Hasil untuk "Toxicology. Poisons"

Xiaotong Wang, Yunqiu Shen, Yan Chen et al.

Persistent inflammation can trigger the development of colorectal cancer, especially in patients with inflammatory bowel disease (IBD). The precise molecular mechanisms underlying this process are not fully understood. This study investigated the molecular modifications that occur in the cellular microenvironment during inflammation-induced and colitis-associated cancers. Studies showed that genetic mutations and post-translational modifications of oncogene proteins can alter the biological functions of macrophage inflammatory proteins, complicating the intricate interactions between inflammation and cancer. The researchers also observed abnormal glycosylation patterns in cases of inflammation and colitis-associated cancers. This observation suggests that glycoproteins present in bodily fluids could potentially serve as valuable disease markers. Additionally, the researchers investigated general signaling alterations that manifest in cases of colitis-associated cancer. They proposed a provisional molecular model that suggests the involvement of endoplasmic reticulum (ER) stress during the transition from inflammation to cancer. This potential pathway is mediated through the FKBP/c-Myc/p53 signaling axis. In the context of protein glycosylation, we summarize the potential molecular mechanisms of IBD-induced carcinogenesis. This knowledge could potentially lead to the development of novel targets for the clinical treatment of colorectal cancer.

Gaby A.M. Eliesen, Milou Fransen, Hedwig van Hove et al.

Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted ex vivo dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the ex vivo perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.

Jan Willem Van der Laan, Joseph Manuppello

James S. Brown, Gary L. Diamond

Abstract Inhalation is a portal-of-entry for aerosols via the respiratory tract where particulate burden accumulates depending on sites of particle deposition, normal clearance mechanisms, and particle solubility. The time available for dissolution of particles is determined by the balance between the rate of particle clearance from a region and their solubility in respiratory solvents. Dissolution is a function of particle surface area divided by particle volume or mass (i.e., dissolution is inversely proportional to the physical diameter of particles). As a conservative approach, investigators commonly assume the complete and instantaneous dissolution of metals from particles depositing in the alveolar region of the respiratory tract. We derived first-order dissolution rate constants to facilitate biokinetic modeling of particle clearance, dissolution, and absorption into the blood. We then modeled pulmonary burden and total dissolution of particles over time as a function of particle size, density, and solubility. We show that assuming poorly soluble particle forms will enter the blood as quickly as highly soluble forms causes an overestimation of concentrations of the compound of interest in blood and other extrapulmonary tissues while also underestimating its pulmonary burden. We conclude that, in addition to modeling dose rates for particle deposition into the lung, physiologically based pharmacokinetic modeling of pulmonary and extrapulmonary tissues concentrations of moderately and poorly soluble materials can be improved by including estimates of lung burden and particle dissolution over time.

Forouzan Akrami, Alireza Zali, Mahmoud Abbasi

Background: Human Rights (HRs) framework supports improving human health status and the reduction of health inequalities through action on Social Determinants of Health (SDH). Given the shortcoming of HRs to protect the children, the question is, how can we ensure child protection and well-being rather than just child health? Methods: In this conceptual analysis study, first, we explain the fundamental rights of the child and the steering role of them in moving towards health equity through action on SDH; second, meanwhile argue the shortcoming of rights-based protection, provide a list of the core capabilities and corresponding rights of the child; and third, we represent a conceptual framework for child protection and well-being using both HRs norms and moral entitlements based on recent ethical theories of justice, with a preventive approach. Results: According to the framework, HRs instruments should lead to the protection of the child and the development of core capabilities through addressing social determinants and providing equal opportunities, of which the ability to live a healthy life is just one. In addition, actualizing these capabilities depends on the context. Since achieving well-being rather than just the health, in addition to acquiring the core capabilities as states of beings, implies their function as doings, that requires considering the socioecological context to provide means necessary to meet the essential dimensions of well-being at the level of adequacy. Conclusion: Implementing the suggested framework requires that each country create a national action framework and determine the role and duties of the responsible organizations.

Leila Ghassemifard, Saeed Sardari, Hajar Safari et al.

Background: Capparis spinosa L. due to its anti-inflammatory and antioxidant properties plays a key role in preventing and treatment of cancer, also reduces the growth rate of cancer cells. This plant can be used in various ways in medicinal compounds, food, etc. as an extract, oil, or essential oil. Objective: In the current study, the rate of antioxidant activity extracts and oils (cold press and n-hexane oils) of Capparis seeds and also the effect of the seeds on the SH-SY5Y cell line have been investigated. Methods: First, extract, cold press, and n-hexane oils were prepared; then all reached concentrations of 50, 100, and 200 mg/ml, and their antioxidant capacity was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. After that, the number of antioxidant compounds in the extract was measured, and finally, the toxicity of the extracts was evaluated by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method on SH-SY5Y cancer cells. Results: The IC50 data showed that the antioxidant activity of the Capparis seeds extracts was significantly (P < 0.001) increased compared to cold press and n-hexane. Antioxidant compounds analysis of Capparis seeds extract indicated high rate of total phenolic, flavonoid as rutin, and quercetin. MTT assay demonstrates that Capparis seeds extracts in a concentration of 1000 μg/ml decreased the viability of the SH-SY5Y cancer cell lines in comparison with hacked cells (P < 0.001). Conclusion: The seed extract of Capparis seeds at high concentrations, probably due to its high antioxidant content, inhibits the growth of SH-SY5Y cancer cells.

Katharina Koch, Kristina Bartmann, Julia Hartmann et al.

There is a call for a paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current in vivo guideline studies. Under the umbrella of the Organisation for Economic Co-operation and Development (OECD), a guidance document is currently being prepared that instructs on the regulatory use of a DNT in vitro battery (DNT IVB) for fit-for-purpose applications. One crucial issue for OECD application of methods is validation, which for new approach methods (NAMs) requires novel approaches. Here, mechanistic information previously identified in vivo, as well as reported neurodevelopmental adversities in response to disturbances on the cellular and tissue level, are of central importance. In this study, we scientifically validate the Neurosphere Assay, which is based on human primary neural progenitor cells (hNPCs) and an integral part of the DNT IVB. It assesses neurodevelopmental key events (KEs) like NPC proliferation (NPC1ab), radial glia cell migration (NPC2a), neuronal differentiation (NPC3), neurite outgrowth (NPC4), oligodendrocyte differentiation (NPC5), and thyroid hormone-dependent oligodendrocyte maturation (NPC6). In addition, we extend our work from the hNPCs to human induced pluripotent stem cell-derived NPCs (hiNPCs) for the NPC proliferation (iNPC1ab) and radial glia assays (iNPC2a). The validation process we report for the endpoints studied with the Neurosphere Assays is based on 1) describing the relevance of the respective endpoints for brain development, 2) the confirmation of the cell type-specific morphologies observed in vitro, 3) expressions of cell type-specific markers consistent with those morphologies, 4) appropriate anticipated responses to physiological pertinent signaling stimuli and 5) alterations in specific in vitro endpoints upon challenges with confirmed DNT compounds. With these strong mechanistic underpinnings, we posit that the Neurosphere Assay as an integral part of the DNT in vitro screening battery is well poised for DNT evaluation for regulatory purposes.

Habibulla D. Attar, Sayed Mohammed Meraj Hussaini, Nasiruddin Itagi et al.

Background: As the epidemic that started at Wuhan spread globally many agents with antiviral activity were evaluated for the treatment of coronavirus disease. Many agents were claimed to be “Game changer” in the management of covid. Likewise Remdesivir received much attention leading to high demand of a scarcely produced antiviral agent, which many a times was out of stock in our region. Methods: In this retrospective observational study data of patients admitted in Al Ameen Medical College Hospital with moderate to severe form of SARS CoV 2 / SEVERE ACUTE RESPIRATORY ILLNESS was evaluated retrospectively. Patients were divided into two groups i.e. those who received remdesivir and those who could not avail. Statistical analysis was done to determine mortality benefit of Remdesivir and influence on hospital stay. Results: 293 patients were studied and out of them 56 received remdesivir. Mortality was 32.1% among those who received and in the other group 17.7%. Mean hospital stay was 11.7 days with SD of 11.6 among those who received remdesivir and in the other group it was 7.3 days mean hospital stay with SD of 4.7days. Conclusion: Our study showed no benefit in the outcome and hospital stay among patients receiving remdesivir. However we concede that the number patients receiving remdesivir was less and this is a limitation. Although this was a small scale study with limited number of patients, it represents a point of reference for the use of remdesivir at other hospitals.

Haozhen Shao, Lei Dong, Yanyan Feng et al.

Abstract Background Cantharidin (CTD) is a compound which have the potential to be exploited as an antitumor drug, and it has been demonstrated antitumor effects in a variety of cancers. However, the use is limited due to its severe toxicity. It has reported that it can induce fatal cardiac arrhythmias. Fortunately, we found that L-glutamine can alleviate cardiac toxicity caused by cantharidin in mice. Methods To investigate the protective effect of L-glutamine, we used a high dose of cantharidin in mice to create a model of cardiotoxicity. In the experimental mice, glutamine was given orally half an hour before they were administrated with cantharidin. The mice of control group were intraperitoneally injected with DMSO solution. The general state of all mice, cardiac mass index, electrocardiogram change and biological markers were determined. Hematoxylin-eosin staining (HE staining) of heart tissue was carried out in each group to reflect the protective effect of glutamine. To investigate the mechanisms underlying the injury and cardio-protection, multiple oxidative stress indexes were determined and succinate dehydrogenase activity was evaluated. Result The results showed that L-glutamine (Gln) pretreatment reduced weight loss and mortality. It also decreased the biological markers (p < 0.05), improved electrocardiogram and histological changes that CTD induced cardiotoxicity in mice. Subsequently, the group pretreated with L-glutamine before CTD treatment increases in MDA but decreases in SOD and GSH, in comparison to the group treated with CTD alone. Besides, succinate dehydrogenase activity also was improved when L-glutamine was administrated before cantharidin compared to cantharidin. Conclusions This study provided evidence that L-glutamine could protect cardiac cells against the acute cantharidin-induced cardiotoxicity and the protective mechanism of glutamine may be related to the myocardial cell membrane or the tricarboxylic acid cycle in the mitochondria.

Milad Tavassoli, Asma Afshari, Andree Letiţia Arsene et al.

Mushrooms account for a part of human diet due to their exquisite taste and protein content as well as their promising health effects unveiled by scientific research. Toxic and non-toxic mushrooms frequently share considerable morphological similarities, which mislead the collectors/consumers, resulting in mycotoxicity. Numerous mushroom species are considered “poisonous” as they produce dangerous toxins. For instance, members of the genus Amanita, especially A. phalloides, A. virosa and A. verna, are responsible for severe and even life-threatening noxious consequences. Globally, mushroom poisoning is a crucial healthcare issue as it leads to a considerable number of deaths annually. However, no definite antidote has been introduced to treat this poisoning. The present article discusses the characteristics of A. virosa in terms of epidemiology, mechanisms of toxicity, poisoning features and management. Keywords: Mushroom poisoning, Epidemiology, Phalloidin, Amanitin, Amanita virosa

Sanhita Mukherjee, Diptakanti Mukhopadhyay

Introduction: This study investigated medical students’ perception of learning difficulties in Physiology during their first year of study and their study habits to overcome these problems. Method: A total of 200 1st year medical students of a Government Medical College in West Bengal, India were surveyed by a pre-validated semi-structured questionnaire that was provided to the 2017-18 batch. Result: Among 147 respondents 74 were males and 73 were females. A majority of students considered less time and vast syllabus was the greatest difficulty faced by them in learning Physiology at 1st year (Score 4.7 out of 7 in male and Score 4.3 out of 7 in females.). Stress, anxiety during course was ranked second. 41.89% male and 46.57% female students agreed that following the instructor and taking class notes simultaneously at Physiology Lecture class was the major problem faced by them at lecture classes. Less hands-on activity was pointed out as the major problem at Physiology practical class. Majority of students (93.24% male students and 91.78% female) reported that they take help of different networking sites to improve their knowledge. Conclusion: Students’ perception of difficulties in learning Physiology at their first year pointed out the need of modification of pre-convinced notion of teaching-learning principles. Curriculum encouraging self-directed learning, andragogic approach, formative assessment and constructive feedback to the students are the need of the day. Faculty members of medical colleges should update themselves accordingly and should modify their teaching mode in more learner-centric pattern.

Cristina Pavan, Massimo Delle Piane, Maria Gullo et al.

Abstract Background Silica continues to represent an intriguing topic of fundamental and applied research across various scientific fields, from geology to physics, chemistry, cell biology, and particle toxicology. The pathogenic activity of silica is variable, depending on the physico-chemical features of the particles. In the last 50 years, crystallinity and capacity to generate free radicals have been recognized as relevant features for silica toxicity. The ‘surface’ also plays an important role in silica toxicity, but this term has often been used in a very general way, without defining which properties of the surface are actually driving toxicity. How the chemical features (e.g., silanols and siloxanes) and configuration of the silica surface can trigger toxic responses remains incompletely understood. Main body Recent developments in surface chemistry, cell biology and toxicology provide new avenues to improve our understanding of the molecular mechanisms of the adverse responses to silica particles. New physico-chemical methods can finely characterize and quantify silanols at the surface of silica particles. Advanced computational modelling and atomic force microscopy offer unique opportunities to explore the intimate interactions between silica surface and membrane models or cells. In recent years, interdisciplinary research, using these tools, has built increasing evidence that surface silanols are critical determinants of the interaction between silica particles and biomolecules, membranes, cell systems, or animal models. It also has become clear that silanol configuration, and eventually biological responses, can be affected by impurities within the crystal structure, or coatings covering the particle surface. The discovery of new molecular targets of crystalline as well as amorphous silica particles in the immune system and in epithelial lung cells represents new possible toxicity pathways. Cellular recognition systems that detect specific features of the surface of silica particles have been identified. Conclusions Interdisciplinary research bridging surface chemistry to toxicology is progressively solving the puzzling issue of the variable toxicity of silica. Further interdisciplinary research is ongoing to elucidate the intimate mechanisms of silica pathogenicity, to possibly mitigate or reduce surface reactivity.

Tingting Ku, Ben Li, Rui Gao et al.

Abstract Background PM2.5 (particulate matter ≤ 2.5 μm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM2.5 exposure are largely unknown. Methods C57BL/6 mice received oropharyngeal aspiration of PM2.5 (1 and 5 mg/kg bw) every other day for 4 weeks. The mice were also stereotaxically injected with β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1) shRNA or LV-miR-574-5p lentiviral constructs in the absence or presence of PM2.5 aspiration at 5 mg/kg bw every other day for 4 weeks. Spatial learning and memory were assessed with the Morris water maze test, and synaptic function integrity was evaluated with electrophysiological recordings of long-term potentiation (LTP) and immunoblot analyses of glutamate receptor subunit expression. The expression of α-secretase (ADAM10), BACE1, and γ-secretase (nicastrin) and the synthesis and accumulation of amyloid β (Aβ) were measured by immunoblot and enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) expression was screened with a microRNA microarray analysis and confirmed by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Dual-luciferase reporter gene and chromatin immunoprecipitation (ChIP) analyses were used to detect the binding of miR-574-5p in the 3’UTR of BACE1 and NF-κB p65 in the promoter of miR-574-5p, respectively. Results PM2.5 aspiration caused neuroinflammation and deteriorated synaptic function integrity and spatial learning and memory, and the effects were associated with the induction of BACE1. The action was mediated by NF-κB p65-regulated downregulation of miR-574-5p, which targets BACE1. Overexpression of miR-574-5p in the hippocampal region decreased BACE1 expression, restored synaptic function, and improved spatial memory and learning following PM2.5 exposure. Conclusions Taken together, our findings reveal a novel molecular mechanism underlying impaired synaptic and cognitive function following exposure to PM2.5, suggesting that miR-574-5p is a potential intervention target for the prevention and treatment of PM2.5-induced neurological disorders.

Yavar Mahmoodzadeh, Mohammad Mazani, Lotfollah Rezagholizadeh

The purpose of this study was to investigate the effects of Tanacetum Parthenium Extract (TPE) on Lipid peroxidation, antioxidant enzymes, biochemical factors, and liver enzymes in the rats damaged by Carbon Tetrachloride (CCl4).54 male Wistar rats were divided into 9 groups each consisting of 6 rats. Two of the groups were control groups (normal and damage control groups), 4 of them were exposure groups which were respectively administered with 40, 80, and 120 mg/kg of TPE and silymarin for 14 days before being damaged by CCl4, and the other 3 groups were post-treatment groups which received 80 and 120 mg/kg of TPE and silymarin 2, 6, 24, and 48 h after being injected with CCl4. At the end of the study, biochemical factors, serum liver enzymes, malondialdehyde level, antioxidant enzymes, and liver morphology were assayed.Pre- and post-treatment with TPE could significantly decrease ALT, AST, ALP, TG, LDL, TC, and glucose levels and increase HDL, and albumin levels and catalase, SOD, and GPx activities compared to the CCl4-damaged control group.The results of this study are indicative of the antioxidant activity of TPE, its potential hepatoprotective effects, and its probable therapeutic properties for laboratory animals damaged by CCl4. Keywords: Tanacetum parthenium, Carbon tetrachloride, Oxidative stress, Antioxidant enzymes, Liver damage

K. Doiron, M. Millour, J.-P. Gagné et al.

Not available

C. Brousseau-Fournier, G. Alix, A. Beaudry et al.

Not available

H Kari Dolatabadi, E Mohammadi Goltapeh, A Moini et al.

Background: Mentha piperita and Thymus vulgaris are two important species of family Lamiaceae that abundantly used in pharmaceutical, food, cosmetic and hygienic industries.   Objective: Objectives in this study were the effect of different concentration of auxin and fungi Piriformospora indica and Sebacina vermifera on the growth and development of peppermint and thyme in vitro condition.    Methodes: Two distinct experiments were conducted the first evaluate the effect of different auxin levels (IAA ، NAA ، IBA) on M. piperita and T. vulgaris growth, and the second examined the effect of two fungi Piriformospora indica and Sebacina vermifera on plant height, root length, shoots and root weight in in vitro in a completely randomized design.   Results: The first study suggested the most effective hormone dose for the M . piperita growth was 1mg per liter of IBA and in the T. vulgaris it was 1 mg per liter of IAA. Increasing of the hormone doses resulted in growth decrease. The second study evolved that growth of the plants inoculated with fungi increased significantly. The data indicated that the plants inoculated with S. vermifera were the highest of all and the plants inoculated with P. indica had the most weight. The nodes of M. piperita and numbers of shoots in T. vulgaris increased significantly.   Conclusion: These results indicate that the best hormone for tissue culture peppermint and thyme are 1mg per liter of IBA and IAA, respectively. Also using these fungi can increase grow and development of plants.

Anoop S. V. Shah, M. Eddleston

B. Mégarbane, N. Deye, I. Malissin et al.

F. Heyerdahl, K. Hovda, M. Bjørnaas et al.