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Ponatinib and tofacitinib, established kinase inhibitors and FDA-approved for chronic myeloid leukemia and rheumatoid arthritis, are recently undergoing investigation in diverse clinical trials for potential repurposing. The aryl hydrocarbon receptor (AhR), a transcription factor influencing a spectrum of physiological and pathophysiological activities, stands as a therapeutic target for numerous diseases. This study employs molecular modelling tools and in vitro assays to identify ponatinib and tofacitinib as AhR ligands, elucidating their binding and molecular interactions in the AhR PAS-B domain. Molecular docking analyses revealed that ponatinib and tofacitinib occupy the central pocket within the primary cavity, similar to AhR agonists 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and (benzo[a]pyrene) B[a]P. Our simulations also showed that these compounds exhibit good stability, stabilizing many hot spots within the PAS-B domain, including the Dα-Eα loop, which serves as a regulatory element for the binding pocket. Binding energy calculations highlighted ponatinib's superior predicted affinity, revealing F295 as a crucial residue in maintaining strong interaction with the two compounds. Our in vitro data suggest that ponatinib functions as an AhR antagonist, blocking the downstream signaling of AhR pathway induced by TCDD and B[a]P. Additionally, both tofacitinib and ponatinib cause impairment in AhR-regulated CYP1A1 enzyme activity induced by potent AhR agonists. This study unveils ponatinib and tofacitinib as potential modulators of AhR, providing valuable insights into their therapeutic roles in AhR-associated diseases and enhancing our understanding of the intricate relationship between kinase inhibitors and AhR.
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The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.
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Sitio Alostérico , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/química , Humanos , Regulación Alostérica/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/química , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Simulación de Dinámica Molecular , Aprobación de Drogas , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inhibidoresRESUMEN
The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effect of ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients.
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The aryl hydrocarbon receptor (AhR) functions as a vital ligand-activated transcription factor, governing both physiological and pathophysiological processes. Notably, it responds to xenobiotics, leading to a diverse array of outcomes. In the context of drug repurposing, we present here a combined approach of utilizing structure-based virtual screening and molecular dynamics simulations. This approach aims to identify potential AhR modulators from Drugbank repository of clinically approved drugs. By focusing on the AhR PAS-B binding pocket, our screening protocol included binding affinities calculations, complex stability, and interactions within the binding site as a filtering method. Comprehensive evaluations of all DrugBank small molecule database revealed ten promising hits. This included flibanserin, butoconazole, luliconazole, naftifine, triclabendazole, rosiglitazone, empagliflozin, benperidol, nebivolol, and zucapsaicin. Each exhibiting diverse binding behaviors and remarkably very low binding free energy. Experimental studies further illuminated their modulation of AhR signaling, and showing that they are consistently reducing AhR activity, except for luliconazole, which intriguingly enhances the AhR activity. This work demonstrates the possibility of using computational modelling as a quick screening tool to predict new AhR modulators from extensive drug libraries. Importantly, these findings hold immense therapeutic potential for addressing AhR-associated disorders. Consequently, it offers compelling prospects for innovative interventions through drug repurposing.
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Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Sitios de Unión , Unión Proteica , Dominios Proteicos , LigandosRESUMEN
BACKGROUND: Identifying the potential factors of depression among medical students is the first step towards academic excellence and future safe medical practice. METHODS: A cross-sectional study was conducted from December 2019 to February 2020 at the University of Bisha, College of Medicine (UBCOM), Bisha Province, Saudi Arabia. Male medical students from year one to year six were involved. A self-administered questionnaire was used to collect data about students' socio-demographic and academic characteristics. The Arabic version of the PHQ-9 scale with a score of ≥10 was used to identify depression. Logistic regression analysis was used to assess the prevalence and correlates of depression. RESULTS: Of the 190 male students enrolled, 26.8% had depressive symptoms, of whom 45.1% were experiencing moderate to severe symptoms. The significantly highest depression rate was found among the second-year students, at 43.8% (OR = 2.544; 95% CI 1.178-5.714; p = 0.018), and the lowest rate was found among year one students, at 8.9% (OR = 0.203; 95% CI 0.075-0.560; p = 0.002). Univariate regression revealed a significant correlation between depression and dissatisfaction with family income, loss of family members, having psychological illness, difficulties in personal relationships, regretting studying medicine, failure in an academic year, a lower grade than expected, conflict with tutors, lack of college facilities and heavy academic load. In multivariate analysis, loss of family members (AOR = 3.69; 95% CI 1.86-7.413), difficulties in personal relationships (AOR = 2.371; 95% CI 1.009-5.575), regretting studying medicine (AOR = 3.764; 95% CI 1.657-8.550), and failing an academic year (AOR = 2.559; 95% CI 1.112-5.887) were independently correlated with depression. CONCLUSIONS: The study concluded that medical students at UBCOM experience depressive symptoms associated with various risk indicators. Optimizing the educational and social environment and infrastructure facilities at UBCOM might promote students' mental health and well-being.
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Dimethylmonothioarsinic acid (DMMTAV), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTAV is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1â¯A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTAV's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice were intraperitoneally injected with 6â¯mg/kg DMMTAV, alone or with 15⯵g/kg TCDD, for 6 and 24â¯h. Similarly, Hepa-1c1c7 cells were exposed to DMMTAV (0.5, 1, and 2⯵M) with or without 1â¯nM TCDD for 6 and 24â¯h. DMMTAV hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6â¯h) and in vitro, associated with reduced CYP1A regulatory element activation. Interestingly, in C57BL/6 mice, DMMTAV boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTAV co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTAV negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTAV-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTAV differentially modulates the TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic.
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Arsénico , Ácido Cacodílico/análogos & derivados , Dibenzodioxinas Policloradas , Humanos , Animales , Ratones , Citocromo P-450 CYP1A1/metabolismo , Ratones Endogámicos C57BL , Sistema Enzimático del Citocromo P-450 , Dibenzodioxinas Policloradas/toxicidad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
Methylmercury (MeHg) and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are potent environmental pollutants implicated in the modulation of xenobiotic-metabolizing enzymes, particularly the cytochrome P450 1 family (CYP1) which is regulated by the aryl hydrocarbon receptor (AHR). However, the co-exposure to MeHg and TCDD raises concerns about their potential combined effects, necessitating thorough investigation. The primary objective of this study was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated CYP1 enzymes in mouse extrahepatic tissues. Therefore, C57BL/6 mice were administrated with MeHg (2.5 mg/kg) in the absence and presence of TCDD (15 µg/kg) for 6 and 24 h. The AHR-regulated CYP1 mRNA and protein expression levels were measured in the heart, lung, and kidney, using RT real-time PCR and western blot, respectively. Interestingly, treatment with MeHg exhibited mainly inhibitory effect, particularly, it decreased the basal level of Cyp1a1 and Cyp1a2 mRNA and protein, and that was more evident at the 24 h time point in kidney followed by heart. Similarly, when mice were co-exposed, MeHg was able to reduce the TCDD-induced Cyp1a1 and Cyp1a2 expression, however, MeHg potentiated kidney Cyp1b1 mRNA expression, opposing the observed change on its protein level. Also, MeHg induced antioxidant NAD(P)H:quinone oxidoreductase (NQO1) mRNA and protein in kidney, while heme-oxygenase (HO-1) mRNA was up-regulated in heart and kidney. In conclusion, this study reveals intricate interplay between MeHg and TCDD on AHR-regulated CYP1 enzymes, with interesting inhibitory effects observed that might be significant for procarcinogen metabolism. Varied responses across tissues highlight the potential implications for environmental health.
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The detoxification of quinones through NAD(P)H:quinone oxidoreductase (NQO1) is a crucial mechanism to maintain cellular homeostasis. The exposure to heavy metals, specifically methylmercury (MeHg), induces several antioxidant enzymes, including NQO1. The nuclear factor erythroid 2-related factor-2 (NRF2) is known to regulate the expression of Nqo1 gene and also the aryl hydrocarbon receptor (AHR) is another Nqo1 gene regulator. This co-regulation prompted us to investigate which transcription factor (NRF2 or AHR) orchestrates the regulation of NQO1 expression upon MeHg exposure. Therefore, we investigated how MeHg can modulate the level of NQO1 expression by exposing Hepa-1c1c7 cells to several concentrations of MeHg with and without the addition of NQO1 inducers, DL-sulforaphane (SUL) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We found that the mRNA expression of Nqo1 is up-regulated by MeHg in time- as well as dose-dependent fashions. Additionally, MeHg increased the NQO1 at all expression levels with and without the presence of its inducers, SUL or TCDD. Furthermore, the MeHg-mediated increase of NQO1 expression was in parallel with a concurrent increase in the nuclear localization of NRF2 protein, but not that of AHR. Mechanistically, the antioxidant response element-driven reporter gene activity was induced by 215% upon MeHg exposure. Also, transfecting Hepa-1c1c7 with Nrf2 siRNA reduced the MeHg-induced NQO1 protein expression by 60%. In conclusion, our findings provide evidence supporting the hypothesis that MeHg upregulates the Nqo1 gene through a transcriptional mechanism at least in part via a NRF2-dependent mechanism.
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BACKGROUND: Cytochrome P450 (CYP) metabolizes arachidonic acid to produce bioactive metabolites such as EETs and HETEs: mid-chain, subterminal, and terminal HETEs. Recent studies have revealed the role of CYP1B1 and its associated cardiotoxic mid-chain HETE metabolites in developing cardiac hypertrophy and heart failure. Subterminal HETEs have also been involved in various physiological and pathophysiological processes; however, their role in cardiac hypertrophy has not been fully defined. OBJECTIVE: The objective of the current study is to determine the possible effect of subterminal HETEs, R and S enantiomers of 16-HETE, on CYP1B1 expression in vitro using human cardiomyocytes RL-14 cells. METHODS: In the study, RL14 cell line was treated with vehicle and either of the 16-HETE enantiomers for 24 h. Subsequently, the following markers were assessed: cell viability, cellular size, hypertrophic markers, CYP1B1 gene expression (at mRNA, protein, and activity levels), luciferase activity, and CYP1B1 mRNA and protein half-lives. RESULTS: The results of the study showed that 16-HETE enantiomers significantly increased hypertrophic markers and upregulated CYP1B1 mRNA and protein expressions in RL-14 cell line. The upregulation of CYP1B1 by 16-HETE enantiomers occurs via a transcriptional mechanism as evidenced by transcriptional induction and luciferase reporter assay. Furthermore, neither post-transcriptional nor post-translational modification was involved in such modulation since there was no change in CYP1B1 mRNA and protein stabilities upon treatment with 16-HETE enantiomers. CONCLUSION: The current study provides the first evidence that 16R-HETE and 16S-HETE increase CYP1B1 gene expression through a transcriptional mechanism.
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Ácidos Hidroxieicosatetraenoicos , Miocitos Cardíacos , Humanos , Ácidos Hidroxieicosatetraenoicos/farmacología , Cardiomegalia/metabolismo , ARN Mensajero/metabolismo , Luciferasas/metabolismo , Luciferasas/farmacologíaRESUMEN
Arsenic is a hazardous heavy metalloid that imposes threats to human health globally. It is widely spread throughout the environment in various forms. Arsenic-based compounds are either inorganic compounds (iAs) or organoarsenicals (oAs), where the latter are biotically generated from the former. Exposure to arsenic-based compounds results in varying biochemical derangements in living systems, leading eventually to toxic consequences. One important target for arsenic in biosystems is the network of metabolic enzymes, especially the superfamily of cytochrome P450 enzymes (CYPs) because of their prominent role in both endobiotic and xenobiotic metabolism. Therefore, the alteration of the CYPs by different arsenicals has been actively studied in the last few decades. We have previously summarized the findings of former studies investigating arsenic associated modulation of different CYPs in human experimental models. In this review, we focus on non-human models to get a complete picture about possible CYPs alterations in response to arsenic exposure.
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Arsénico , Arsenicales , Humanos , Arsenicales/metabolismo , Arsénico/metabolismo , Arsénico/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Inactivación Metabólica , Modelos TeóricosRESUMEN
Background: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) 4C mortality score has been used before as a valuable tool for predicting mortality in COVID-19 patients. We aimed to address the utility of the 4C score in a well-defined Saudi population with COVID-19 admitted to a large tertiary referral hospital in Saudi Arabia. Methods: A retrospective study was conducted that included all adults COVID19 patients admitted to the Armed Forces Hospital Southern Region (AFHSR), between January 2021 and September 2022. The receiver operating characteristic (ROC) curve depicted the diagnostic performance of the 4C Score for mortality prediction. Results: A total of 1,853 patients were enrolled. The ROC curve of the 4C score had an area under the curve of 0.73 (95% CI: 0.702-0.758), p<0.001. The sensitivity and specificity with scores >8 were 80% and 58%, respectively, the positive and negative predictive values were 28% and 93%, respectively. Three hundred and sixteen (17.1%), 638 (34.4%), 814 (43.9%), and 85 (4.6%) patients had low, intermediate, high, and very high values, respectively. There were significant differences between survivors and non-survivors with regard to all variables used in the calculation of the 4C score. Multivariable logistic regression analysis revealed that all components of the 4C score, except gender and O2 saturation, were independent significant predictors of mortality. Conclusions: Our data support previous international and Saudi studies that the 4C mortality score is a reliable tool with good sensitivity and specificity in the mortality prediction of COVID-19 patients. All components of the 4C score, except gender and O2 saturation, were independent significant predictors of mortality. Within the 4C score, odds ratios increased proportionately with an increase in the score value. Future multi-center prospective studies are warranted.
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Arsenic trioxide (ATO) is a highly toxic arsenical which has been successfully exploited for treating acute promyelocytic leukemia (APL). Unfortunately, its therapeutic efficacy is accompanied by serious toxicities with undeciphered mechanisms. Cytochrome P450 1A (CYP1A) enzymes undergo modulation by arsenicals, with ensuing critical consequences regarding drug clearance or procarcinogen activation. Here, we investigated the potential of ATO to alter basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1/1A2 expressions. Mouse-derived hepatoma Hepa-1c1c7 cells were exposed to 0.63, 1.25, and 2.5 µM ATO with or without 1 nM TCDD. ATO increased TCDD-induced CYP1A1/1A2 mRNA, protein, and activity. Constitutively, ATO induced Cyp1a1/1a2 transcripts and CYP1A2 protein. ATO increased AHR nuclear accumulation and subsequently increased XRE-luciferase reporter activity. ATO enhanced CYP1A1 mRNA and protein stabilities. In conclusion, ATO up-regulates CYP1A in Hepa-1c1c7 cells transcriptionally, post-transcriptionally, and post-translationally. Therefore, ATO can be implicated in clearance-related interactions with CYP1A1/1A2 substrates, or in excessive activation of environmental procarcinogens.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Dibenzodioxinas Policloradas , Ratones , Animales , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Trióxido de Arsénico/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromo P-450 CYP1A2/genética , Línea Celular , Dibenzodioxinas Policloradas/toxicidad , ARN Mensajero/genética , Receptores de Hidrocarburo de ArilRESUMEN
Coronavirus disease 2019 is a severe acute respiratory syndrome, and wearing a mask is an important preventive measure. However, long-term use can cause maskne, or mask-induced acne. This study evaluated the prevalence, clinical characteristics, and severity of mask-induced acne and its effect on pre-existing dermatosis using an online questionnaire. The questionnaire comprised 15 questions on 6 primary topics: demographic data, type of face mask, dermatological symptoms after using a mask, preexisting dermatological conditions, the duration of use, and the effects of mask use on existing dermatological conditions. We included 1,025 participants; 48.6% had dermatological symptoms after using masks. The most common symptoms were red papules (33.8%) and itching (27.2%). Individuals who wore masks for more than 4 hours daily experienced more dermatological symptoms, for example, healthcare providers, who had a higher risk of maskrelated dermatosis than participants with other occupations. Moreover, masks significantly increased the severity of rosacea, contact dermatitis, and seborrheic dermatitis. These results suggest that board-certified dermatologists should assess patients in larger-scale studies to determine adequate management strategies.
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Inorganic arsenic (iAs) is a natural toxicant which, upon entering the biosphere, undergoes extensive biotransformation and becomes a portal for generating various organic intermediates/products. The chemical diversity of iAs-derived organoarsenicals (oAs) is accompanied by varying degree of toxicity that can be held responsible, at least partly, for the overall health outcome of the originally encountered parent inorganic molecule. Such toxicity may originate from arsenicals ability to modulate cytochrome P450 1A (CYP1A) enzymes, whose activity is critical in activating/detoxifying procarcinogens. In this study, we evaluated the effect of monomethylmonothioarsonic acid (MMMTAV) on CYP1A1 and CYP1A2 in absence and presence of their inducer; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, C57BL/6 mice were intraperitoneally injected with 12.5 mg/kg MMMTAV, with or without 15 µg/kg TCDD for 6 and 24 h. Moreover, murine Hepa-1c1c7 and human HepG2 cells were treated with MMMTAV (1, 5, and 10 µM), with or without 1 nM TCDD for 6 and 24 h. MMMTAV significantly inhibited TCDD-mediated induction of CYP1A1 mRNA, both in vivo and in vitro. This effect was attributed to decreased transcriptional activation of CYP1A regulatory element. Interestingly, MMMTAV significantly increased TCDD-induced CYP1A1 protein and activity in C57BL/6 mice and Hepa-1c1c7 cells, while both were significantly inhibited by MMMTAV treatment in HepG2 cells. CYP1A2 mRNA, protein and activity induced by TCDD were significantly increased by MMMTAV co-exposure. MMMTAV had no effect on CYP1A1 mRNA stability or protein stability and did not alter their half-lives. At basal level, only CYP1A1 mRNA was significantly decreased in MMMTAV-treated Hepa-1c1c7 cells. Our findings show that MMMTAV exposure potentiates procarcinogen-induced catalytic activity of both CYP1A1 and CYP1A2 in vivo. This effect entails excessive activation of such procarcinogens upon co-exposure, with potentially negative health-related outcomes.
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Arsenicales , Dibenzodioxinas Policloradas , Humanos , Animales , Ratones , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Ratones Endogámicos C57BL , Sistema Enzimático del Citocromo P-450/genética , Arsenicales/farmacología , Dibenzodioxinas Policloradas/toxicidad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
OBJECTIVE: To assess the effect of bleaching on surface roughness and gloss of different CAD/CAM ceramic materials. METHODS: The ceramic materials included IPS e.max CAD (lithium disilicate), VITA ENAMIC (polymer infiltrated ceramic), and Celtra Duo CAD (zirconia reinforced lithium silicate). Samples of each material were randomly divided into four groups (n = 10); a control group immersed in distilled water, the second and third groups were treated with 20% carbamide peroxide (20% CP) and 35% carbamide peroxide (35% CP) bleaching agents for 4 h/day and 60 min/day respectively for 7 days. The fourth group was treated with 40% hydrogen peroxide (40% HP) applied twice, each turn for 20 min. After treatment, the surface roughness (using 3D non-contact profilometry) and surface gloss were assessed followed by imaging with a scanning electron microscope. The data were analyzed using multiple linear regression and Kruskal-Wallis one-way ANOVA tests (α = 0.05). RESULTS: The surface roughness (p = 0.157) and gloss (p = 0.073) of IPS e.max CAD were not significantly affected by the different bleaching treatments. Similarly, no significant effect on surface roughness (p = 0.162) and gloss (p = 0.965) were shown for Celtra Duo CAD. On the other hand, VITA ENAMIC was significantly affected when treated with 20% CP and 35% CP showing increased roughness (p = 0.001) and gloss (p = 0.008). CONCLUSIONS: Home bleaching treatments (20% CP and 35% CP) significantly affected the surface roughness and gloss of VITA ENAMIC while IPS e.max CAD and Celtra Duo CAD were not affected by the different bleaching treatments.
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Cerámica , Silicatos , Peróxido de Carbamida , Diseño Asistido por Computadora , Porcelana Dental , Ensayo de Materiales , Propiedades de SuperficieRESUMEN
The cytochrome P450 1 A (CYP1A) subfamily enzymes are involved in the metabolic activation of several xenobiotics to toxic metabolites and reactive intermediates, resulting ultimately in carcinogenesis. Mercury and halogenated aromatic hydrocarbons (HAHs), typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are persistent environmental pollutants involved in the modulation of aryl hydrocarbon receptor (AHR) gene battery, including cytochrome P450 (CYP) genes. We previously investigated the effect of coexposure to either inorganic or organic mercury (Hg+2 and MeHg) with TCDD on CYP1A1 in vitro. Thus, we examined the impact of coexposure to Hg+2 or MeHg and TCDD on AHR-regulated genes (Cyp1a1/1a2) in vivo and in vitro. Therefore, male C57BL/6 mice were injected intraperitoneally with MeHg or Hg+2 (2.5 mg/kg) in the absence and presence of TCDD (15 µg/kg) for 6 or 24 h. The concentration-dependent effect of MeHg was examined in murine hepatoma Hepa1c1c7 cells. In vivo, both MeHg and Hg2+ inhibited the TCDD-mediated induction of Cyp1a1/1a2 mRNA levels. However, Only Hg2+ was able to inhibit the TCDD-mediated induction at posttranscriptional levels of CYP1A1/1A2 protein and catalytic activity, suggesting differential modulation effects by Hg+2 and MeHg. In addition, the inhibitory role of HO-1 (Heme oxygenase-1) on CYP1A activity induced by TCDD was investigated using a HO-1 competitive inhibitor, tin-mesoporphyrin, that partially restored the MeHg-mediated decrease in CYP1A1 activity. This study demonstrates that MeHg, alongside Hg2+ , can differentially modulate the TCDD-induced AHR-regulated genes (Cyp1a1/1a2) at different expression levels in C57BL/6 mice liver and Hepa1c1c7 cells.
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Mercurio , Compuestos de Metilmercurio , Dibenzodioxinas Policloradas , Masculino , Ratones , Animales , Citocromo P-450 CYP1A1/genética , Compuestos de Metilmercurio/toxicidad , Compuestos de Metilmercurio/metabolismo , Mercurio/toxicidad , Mercurio/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
The aim of this study is to assess the effect of different bleaching agents on microhardness and color of CAD/CAM ceramics including IPS e.max CAD (lithium disilicate), VITA ENAMIC (polymer-infiltrated ceramic), and Celtra Duo CAD (zirconia-reinforced lithium silicate). Materials' samples were divided into three groups (n = 10) and each received a different bleaching treatment; 20% carbamide peroxide, 35% carbamide peroxide, and 40% hydrogen peroxide. A fourth group was stored in water acting as a control. Vickers microhardness and spectrophotometric color measurements were taken at baseline and after bleaching. IPS e.max CAD showed a significant reduction (about 14%), while VITA ENAMIC showed a significant increase (about 78%) in microhardness after bleaching (p Ë 0.001). Celtra Duo CAD did not demonstrate a significant change in microhardness (p ≥ 0.609). The color difference (ΔEab) after bleaching was 0.29 (±0.08), 2.84 (±0.64), and 1.99 (±0.37) for IPS e.max CAD, VITA ENAMIC, and Celtra Duo CAD, respectively. It could be concluded that the effect of bleaching on color and microhardness was mainly material-dependent. Bleaching significantly affected the microhardness of IPS e.max CAD and VITA ENAMIC. The color difference was within the clinically imperceptible range for IPS e.max CAD, while VITA ENAMIC and Celtra Duo CAD demonstrated perceptible color change.
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Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 µg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 µM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination.
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Citocromo P-450 CYP1A1 , Dibenzodioxinas Policloradas , Animales , Trióxido de Arsénico/farmacología , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Regulación hacia Abajo , Hemo-Oxigenasa 1/metabolismo , Ratones , Ratones Endogámicos C57BL , Dibenzodioxinas Policloradas/toxicidad , ARN MensajeroRESUMEN
The coronavirus vaccine was developed to help overcome the COVID-19 crisis. This study aimed to identify the cutaneous side effects secondary to Pfizer-BioNTech and Oxford-AstraZeneca COVID-19 vaccines in the general population of Saudi Arabia and to list the risk factors for the development of cutaneous side effects. This cross-sectional study was conducted in 2021, self-administered surveys were distributed electronically through social media, and telephonic interviews were conducted with a sample size of 1000 participants. Data analysis was performed using Statistical Package for the Social Sciences. A total of 1021 patients (229 male and 722 female) aged 12 years or older were included. While 833 participants were medically free, 188 had chronic illnesses. While 802 participants were not taking any medications, 219 were taking medications regularly. Oxford-Astra Zeneca and Pfizer BioNTech vaccines were administered to 319 and 702 participants, respectively. One-hundred and twenty-five participants previously had COVID-19 infection and 407 were exposed to a PCR positive case of COVID. Six hundred and fifty-nine patients (64.5%) reported experiencing injection site reactions: 606 (59.4%) had injection site pain, 168 (16.5%) had injection site swelling, and 107 (10.5%) had injection site redness. Only 51 patients (5%) experienced cutaneous side effects after injection. A significant association was found between chronic illnesses and cutaneous side effects post-vaccine (9% vs. 4.1%; p value = 0.005). Patients on medications showed a higher rate of symptoms (8.2% vs. 4.1%; p value = 0.005). Age, gender, vaccine types, and history of COVID-19 infection were not significantly associated with cutaneous side effects post-vaccine.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Estudios Transversales , Femenino , Humanos , Reacción en el Punto de Inyección/epidemiología , Masculino , SARS-CoV-2 , Arabia Saudita/epidemiologíaRESUMEN
The aim of this study is to discover the impact of software security and e-mail security on overall cybersecurity among the students of Imam Abdulrahman Bin Faisal University in Dammam. Another main purpose to conduct this study is to know the level of knowledge students have in the developing countries about the cybersecurity and how much are they mindful of cyber-attacks and the level of awareness among the university students. Two important hypotheses were studied to discover their importance in awareness of cybersecurity. One is software security, and the other is e-mail security. A total of 11 relevant questions were drafted, and then these questions were distributed among the university students, and around 390 responded to the questionnaires. Statistical analysis was performed on the responses using tools. Initial tests such as validity and reliability test, feasibility test of a variable, correlation test, multicollinearity test, multiple regression, and Heteroskedasticity test were conducted using SPSS. And furthermore, multiple linear regression model and coefficient of determination, hypothesis test, ANOVA test, and partial test were conducted using ANOVA. The outcome of the analysis is software security variable (X1) that has a significant and positive effect on cybersecurity awareness (p value ≤0.001, ß = 0.192). This shows that having a thorough understanding of software security can raise cybersecurity awareness up to 19.2%. E-mail security variable (X2) has a significant and positive effect on cybersecurityawareness (p-value ≤0.000). This shows that having a thorough understanding of email security can raise cybersecurity awareness up to 31.3%. Software security (X1) and e-mail security (X2) variables simultaneously have a significant effect on cybersecurity awareness (p-value ≤0.000) with a correlation coefficient of 12.1% (R2 = 0.121). This shows that the independent variable used can explain the level of cybersecurity awareness up to 12.1%. Research results show that students are aware of software or application updates. Furthermore, students' awareness of email security is also good.