results: Silymarin led to a decrease in lung lipid peroxidation (0.19 and 0.17 nmol/mg protein) in bleomycin-injected animals. Glutathione-S-transferase (GST) which was inhibited by bleomycin (32.4 nmol/min/mg protein) induced by higher dose of silymarin (41 nmol/min/mg protein). Silymarin caused an elevation in glutathione (GSH): 2.6 and 3.1 µmol/g lung compare with bleomycin-injected animals 1.8 µmol/g lung. Catalase (CAT) was increased due to high dose of silymarin (65.7 µmol/min/ml protein) compare with bleomycin treated-mice. Myeloperoxidase (MPO) which was induced due to bleomycin (p < 0.05) reduced again by high dose of silymarin (0.51 U/min/mg protein). Bleomycin led to an increase in TNF-α and interleukin-6 (IL-6) (7.9 and 11.8 pg/ml). These parameters were reduced by silymarin (p < 0.05)., Conclusions: Silymarin attenuated bleomycin induced-pulmonary toxicity. This protective effect may be due to the ability of silymarin in keeping oxidant-antioxidant balance and regulating of inflammatory mediator release.

Alzheimer's disease (AD) is a neurodegenerative disease that was characterized with deposit of beta amyloid (Aβ) aggregate in senile plaque. Oxidative damage to neurons and loss of cholinergic neurons in forebrain region are observed in this disease. Melissa officinalis is a medicinal plant from Lamiaceae family, used traditionally in the treatment of cognitive disorders. It has cholinomimetic and potent antioxidant activity. In the present study, we investigated the possible neuroprotective effects of total ethanolic extract, acidic and nonacidic fraction of Melissa officinalis on Aβ-induced cytotoxicity and oxidative stress in PC12 cells and also measured their in-vitro anticholinesterase activity. PC12 cells were incubated with the extract and fractions prior to the incubation with Aβ and cell toxicity was assessed by MTT assay. In addition, productions of reactive oxygen species (ROS), Malondialdehyde (MDA) as a biomarker of lipid peroxidation and glutathione peroxidase activity were measured. Pretreatment of cells with total extract and acidic fraction (not non-acidic fraction) had protective effect against Aβ-induced oxidative changes and cell death. In concentrations in which both total extracts of an acidic fraction showed neuroprotective effects, inhibition of cholinesterase activity was not significant. Then, the protective effects of Melissa officinalis total extract and acidic fraction were not attributed to their anticholinesterase activity. Acidic fraction showed more potent protective effect compared to the total extract, leading to the fact that polyphenolic compounds and terpenoic acids are the most effective components in the total extract concentrated in this fraction.