Ratna Dewi, Tongku Nizwan Siregar, Amalia Sutriana
et al.
Background: Morinda citrifolia L. possesses antioxidant activity that can ameliorate the decline in semen quality of male rats due to exposure to cigarette smoke. Objectives: This study intend to assess the effectiveness of M._citrifolia leaves extract in ameliorating male infertility associated with oxidative dysregulation induced by exposure to tobacco smoke. Methods: The animals used in the study were evenly and randomly divided into five groups, each containing five rats. Group X1 served as the normal control without any treatment, whereas group X2 comprised rats that were exclusively subjected to cigarette smoke exposure. Groups X3, X4, and X5 were exposed to cigarette smoke and subsequently administered M. citrifolia leaves extract orally via a nasogastric tube at doses of 100, 200, and 300 mg/kg BW, respectively, for a period of 52 days. Twenty-four hours after the final treatment, blood samples were collected to examine FSH, LH, and testosterone levels using ELISA technique. Semen was collected from the cauda epididymis to analyze the quality of spermatozoa. Results: The administration of M. citrifolia leaves extract improved sperm concentration, progressive motility, and viability, while sperm morphological abnormalities were not affected by the extract (P = 0.618). FSH concentration decreased following M. citrifolia leaves extract administration, particularly at dose of 100, and 200 mg/kg BW. LH concentration increased significantly after treatment with 100_mg/kg BWof M. citrifolia leaves extract and testosterone levels improved after treated with leaves extract of M. citrifolia (P <0.001). Conclusions: Methanol extract of M. citrifolia leaves enhance sperm quality and testosterone levels but does not affect FSH and LH concentrations in male rats exposed to cigarette smoke.
Abstract Background The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. Methods We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. Results The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model’s prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. Conclusions The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.
Exposure to fine particulate matter (PM2.5) has been associated with the development and progression of renal disease. Peroxisome proliferator-activated receptor gamma (PPARγ), a key transcription factor involved in inflammation as well as lipid and glucose metabolism, helps maintain the integrity of tubular epithelial cells. However, the precise role of PPARγ in PM2.5-induced tubular injury remains unclear. In this study, we investigated the regulatory effects of PPARγ on PM2.5-induced ferroptotic stress and epithelial–mesenchymal transition (EMT) in tubular (HK-2) cells. We found that downregulation of PPARγ expression was correlated with EMT in PM2.5-exposed cells. Pretreatment with the PPARγ agonist 15d-PGJ2 protected the cells from EMT by reducing ferroptotic stress, whereas that with the PPARγ antagonist GW9662 promoted EMT. Furthermore, pretreatment with ferrostatin-1 (Fer-1) significantly prevented PM2.5-induced EMT and downregulation of PPARγ expression. Notably, overexpression of PPARγ blocked PM2.5-induced downregulation of E-cadherin and GPX4 expression and upregulation of α-SMA expression. This study highlights the complex associations of PPARγ with ferroptosis and EMT in PM2.5-exposed tubular cells. Our findings suggest that PPARγ activation confers protection against PM2.5-induced renal injury.
Introducing a Special Issue on mechanism of reproductive disorders in mammals originating from exposure to environmental chemicals during perinatal life.
Prlić Ivica, Šiško Jerko, Varnai Veda Marija
et al.
An enormous increase in the application of wireless communication in recent decades has intensified research into consequent increase in human exposure to electromagnetic (EM) radiofrequency (RF) radiation fields and potential health effects, especially in school children and teenagers, and this paper gives a snap overview of current findings and recommendations of international expert bodies, with the emphasis on exposure from Wi-Fi technology indoor devices. Our analysis includes over 100 in vitro, animal, epidemiological, and exposure assessment studies (of which 37 in vivo and 30 covering Wi-Fi technologies). Only a small portion of published research papers refers to the “real” health impact of Wi-Fi technologies on children, because they are simply not available. Results from animal studies are rarely fully transferable to humans. As highly controlled laboratory exposure experiments do not reflect real physical interaction between RF radiation fields with biological tissue, dosimetry methods, protocols, and instrumentation need constant improvement. Several studies repeatedly confirmed thermal effect of RF field interaction with human tissue, but non-thermal effects remain dubious and unconfirmed.
Dennis Sinitsyn, Dennis Sinitsyn, Natàlia Garcia-Reyero
et al.
Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.
Background: Peppermint (Mentha x piperita L.) is one of the most important medicinal plants which used in food, pharmaceutical, perfumery, and flavoring industry. Objective: This study was planned to investigate the effects of foliar application of salicylic acid and yeast extract on production of valuable essential oil components in peppermint. Methods: A completely randomized design experiment with nine treatments consisting salicylic acid (40, 80, 160 and 320 mg/l), yeast extract (0.25, 0.75, 1 and 1.5 g/l) and distilled water (control) with three replications was carried out under greenhouse conditions. Results: In total, forty compounds were identified in the essential oils of the plant aerial parts. Menthone, menthol, piperitone, isopulegol and
γ-terpinene were the major compounds of the oils studied. Menthone and menthol were 16.69 % and 14.39 % of the essential oils, respectively. Salicylic acid and yeast extract were increased menthone, neomenthol, piperitone, γ-terpinene and isomenthol acetate production 42, 60, 39, 59 and 34 % higher than control plants, respectively. Foliar application with 320 mg/l salicylic acid gave the best result in the enhancement of the major essential oil components of treated plants. The results of correlation between essential oil constituents showed that the neomenthol content had a significant positive correlation with menthone (r = 0.865**), γ-terpinene (r = 0.848**) and negative correlation with isopulegol (r = -0.886**). Conclusion: The quality of essential oil of M. piperita were influenced by the foliar application of salicylic acid and yeast extract at the appropriate concentrations. Elicitation by 320 mg/l salicylic acid was the optimum treatment for menthone, neomenthol, γ-terpinene and piperitone production.
The zero-added exogenous monosodium glutamate (MSG) soy sauce market is developing rapidly, but its authenticity remains a challenge for the industry. In this study, carbon stable isotope ratio mass spectrometry was utilized to determine 13C/12C ratio (δ13C value) of a variety of commercially available natural plain fermented soy sauces, and the main amino acid distribution and glutamic acid content were analyzed. δ13C value of glutamic acid in soy sauce showed strong positive correlation with the amount of exogenous glutamic acid/glutamate added; increment in exogenous glutamic acid/glutamate concentration resulted an increased δ13C value. δ13C value of a variety of authentic natural plain fermented soy sauces with zero added glutamate accounted for less than −24.45‰ with glutamic acid content lower than 12.89 mg/mL. On the other hand, high monosodium glutamate soy sauce added with MSG, δ13C values are greater than −15.51‰ while glutamic acid content exceeded 35.12 mg/mL. δ13C values of glutamic acid in soy sauce suspected to adulterate with exogenous glutamic acid/glutamate ranging between −17.91‰ and −17.30‰ and its glutamic acid content ranging from 30.42 to 37.82 mg/mL. The method specified in Association Standard accurately discriminated a variety of real “zero-added-glutamate” soy sauces currently available on the market accurately.
Food processing and manufacture, Toxicology. Poisons
Allan Peter Davis, Thomas C. Wiegers, Jolene Wiegers
et al.
The Comparative Toxicogenomics Database (CTD) is a freely available public resource that curates and interrelates chemical, gene/protein, phenotype, disease, organism, and exposure data. CTD can be used to address toxicological mechanisms for environmental chemicals and facilitate the generation of testable hypotheses about how exposures affect human health. At CTD, manually curated interactions for chemical-induced phenotypes are enhanced with anatomy terms (tissues, fluids, and cell types) to describe the physiological system of the reported event. These same anatomy terms are used to annotate the human media (e.g., urine, hair, nail, blood, etc.) in which an environmental chemical was assayed for exposure. Currently, CTD uses more than 880 unique anatomy terms to contextualize over 255,000 chemical-phenotype interactions and 167,000 exposure statements. These annotations allow chemical-phenotype interactions and exposure data to be explored from a novel, anatomical perspective. Here, we describe CTD’s anatomy curation process (including the construction of a controlled, interoperable vocabulary) and new anatomy webpages (that coalesce and organize the curated chemical-phenotype and exposure data sets). We also provide examples that demonstrate how this feature can be used to identify system- and cell-specific chemical-induced toxicities, help inform exposure data, prioritize phenotypes for environmental diseases, survey tissue and pregnancy exposomes, and facilitate data connections with external resources. Anatomy annotations advance understanding of environmental health by providing new ways to explore and survey chemical-induced events and exposure studies in the CTD framework.
Sandra Mara Burin, Maira da Costa Cacemiro, Juçara Gastaldi Cominal
et al.
Abstract Background: Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl+ leukemic cells and improve the disease treatment. Methods: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl+ cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro. Results: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl+ cells. Conclusion: BmooLAAO-I exerts selective antitumor action mediated by H2O2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.
Ibrahim Hassan, Wan Norhamidah Wan Ibrahim, Ferdaus Mohamat Yusuf
et al.
Background. Pathophysiological changes leading to the death of nerve cells present in the brain and spinal cord are referred to as neurodegenerative diseases. Presently, treatment of these diseases is not effective and encounters many challenges due to the cost of drug and side effects. Thus, the search for the alternative agents to replace synthetic drugs is in high demand. Therefore, the aim of this study is to evaluate the anticholinesterase properties of Ginkgo biloba seed. Methods. The seed was extracted with 80% methanol. Toxicity studies and evaluation of anticholinesterase activities were carried out in adult Javanese medaka (Oryzias javanicus). Phytochemical study to identify the bioactive lead constituents of the crude extract was also carried out using high performance liquid chromatography (HPLC). Results. The result shows activities with high significant differences at P<0.001 between the treated and nontreated groups. A bioactive compound (vitaxin) was identified with the aid of HPLC method. Conclusion. The presence of bioactive compound vitaxin is among the major secondary metabolites that contribute to increasing activities of this plant extract. High anticholinesterase activities and low toxicity effect of this plant show its benefit to be used as natural medicine or supplements.
Atefeh Varmazyari, Ali Taghizadehghalehjoughi, Cigdem Sevim
et al.
Living organisms have an innate ability to regulate the synthesis of inorganic materials, such as bones and teeth in humans. Cadmium sulfide (CdS) can be utilized as a quantum dot that functions as a unique light-emitting semiconductor nanocrystal. The increased use in CdS has led to an increased inhalation and ingestion rate of CdS by humans which requires a broader appreciation for the acute and chronic toxicity of CdS. We investigated the toxic effects of CdS on cerebellar cell cultures and rat brain. We employed a ‘green synthesis’ biosynthesis process to obtain biocompatible material that can be used in living organisms, such as Viridibacillus arenosi K64. Nanocrystal formation was initiated by adding CdCl2 (1 mM) to the cell cultures. Our in vitro results established that increased concentrations of CdS (0.1 μg/mL) lead to decreased cell viability as assessed using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), total antioxidant capacity (TAC), and total oxidant status (TOS). The in vivo studies showed that exposure to CdS (1 mg/kg) glial fibrillary acidic protein (GFAP) and 8-hydroxy-2' -deoxyguanosine (8-OHdG) were increased. Collectively, we describe a model system that addresses the process from the synthesis to the neurotoxicity assessment for CdS both in vitro and in vivo. These data will be beneficial in establishing a more comprehensive pathway for the understanding of quantum dot-induced neurotoxicity.
Ruba S. Darweesh, Tamam El-Elimat, Aref Zayed
et al.
Abstract Background Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. Methods Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. Results h-GS dose significantly decreased imatinib’s Cmax and the AUC 0 ∞ $$ {\mathrm{AUC}}_0^{\infty } $$ by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib’s exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib’s Cmax and AUC 0 ∞ $$ {\mathrm{AUC}}_0^{\infty } $$ by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib’s exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in Cmax of N-desmethyl imatinib by 71.5%. Conclusions These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized. Graphical abstract
Abstract Background Colchicine is a clinical medicine used for relief from gout and familial Mediterranean fever. Because of its toxic effects, intravenous injection of colchicine has been banned, but it is still widely administered orally. We assayed the toxic effects of colchicine in cultured primary chorionic villus cells and amniotic fluid cells to interpret its influence on the placenta and foetus. Methods Bright field record and cell count kit 8 were used to value cell viability. Flow cytometer was used to identify cells markers, cell cycle and cell apoptosis. G-banding was used for karyotype analysis for sample genetic and drug effect evaluation. Results Chorionic villus cells and amniotic fluid cells were characterized as mesenchymal cells that share most cell surface markers and have a similar response to colchicine. Colchicine did not induce a decline in cell viability at low concentrations but suppressed cell proliferation by arresting the cell cycle in the G2/M phase and increased the risk of tetraploid generation in a small subset of cases. Conclusions Our study revealed the results of a colchicine-induced toxicity test in prenatal cells and determined the anti-mitotic biologically functional dose and manner of administration that might reduce the risk of tetraploid generation.