Showing papers in "Human & Experimental Toxicology in 2020"
TL;DR: The data suggest that the worldwide burden of CO poisoning remains stable, and the number of fatal outcomes and percentage of patients who die have both consistently declined during the last 25 years, but the unreliability of the primary data sources in many countries with respect to accurate diagnosis means that caution is required, and that field studies, particularly in poorer countries, are required.
Abstract: This article presents updated information on the worldwide burden of carbon monoxide (CO) poisoning. The worldwide epidemiologic data were obtained from the Global Health Data Exchange registry, a large database of health-related data maintained by the Institute for Health Metrics and Evaluation. The worldwide cumulative incidence and mortality of CO poisoning are currently estimated at 137 cases and 4.6 deaths per million, respectively. The worldwide incidence has remained stable during the last 25 years, while both mortality and percentage of patients who died have declined by 36% and 40%, respectively. The incidence of CO poisoning does not differ between sexes, whilst mortality is double in men. The incidence shows two apparent peaks, between 0-14 years and 20-39 years. The percentage of patients who died constantly increases in parallel with aging, peaking in patients aged 80 years or older. The number of CO poisoning grows in parallel with the socio-demographic index (SDI), though more detailed analyses would be needed to confirm our findings. Mortality displays a similar trend, being approximately 2.1- and 3.6-fold higher in middle and middle-to-high than in low-to-middle SDI countries. In conclusion, while these data suggest that the worldwide burden of CO poisoning remains stable, and the number of fatal outcomes and percentage of patients who die have both consistently declined during the last 25 years, the unreliability of the primary data sources in many countries with respect to accurate diagnosis of CO poisoning means that caution is required, and that field studies, particularly in poorer countries, are required.
70 citations
TL;DR: The cytoprotective and anti-inflammatory properties of tert-butylhydroquinone, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, against gastric mucosal damage induced by acute exposure of ethanol are investigated.
Abstract: Gastric ulcer (GU) is the most common health concern that occurs due to alcohol consumption, smoking and physiological stress. Ethanol-induced GU in animal model resembles the pathophysiology of human ulcer. The present study was designed to investigate the cytoprotective and anti-inflammatory properties of tert-butylhydroquinone (tBHQ), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, against gastric mucosal damage induced by acute exposure of ethanol (5 ml/kg). The intervention of tBHQ (25 and 50 mg/kg, per os (po)) and omeprazole (20 mg/kg, po) was done for 10 consecutive days. Omeprazole was chosen as a standard drug because it is prescribed for the treatment of GU. Pretreatment of tBHQ decreased gastric mucosal lesion, ulcer index, apoptotic cells and lipid peroxidation level induced by ethanol. Furthermore, the intervention of tBHQ increased gastric mucosa integrity, pH, reduced glutathione, collagen and mucus-producing goblet cells. Intervention of tBHQ increased the expression of antioxidant markers such as Nrf2, haeme oxygenase-1 and catalase and decreased the expressions of inflammatory markers such as nuclear factor kappa-light-chain-enhancer of activated B cells and cyclooxygenase-2. The cytoprotective potential of tBHQ against gastric mucosal damage might be due to its ability to enhance cellular antioxidants and anti-inflammatory responses.
49 citations
TL;DR: This study found that Exos derived from mmu_circ_0000623-modified ADSCs prevented liver fibrosis via activating autophagy, and circRNA expression profiles of hepatic tissue from normal and CCl4-induced mice were analyzed using high-throughput circRNA microarrays.
Abstract: Prolonged parenchymal cell death leads to activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Increasing evidence shows that exosomes (Exos) secreted by adipose-derived mesenchymal stem cells (ADSCs) can be used to deliver circular RNAs (circRNAs) to treat liver fibrosis. To explore the uses of circRNA, circRNA expression profiles of hepatic tissue from normal and CCl4-induced mice were analyzed using high-throughput circRNA microarrays. The result showed that mmu_circ_0000623 expression was downregulated in CCl4-induced mice. Bioinformatics analysis and luciferin reporter experiments showed that mmu_circ_0000623 interacted with and regulated miR-125/ATG4D. In vitro and in vivo experiments showed that Exos from ADSCs, especially from mmu_circ_0000623-modified ADSCs, significantly suppressed CCl4-induced liver fibrosis by promoting autophagy activation. Autophagy inhibitor treatment significantly reversed the treatment effects of Exos. Proteins involved in autophagy and autophagy plaques positive for ATG4D expression were regulated by mmu_circ_0000623/miR-125. Our study found that Exos derived from mmu_circ_0000623-modified ADSCs prevented liver fibrosis via activating autophagy.
36 citations
TL;DR: It was concluded that H2S provided significant hepatoprotection in MTX-challenged rats through its antioxidant, anti-inflammatory, and anti-apoptotic effects.
Abstract: Methotrexate (MTX) is a commonly used anticancer and immunosuppressive agent. However, MTX can induce hepatotoxicity due to oxidative stress, inflammation, and apoptosis. Hydrogen sulfide (H2S), the endogenous gaseous molecule, has antioxidant, anti-inflammatory, and anti-apoptotic effects. The present work explored the probable protective effect of H2S against MTX hepatotoxicity in rats and also the possible mechanisms underlying this effect. MTX was given at a single intraperitoneal (i.p.) dose of 20 mg/kg. Sodium H2S (56 µmol /kg/day, i.p.), as H2S donor, was given for 10 days, starting 6 days before MTX administration. H2S significantly reduced serum alanine aminotransferase, hepatic malondialdehyde, interleukin 6, nuclear factor κB p65, cytosolic cytochrome c, phosphorylated signal transducer and activator of transcription 3, and Bax/Bcl-2 ratio and significantly increased hepatic total antioxidant capacity and endothelial nitric oxide synthase (eNOS) in rats received MTX. In addition, H2S minimized the histopathological injury and significantly decreased the expression of STAT3 in liver tissue of MTX-challenged rats. The effects of H2S were significantly antagonized by administration of glibenclamide as KATP channel blocker, Nω-nitro-l-arginine, as eNOS inhibitor, or ruthenium red, as transient receptor potential vanilloid 1 (TRPV1) antagonist. It was concluded that H2S provided significant hepatoprotection in MTX-challenged rats through its antioxidant, anti-inflammatory, anti-apoptotic effects. These effects are most probably mediated by the ability of H2S to act as IL-6/STAT3 pathway modulator, KATP channel opener, eNOS activator, and TRPV1 agonist.
35 citations
TL;DR: Piperine ameliorated the progression of TNBS-induced colitis by modulating the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha/nuclear factor-kappa B signaling pathway, thus inhibiting the overexpression of proinflammatory cytokines and proapoptotic proteins.
Abstract: Background:Inflammatory bowel disease is a chronic immunoinflammatory disease of the gastrointestinal tract. Piperine, an alkaloid, has been reported to possess antioxidant, anti-inflammatory, anti...
32 citations
TL;DR: ZnO NPs have shown effective antimicrobial and antibiofilm activities against tested microorganisms and could be used as coating materials and in a wide range of industrial applications, such as pharmaceutical industries and cosmetics.
Abstract: In the present study, Veronica multifida leaf extract and zinc acetate dihydrate were utilized to synthesize zinc oxide (ZnO) nanoparticles (NPs) eco-friendly and cost-effectively under different physical conditions. Soxhlet extractor was used for the preparation of aqueous plant extract. UV-Vis (ultraviolet-visible) spectrophotometer, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and transmission electron microscope (TEM) were used to characterize the ZnO NPs. UV-Vis spectrophotometer in the range of 200-800 nm was used to get information about the formation of ZnO NPs at different pH and temperatures. FTIR spectrum revealed the presence of functional groups in ZnO NPs. XRD, scanning electron microscope, and TEM analyses confirmed the crystal structure and average size of ZnO NPs. The antimicrobial activities of ZnO NPs were tested on microorganisms, that is, Escherichia coli ATCC 43895, Staphylococcus aureus ATCC 29213, Bacillus subtilis, Bacillus licheniformis, Pseudomonas aeruginosa, and Salmonella typhimurium. Moreover, antibiofilm activity of ZnO NPs was performed against P. aeruginosa and S. aureus ATCC 29213. ZnO NPs have shown effective antimicrobial and antibiofilm activities against tested microorganisms. The results elucidated that eco-friendly and cost-effectively produced ZnO NPs could be used as coating materials and in a wide range of industrial applications, such as pharmaceutical industries and cosmetics.
31 citations
TL;DR: It is concluded that the toxicity of CNTs in specific organs can be minimized through particular surface functionalizations, and the SWCNTs-COOH had the least alterations in most of the parameters.
Abstract: Carbon nanotubes (CNTs) have emerged as a new class of multifunctional nanoparticles in biomedicine, but their multiple in vivo effects remain unclear. Also, the impact of various functionalization types and duration of exposures are still unidentified. Herein, we report a complete toxicological study to evaluate the effects of single- and multiwalled carbon nanotubes (SWCNTs and MWCNTs) with either amine or carboxylic acid (COOH) surface functional groups. The results showed that significant oxidative stress and the subsequent cell apoptosis could be resulted in both acute and, mainly, in chronic intravenous administrations. Also, male reproductive parameters were altered during these exposures. The amino-functionalized CNTs had more toxic properties compared with the COOH functionalized group, and also, in some groups, the multiwalled nanotubes were more active in eliciting cytotoxicity than the single-walled nanotubes. Interestingly, the SWCNTs-COOH had the least alterations in most of the parameters. Evidently, it is concluded that the toxicity of CNTs in specific organs can be minimized through particular surface functionalizations.
29 citations
TL;DR: The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin, and attenuated the various events in the progression of liver fibrosis via PPar-γ mediated modulation of inflammatory and fibrogenic pathways.
Abstract: Background:Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide. In the present study, we have evaluated the antifibrotic effect of crocin, a...
29 citations
TL;DR: Evidence is provided that lycopene exerted a neuroprotective effect against BPA intoxication in hippocampi of rats via its antioxidant properties, activation of MAPK/ERK pathway, and inhibiting a neuronal apoptosis which reflected on improving the learning and cognition memory.
Abstract: Bisphenol A (BPA) is used to produce polycarbonate plastic and epoxy resins which are used in many consumer products. Most people encounter BPA in their daily routines. However, it has been heavily reported that BPA has a neurotoxic effect. The present study aimed to investigate the effect of lycopene on cognitive deficits induced by a high dose of BPA focusing on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, oxidative stress, apoptosis, and memory retrieval in adult male rats. Therefore, 72 rats were divided into four groups: control group, BPA group (50 mg/kg body weight (bw)) 3 days a week for 42 days, lycopene group (10 mg/kg bw) daily for 42 days, and lycopene + BPA group. Concurrent treatment of lycopene with BPA improved the learning and cognition memory in Morris water maze and novel object recognition tests along with an increase in acetylcholine esterase activity as well as inhibition of oxidative stress by restoring reduced glutathione and suppressing malondialdehyde hippocampal level to their normal levels. Mechanistically, lycopene upregulated the protein expression of tyrosine receptor kinase B, which resulted in an upsurge in its downstream cascades MAPK/ERK1/2/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus of BPA-intoxicated rats. Furthermore, concurrent treatment of lycopene with BPA prevented apoptosis by marked decrease in Bcl-2 associated X protein (Bax) gene expression and caspase 3 activity while restoring B-cell leukemia/lymphoma-2 (Bcl-2) gene expression. In conclusion, the present study provided evidence that lycopene exerted a neuroprotective effect against BPA intoxication in hippocampi of rats via its antioxidant properties, activation of MAPK/ERK pathway, and inhibiting a neuronal apoptosis which reflected on improving the learning and cognition memory.
28 citations
TL;DR: CRV administration could prevent the deleterious effects of DM on testicular germ cells, and it increases the levels of hormones and some essential genes, such as SF-1, LHCGR, and FSHR, involved in the process of spermatogenesis.
Abstract: Diabetes mellitus (DM) is a complex metabolic disease and it is also closely associated with a reduction in fertility in male patients. The purpose of the present study was to investigate the antidiabetic effect of carvacrol (CRV), as a potent antioxidant, on the numbers of germ cells and Sertoli cells in testicular tissue, and the messenger RNA (mRNA) and protein expression of some genes involved in spermatogenesis, including luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), and steroidogenic factor 1 (SF-1), as well as hormones such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and insulin. Adult male Wistar rats (n = 32) were randomly divided into four groups (eight animals per group), including healthy control that received 0.2% Tween 80, diabetic control group, the diabetic group treated orally with CRV (75 mg/kg), and CRV group that received orally CRV (75 mg/kg). The duration of the treatment period lasted 8 weeks. In the diabetic group, the numbers of Sertoli cells and germ cells were significantly decreased, while the treatment with CRV prevented the degree of the damage to the cells mentioned earlier. CRV administration elevated the concentrations of insulin, T, FSH, and LH. Moreover, treatment with CRV significantly enhanced the levels of the mRNA and protein expression of SF-1, LHCGR, and FSHR. According to the obtained results, CRV administration could prevent the deleterious effects of DM on testicular germ cells, and it increases the levels of hormones and some essential genes, such as SF-1, LHCGR, and FSHR, involved in the process of spermatogenesis.
27 citations
TL;DR: Findings may suggest that LUT may be useful for attenuating neuronal damage induced by PbAc through inhibiting the oxidative damage, neuroinflammation, and the cortical cell death.
Abstract: Luteolin (LUT) is a glycosylated flavonoid compound that has multiple beneficial pharmacological and biological impacts. The current investigation was undertaken to evaluate the putative neuroprotective potency of LUT against neuronal damage induced by lead acetate (PbAc). Twenty-eight rats were placed into four equal groups. Group 1: served as the control group, group 2: rats were supplemented orally with LUT (50 mg kg-1), group 3: rats were intraperitoneally injected with PbAc (20 mg kg-1), and group 4: rats were pretreated with LUT before PbAc injection with the same doses. All animals were treated for 7 days. The exposure to PbAc increased the concentration of lead in the cortical tissue, neuronal lipid peroxidation, and nitric oxide (NO) production and decreased the antioxidant enzymes. Additionally, PbAc enhanced a neuroinflammatory response in the cortical tissue through increasing the pro-inflammatory cytokines secretion and inducible NO synthase expression. Moreover, cortical cell death was recorded following PbAc intoxication as evidenced by the enhancement of the proapoptotic and inhibiting the antiapoptotic markers. Interestingly, LUT supplementation reversed the cortical adverse reactions induced by PbAc. Taken together, these findings may suggest that LUT may be useful for attenuating neuronal damage induced by PbAc through inhibiting the oxidative damage, neuroinflammation, and the cortical cell death.
TL;DR: THQ can be used as a protective agent to reduce the toxic effects of DOX and there was improvement in testicular tissue in DOX + THQ group compared to the DOX group.
Abstract: Background:Doxorubicin (DOX) is used for treatment of many cancer types. Thymoquinone (THQ) is a powerful antioxidant agent used for reducing side effects of several drugs. The aim of this study is...
TL;DR: Phytoremediation is important in that it is a prevalent in situ remediation technique and its advantages include the use of solar energy, cost-effectiveness, easy operation, reduction in secondary contaminants, theUse of biomass for biofuel production and low-cost adsorbents.
Abstract: Environmental pollution is significant and oftentimes hazardous in the areas, where mining, foundries and smelters and other metallurgical operations are located. Systematic research on the chronic effects of metals started during the past century; nevertheless, it is evident that even today, there are large gaps in knowledge regarding the assessment of the health effects caused by environmental and occupational exposures to these metals. Heavy metals induce the production of reactive oxygen species (ROS) causing oxidative stress, make several repair-inhibiting cellular changes and alter the DNA repair processes. They favour the 'false' repairing of double-strand breaks (DSBs), propagate DNA mutations and induce carcinogenesis. A detailed literature search was performed using the MedLine/PubMed database. Depending on the mechanism of action, arsenicals can act as genotoxins, non-genotoxic agents and carcinogens. Cadmium can bind to proteins, reduce DNA repair, activate protein degradation, up-regulate cytokines and proto-oncogenes (c-fos, c-jun and c-myc), induce the expression of metallothionein, haeme-oxygenases, glutathione transferases, heat-shock proteins, acute-phase reactants and DNA polymerase β at lower concentrations. Inorganic mercury damages oxidative phosphorylation and electron transport pathways at the ubiquinone-cytochrome b5 locus and thus induces ROS production. Abandoned mining areas generate environmentally persistent waste. These specific sites urgently require maximally efficient and cheap remediation. This bears the need for methodologies employing green and sustainable remediation. Phytoremediation is important in that it is a prevalent in situ remediation technique. Its advantages include the use of solar energy, cost-effectiveness, easy operation, reduction in secondary contaminants, the use of biomass for biofuel production and low-cost adsorbents.
TL;DR: The literature reviewed in the present report supports the hypothesis that MET can reduce the cardiotoxicity that often occurs with DOX treatment.
Abstract: Doxorubicin (DOX) is an antineoplastic agent obtained from Streptomyces peucetius. It is utilized in treating different kinds of cancers, such as leukemia, lymphoma, and lung, and breast cancers. The main side effect of DOX is cardiotoxicity. Metformin (MET) is an antihyperglycemic drug used for type 2 diabetes treatment. It is proposed that MET has a protective effect against DOX cardiotoxicity. Our review demonstrated that MET has several possible mechanisms of action, which can prevent or at least reduce DOX cardiotoxicity including a decrease of free radical generation and oxidative stress, 5' adenosine monophosphate-activated protein kinase activation, and ferritin heavy chain expression in cardiomyocytes cells. The combination of MET and DOX has been shown to enhance the anticancer activity of DOX by a number of authors. The literature reviewed in the present report supports the hypothesis that MET can reduce the cardiotoxicity that often occurs with DOX treatment.
TL;DR: Curcumin, as a potent antioxidant, could compensate the adverse effects of cadmium on lipid and protein peroxidation, potentiated serum antioxidant defense system, and ameliorated some morphometrical parameters in the testis of cadMium-treated mice.
Abstract: Background:Cadmium is an environmental pollutant which can induce the overproduction of free radicals while suppressing the antioxidant defense system. Curcumin is considered a free-radical scaveng...
TL;DR: Both selenium and nanoselenium show potential antioxidant activity and promote recovery from the neurotoxic action of Cd, revealing that Cd decreases antioxidant enzymes and increases oxidative stress in the brain.
Abstract: Because cadmium (Cd) is not naturally degradable by ecosystems, it interferes with many types of food chains. Cd accumulates in the kidney, liver and in the nervous tissues, especially the brain. The neurotoxicity of Cd is very high, as it alters the integrity, and increases the permeability, of the blood-brain barrier. Cd penetrates and accumulates in neurons in the brains of rats. This study reveals that Cd decreases antioxidant enzymes and increases oxidative stress in the brain. In addition, Cd increases lipid peroxidation of brain tissues. Cd increases the expression of the Cu/Zn superoxide dismutase gene. It also affects cholinergic, glutamatergic, gamma-Aminobutyric acid (GABAergic), dopamine, serotonin and acetylcholine neurotransmitters in brain tissue. Consequently, Cd increases the formation of amyloid β, a neurotoxic index, and induces apoptosis by changing the quality and the quantity of Bcl-2, Bax and p53 proteins. In conclusion, both selenium and nanoselenium show potential antioxidant activity and promote recovery from the neurotoxic action of Cd.
TL;DR: The toxic effects of N. oleander are mostly related to its inhibitory effects on the Na+-K+ ATPase pump in the cellular membrane, however, the exact molecular mechanism involved in the toxicity is not clear.
Abstract: Introduction: Nerium oleander is a plant that is frequently grown in gardens and public areas. N. oleander is distributed originally in subtropical Asia but is now growing in many parts of the worl...
TL;DR: It is highlighted that Zn and Se combination treatment might be a better strategy for the germ cell protection in diabetes and deserve further investigation.
Abstract: Diabetes increases the possibility of germ cell damage, hypogonadism, and male infertility. Diabetic condition negatively impacts zinc (Zn) and selenium (Se) levels in the body. Zn and Se are among the most important trace elements involved in the regulation of redox reaction, antioxidants enzymes activities, and DNA expression in a germ cell. The present study aimed to elucidate the combined effects of Zn and Se treatment on diabetes-induced germ cell damage in male Sprague Dawley rats. Type 1 diabetes was induced by the single intraperitoneal (i.p.) injection of streptozotocin (55 mg/kg). Zn (3 mg/kg, i.p.) and Se (0.5 mg/kg, i.p.) were administered daily for 8 consecutive weeks. All the animals were provided with normal feed and water throughout the study. The effects on germ cell damage were evaluated by body weight, feed-water intake, organ weight, sperm count, motility, sperm head morphology, biochemical analysis, histology, immunohistochemistry, halo assay, germ cell comet assay, testes terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling (TUNEL) assay, sperm TUNEL assay, serum protein pattern analysis, and subcellular analysis using transmission electron microscopy. Further, the expressions of nuclear erythroid-derived related factor 2, catalase, glutathione peroxidase 4, and glutathione peroxidase 5 were carried out to ascertain the mechanism of protection. The present results demonstrated that 8 weeks combined treatment of Zn (3 mg/kg, i.p.) and Se (0.5 mg/kg, i.p.) reduced diabetes-induced germ cell damage. This study further highlighted that Zn and Se combination treatment might be a better strategy for the germ cell protection in diabetes and deserve further investigation.
TL;DR: Current evidence supporting the role of miRNAs in ALI is summarized and proposed as potential biomarkers for ALI and as therapeutic targets for this disease.
Abstract: MicroRNAs (miRNAs) are small noncoding RNAs stretching over 18-22 nucleotides and considered to be modifiers of many respiratory diseases. They are highly evolutionary conserved and have been implicated in several biological processes, including cell proliferation, apoptosis, differentiation, among others. Acute lung injury (ALI) is a fatal disease commonly caused by direct or indirect injury factors and has a high mortality rate in intensive care unit. Changes in expression of several types of miRNAs have been reported in patients with ALI. Some miRNAs suppress cellular injury and accelerate the recovery of ALI by targeting specific molecules and decreasing excessive immune response. For this reason, miRNAs are proposed as potential biomarkers for ALI and as therapeutic targets for this disease. This review summarizes current evidence supporting the role of miRNAs in ALI.
TL;DR: It is shown that the groups with the highest levels of Pb, Hg, and Cd had a 56%, 73%, and 41% chance, respectively, of having a high total cholesterol level, after adjusting for age, sex, and socioeconomic status.
Abstract: Background:Few studies have examined the relationship between heavy metal and serum cholesterol levels, and no recent study has examined this relationship in the US population.Methods and Results:A...
TL;DR: It was found that AAI reduced cell viability and increased cell apoptosis in a dose- and time-dependent manner, which suggested that mitochondrial dysfunction may be involved in AAI-induced apoptosis and mitochondrial function in PTEC.
Abstract: Aristolochic acid (AA) is a compound extracted from the Aristolochia species of herbs. AA exposure is associated with kidney injury known as aristolochic acid nephropathy (AAN). Proximal tubular epithelial cell (PTEC) is the primary target of AA and rich in mitochondria. Recently, increasing evidence suggests that mitochondrial dysfunction plays a critical role in the pathogenesis of kidney disease. However, the status of mitochondrial function in PTEC after exposure to AA remains largely unknown. The aim of this study was to explore the effect of aristolochic acid I (AAI) on cell apoptosis and mitochondrial function in PTEC. Normal rat kidney-52E (NRK-52E) cells were exposed to different concentrations of AAI for different time periods. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, cell apoptosis was analyzed by flow cytometry, and the expression of cleaved caspase-3 by Western blotting. Mitochondrial function was evaluated by reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP). It was found that AAI reduced cell viability and increased cell apoptosis in a dose- and time-dependent manner. In parallel to increased apoptosis, NRK-52E cell manifested signs of mitochondrial dysfunction in response to AAI treatment. The data indicated that AAI could increase ROS level, lower MMP, decrease mtDNA copy number, and reduce ATP production. In addition, Szeto-Schiller 31, a mitochondria-targeted antioxidant peptide, attenuated AAI-induced mitochondrial dysfunction and apoptosis. Our study depicted significant aberrant of mitochondrial function in AAI-treated NRK-52E cell, which suggested that mitochondrial dysfunction may be involved in AAI-induced apoptosis in PTEC.
TL;DR: In this paper, the authors investigated the function of miR-182-5p in pulmonary fibrosis, established bleomycin (BLM)-induced fibrotic mice model and transforming growth factorβ1 (TGF-β1)-treated human embryonic lung fibroblasts model.
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with high morbidity and mortality. miR-182-5p is overexpressed in several fibrosis-related diseases but its effect in pulmonary fibrosis has not been reported yet. To investigate the function of miR-182-5p in pulmonary fibrosis, we established bleomycin (BLM)-induced fibrotic mice model and transforming growth factor-β1 (TGF-β1)-treated human embryonic lung fibroblasts model. In this study, miR-182-5p was highly expressed in pulmonary tissues of BLM-induced fibrotic mice. The content of hydroxyproline and TGF-β1 was decreased by downregulating the expression of miR-182-5p, indicating that fibrosis was alleviated in mice treated with Lentivirus-anti-miR-182-5p.Quantification of fibrosis-related proteins demonstrated that downregulation of miR-182-5p inhibited the expression of profibrotic proteins (fibronectin, α-smooth muscle actin, p-Smad2/p-Smad3) as well as enhanced the level of Smad7. In vitro assays validated that miR-182-5p was induced by TGF-β1 with the function of promoting fibrosis. In dual-luciferase reporter assay, Smad7 was demonstrated to be negatively regulated by miR-182-5p. Moreover, the effect of knocking down miR-182-5p on inhibiting fibrosis was achieved by upregulating the expression of Smad7. Therefore, miR-182-5p can be regarded as a biomarker of IPF and its inhibition may be a promising therapeutic approach in treating IPF.
TL;DR: Findings of this study provided clear evidence that maternal exposure to TCDD during the critical stage of development results in suppressed reproductive health in adulthood.
Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant in the environment. The developmental period is more sensitive to TCDD and there is a possibility that maternal exposure to TCDD may affect in adulthood. Adult female Wistar rats were exposed to 0.5, 1.0, and 2.0 µg/kg TCDD during the critical stage of organogenesis, that is, on GD15. The results revealed a significant decrease in indices of reproductive organ weight in adult male rats exposed to prenatal TCDD, and dose-dependent reduction in epididymal sperm reserves, percent motile, and viable sperm with an increase in percent morphological abnormal sperm. Polymerase chain reaction analysis revealed downregulated expression levels of steroidogenic markers such as steroidogenic acute regulatory, cholesterol side-chain cleavage, and 3β- and 17β-hydroxysteroid dehydrogenase (HSDs) in experimental rats. Immunofluorescence sections portrayed reduced distribution of 3β- and 17β-HSD proteins in testes of experimental rats. Furthermore, spermatogenic markers (acid phosphatase, alkaline phosphatase, lactate dehydrogenase, and sorbitol dehydrogenase) were significantly altered in the testes. Serum levels of testosterone, follicle stimulating hormones, and luteinizing hormone were significantly decreased. Testicular levels of hydrogen peroxide and lipid peroxidation were significantly elevated with a decline in superoxide dismutase, catalase, glutathione peroxidase activities, and total thiol levels. Moreover, histological and morphometric examination of testicular cross-sections depicted degenerative changes. Male fertility assessment in adult rats revealed a significant decrease in mating index, fertility index, and mean number of pre- and postimplantations with an increase in pre- and postimplantation losses in rats cohabited with in utero TCDD-exposed adult males. In conclusion, the findings of this study provided clear evidence that maternal exposure to TCDD during the critical stage of development results in suppressed reproductive health in adulthood.
TL;DR: Suicide gene approach combining reengineered CYP4B1 and prodrug 4-ipomeanol (4-IPO) has shown a promising potential for targeted cancer therapy and further studies should focus on the verification of human CYP 4B1 catalytic activities.
Abstract: Cytochrome P450 4B1 (CYP4B1) plays crucial roles in biotransforming of xenobiotics. Its predominant extrahepatic expression has been associated with certain tissue-specific toxicities. However, the expressions of CYP4B1 in various cancers and hence their potential roles in cancer development were inclusive. In this work, existing knowledge on expression and regulation of CYP4B1 gene and protein, catalysis of CYP4B1, association of CYP4B1 with cancers, contradicting findings about human CYP4B1 activities as well as the employing CYP4B1 in suicide gene approach for cancer treatment were reviewed. To date, it appears that there is a wide spectrum of tissue distribution of CYP4B1 with lungs as the predominant sites. Several nuclear receptors are possibly responsible for regulating its gene expression. The involvement of CYP4B1 in cancer was considered via activation of procarcinogens and neovascularization. However, human CYP4B1 was found to be inactive due to a substitution of proline with serine at position 427. Suicide gene approach combining reengineered CYP4B1 and prodrug 4-ipomeanol (4-IPO) has shown a promising potential for targeted cancer therapy. Further studies should focus on the verification of human CYP4B1 catalytic activities. More compounds with similar structure as 4-IPO should be tested to identify more alternative agents for the suicide gene approach in cancer treatment.
TL;DR: Gastrodin has neuroprotective effects against MA-induced neurotoxicity, which exerts neuroprot protective effects via regulation of cAMP/PKA/CREB signaling pathway and upregulates the expression of BDNF.
Abstract: Objective:Methamphetamine (MA) abuse induces neurotoxicity and causes neuronal cell apoptosis. Gastrodin is a traditional Chinese herbal medicine used for the treatment of nerve injuries, spinal co...
TL;DR: The potential role of icariin in the restoration of the ISO-induced cardiac toxicity and restored membrane integrity through modulation of cGMP and NF-κB signaling is indicated.
Abstract: Icariin, a major component of Epimedium species, was evaluated using isoproterenol (ISO)-induced cardiotoxicity in Wistar rats. Rats were treated with icariin at the doses of 1, 5, and 10 mg kg-1 orally for 15 days. Afterward, rats were administered with ISO (85 mg kg-1, subcutaneous) on 14th and 15th day to produce cardiac injury. Sildenafil (0.7 mg kg-1, intraperitoneal) was used as a positive reference to compare the effects of icariin. ISO-treated rats showed significant changes in hemodynamic parameters. Elevated levels of cardiac troponin T, nitric oxide, and tumor necrosis factor-alpha in serum, positive expression of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase in cardiac tissue, and a decrease in serum level of interleukin-10, manifested inflammation and associated cardiac injury. However, pretreatment with icariin and sildenafil significantly prevented the hemodynamic fall and showed improved contractile and lusitropic states. Furthermore, pretreatment groups also showed a reversal of other toxicity markers to normal. Additionally, pretreatment with icariin and sildenafil significantly increased the myocardial cyclic guanosine monophosphate (cGMP) levels. Our results thus indicated the potential role of icariin in the restoration of the ISO-induced cardiac toxicity and restored membrane integrity through modulation of cGMP and NF-κB signaling.
TL;DR: This study provides an experimental basis for the safe application of NCDs in rats and explores the potential mechanisms of hepatotoxicity of CSN modified with oxalate ester in rats.
Abstract: Chemical modification of cellulose is currently attracting attention as researchers attempt to take advantage of the abundance of hydroxyl groups on its surface to introduce extra biological functionality. However, the possible deleterious effect of exposure to functionalized nanocellulose (CSN) remains a concern. Therefore, this study aims to explore the potential mechanisms of hepatotoxicity of CSN modified with oxalate ester (NCD) in rats. A 7-day repeated oral toxicity study of NCD at the doses of 50 and 100 mg kg-1 body weight was conducted, and plasma and liver tissue samples were assayed using biochemical analysis, liver histopathology, and protein expression. NCD, at both doses, did not significantly (p > 0.05) alter the relative weight of liver, alkaline phosphatase activity, and lipid peroxidation levels of the animals. However, NCD at the dose of 100 mg kg-1 body weight significantly elevated aspartate aminotransferase, alanine aminotransferase, and myeloperoxidase activities. NCD also enhanced the immunohistochemical expression of inducible nitric oxide synthase and Bcl-2-associated X protein in the liver of rats. Histological observations revealed necrosis and severe cellular infiltration at the high-dose treatment. Our study provides an experimental basis for the safe application of NCDs.
TL;DR: MiR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic, and this study provides a scientific basis for further studies of the causes of the arsenic-induced renal dysfunction, the biological role of miR- 191, and targeted prevention strategies.
Abstract: Chronic exposure to arsenic may result in the manifestation of damage in multiple organs or systems of the body. Arsenic-induced renal dysfunction has been determined, but their pathogenesis has not been fully examined. In this study, we measured the expression levels of miR-191 in plasma, the contents of pro-inflammatory (interleukin (IL)-6 and tumor necrosis factor alpha) and anti-inflammatory (IL-2 and transforming growth factor beta) cytokines, and renal dysfunction indicators (blood urea nitrogen, blood creatinine, uric acid, and cystatin C) in serum from control and arsenic poisoning populations and analyzed the relationship between the miR-191, cytokines, and renal dysfunction indicators. The results clearly show the alteration of miR-191 expression was significantly associated with arsenic-induced renal dysfunction. Overall, the association of miR-191, inflammatory response and renal dysfunction, is clearly supported by the current findings. In other words, miR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic. The study provides a scientific basis for further studies of the causes of the arsenic-induced renal dysfunction, the biological role of miR-191, and targeted prevention strategies.
TL;DR: The results of the present study showed that betaine pretreatment improved hepatotoxicity through the reduction of serum ALT and AST levels and ameliorating histopathological finding and demonstrated that the increased expression of Nrf2 and HO-1 genes and proteins by APAP is a compensatory mechanism to combat acute liver toxicity.
Abstract: Overdose of acetaminophen (APAP) is the main reason for acute liver failure. Oxidative stress is associated with hepatotoxicity caused by APAP. Betaine is a methyl donor and S-adenosylmethionine precursor. The present study investigated the effect of betaine and the role of nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) genes in hepatotoxicity induced by APAP in mice. In this study, male Naval Medical Research Institute (NMRI) mice were treated with 500 mg/kg of betaine for 5 days followed with a single dose of APAP 300 mg/kg on the fifth day. Biochemical, histological, immunohistochemical, Western blot, and real-time polymerase chain reaction (PCR) analyses were then conducted. The results of the present study showed that betaine pretreatment improved hepatotoxicity through the reduction of serum ALT and AST levels and ameliorating histopathological finding. Betaine pretreatment also increased glutathione level and decreased malondialdehyde level. Importantly, the results of immunohistochemical, Western blot and real-time PCR showed that the APAP increased the expression of the genes and proteins of Nrf2 and HO-1. While betaine decreased Nrf2 and HO-1 expression in comparison with the APAP group. The findings of this study demonstrated that the increased expression of Nrf2 and HO-1 genes and proteins by APAP is a compensatory mechanism to combat acute liver toxicity. While the protective effect of betaine against acute liver injury induced by APAP is independent on the Nrf2 and HO-1 genes but occurs via modifying cysteine supply as a precursor of glutathione in the transsulfuration pathway in the liver.
TL;DR: Each of the NPs tested affected either the microglia phagocytic activity (AgNPs and CeO2NPs) and/or its viability (Ag NPs and CdTeQDs) that may favor the occurrence of AD and accelerate its development.
Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disease leading to progressive dementia in elderly people. The disease is characterized, among others, by formation of amyloid-β (Aβ) polypeptide plaques in the brain. Although etiology of the disease is not fully understood, recent research suggest that nanomaterials may affect AD development. Here, we described the consequences of exposure of mouse BV-2 microglia to silver nanoparticles (AgNPs, 50 µg/mL), cerium oxide nanoparticles (CeO2NPs, 100 µg/mL), and cadmium telluride quantum dots (CdTeQDs, 3 or 10 µg/mL) in the context of its ability to clear Aβ plaques. The brain microglial cells play an important role in removing Aβ plaques from the brain. Cell viability and cycle progression were assessed by trypan blue test and propidium iodide binding, respectively. The uptake of Aβ and NPs was measured by flow cytometry. Secretion of proinflammatory cytokines was measured with the use of cytometric bead array. Aβ (0.1 μM) did not affect viability, whereas NPs decreased microglia growth by arresting the cells in G1 phase (CdTeQDs) or in S phase (AgNPs and CeO2NPs) of cell cycle. The uptake of Aβ was significantly reduced in the presence of AgNPs and CeO2NPs. In addition, the least toxic CeO2NPs induced the release of proinflammatory cytokine, tumor necrosis factor α. In summary, each of the NPs tested affected either the microglia phagocytic activity (AgNPs and CeO2NPs) and/or its viability (AgNPs and CdTeQDs) that may favor the occurrence of AD and accelerate its development.