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Environment International Nov 2022Oxidative stress from excess reactive oxygen species (ROS) is a hypothesized contributor to preterm birth. Per- and polyfluoroalkyl substances (PFAS) exposure is...
BACKGROUND
Oxidative stress from excess reactive oxygen species (ROS) is a hypothesized contributor to preterm birth. Per- and polyfluoroalkyl substances (PFAS) exposure is reported to generate ROS in laboratory settings, and is linked to adverse birth outcomes globally. However, to our knowledge, the relationship between PFAS and oxidative stress has not been examined in the context of human pregnancy.
OBJECTIVE
To investigate the associations between prenatal PFAS exposure and oxidative stress biomarkers among pregnant people.
METHODS
Our analytic sample included 428 participants enrolled in the Illinois Kids Development Study and Chemicals In Our Bodies prospective birth cohorts between 2014 and 2019. Twelve PFAS were measured in second trimester serum. We focused on seven PFAS that were detected in >65 % of participants. Urinary levels of 8-isoprostane-prostaglandin-F, prostaglandin-F, 2,3-dinor-8-iso-PGF, and 2,3-dinor-5,6-dihydro-8-iso-PGF were measured in the second and third trimesters as biomarkers of oxidative stress. We fit linear mixed-effects models to estimate individual associations between PFAS and oxidative stress biomarkers. We used quantile g-computation and Bayesian kernel machine regression (BKMR) to assess associations between the PFAS mixture and averaged oxidative stress biomarkers.
RESULTS
Linear mixed-effects models showed that an interquartile range increase in perfluorooctane sulfonic acid (PFOS) was associated with an increase in 8-isoprostane-prostaglandin-F (β = 0.10, 95 % confidence interval = 0, 0.20). In both quantile g-computation and BKMR, and across all oxidative stress biomarkers, PFOS contributed the most to the overall mixture effect. The six remaining PFAS were not significantly associated with changes in oxidative stress biomarkers.
CONCLUSIONS
Our study is the first to investigate the relationship between PFAS exposure and biomarkers of oxidative stress during human pregnancy. We found that PFOS was associated with elevated levels of oxidative stress, which is consistent with prior work in animal models and cell lines. Future research is needed to understand how prenatal PFAS exposure and maternal oxidative stress may affect fetal development.
Topics: Alkanesulfonic Acids; Animals; Bayes Theorem; Biomarkers; Dimaprit; Environmental Pollutants; Female; Fluorocarbons; Humans; Infant, Newborn; Oxidative Stress; Pregnancy; Premature Birth; Prospective Studies; Reactive Oxygen Species
PubMed: 36191484
DOI: 10.1016/j.envint.2022.107541 -
Proteins Sep 2022The contact topology of a protein determines important aspects of the folding process. The topological measure of contact order has been shown to be predictive of the...
The contact topology of a protein determines important aspects of the folding process. The topological measure of contact order has been shown to be predictive of the rate of folding. Circuit topology is emerging as another fundamental descriptor of biomolecular structure, with predicted effects on the folding rate. We analyze the residue-based circuit topological environments of 21 K mutations labeled as pathogenic or benign. Multiple statistical lines of reasoning support the conclusion that the number of contacts in two specific circuit topological arrangements, namely inverse parallel and cross relations, with contacts involving the mutated residue have discriminatory value in determining the pathogenicity of human variants. We investigate how results vary with residue type and according to whether the gene is essential. We further explore the relationship to a number of structural features and find that circuit topology provides nonredundant information on protein structures and pathogenicity of mutations. Results may have implications for the polymer physics of protein folding and suggest that "local" topological information, including residue-based circuit topology and residue contact order, could be useful in improving state-of-the-art machine learning algorithms for pathogenicity prediction.
Topics: Algorithms; Humans; Mutation, Missense; Protein Folding; Proteins; Virulence
PubMed: 35394672
DOI: 10.1002/prot.26342 -
PLoS Computational Biology Aug 2021In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis...
In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid β-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct stable and one unstable steady state could be attained with different fluxes. The two stable states were referred to as low-flux (disease) and high-flux (healthy) state. By a modular kinetic approach we traced the origin and causes of the bistability back to the distributive kinetics and the conservation of CoA, in particular in the last rounds of the β-oxidation. We then extended the model to investigate various interventions that may confer health benefits by activating the pathway, including (i) activation of the last enzyme MCKAT via its endogenous regulator p46-SHC protein, (ii) addition of a thioesterase (an acyl-CoA hydrolysing enzyme) as a safety valve, and (iii) concomitant activation of a number of upstream and downstream enzymes by short-chain fatty-acids (SCFA), metabolites that are produced from nutritional fibers in the gut. A high concentration of SCFAs, thioesterase activity, and inhibition of the p46Shc protein led to a disappearance of the bistability, leaving only the high-flux state. A better understanding of the switch behavior of the mitochondrial fatty-acid oxidation process between a low- and a high-flux state may lead to dietary and pharmacological intervention in the treatment or prevention of obesity and or non-alcoholic fatty-liver disease.
Topics: Acetyl-CoA C-Acyltransferase; Animals; Computational Biology; Computer Simulation; Enzyme Stability; Fatty Acids; Humans; Kinetics; Metabolic Networks and Pathways; Mitochondria; Models, Biological; Non-alcoholic Fatty Liver Disease; Obesity
PubMed: 34383741
DOI: 10.1371/journal.pcbi.1009259 -
International Journal of Pharmaceutics Feb 2020Interest in orodispersible films (ODF) is growing day-by-day, since this dosage form overcomes some therapeutic obstacles, such as impaired swallowing, and offers... (Review)
Review
Interest in orodispersible films (ODF) is growing day-by-day, since this dosage form overcomes some therapeutic obstacles, such as impaired swallowing, and offers several benefits, such as the possibility to adapt the dosing requirements for a subset of patients. As a consequence, technologies to produce ODF have risen attention for possible applications in the development of patient-centric formulations. This review critically discusses current trends in the technology platforms proposed to manufacture ODF, including the innovation and opportunities to produce very small batches in a pharmacy setting. Although the main Pharmacopoeias recommend testing customized dosage forms for quality assurance, pharmaceutical assays are a matter of debate due to the complexity and high cost of conventional methods. Alternatively, non-disruptive online analytic methods can be proposed to assay ODF properties, above all to assure the uniformity of drug content.
Topics: Administration, Oral; Animals; Chemistry, Pharmaceutical; Dosage Forms; Drug Compounding; Drug Delivery Systems; Humans; Pharmaceutical Preparations
PubMed: 31857185
DOI: 10.1016/j.ijpharm.2019.118963 -
Medicina Oral, Patologia Oral Y Cirugia... Sep 2023A new classification for periodontitis has been adopted in clinical practice. However, there are still discussions regarding this new classification and difficulties in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A new classification for periodontitis has been adopted in clinical practice. However, there are still discussions regarding this new classification and difficulties in its adoption, both by professionals and researchers. Thus, this study aimed to evaluate which salivary biomarkers are present in periodontitis, following the new classification of periodontal diseases through meta-analysis.
MATERIAL AND METHODS
A literature search was carried out in the scientific databases: PubMed, Scielo and Google scholar to select studies. The selection of studies was followed by two authors upon reading of the title, abstract and full text. The necessary data were collected and statistical analyses were performed using the Review Manager statistical software version 5.4, with calculation of Mean Difference, heterogeneity (I²) and funnel plot with P < 0.05.
RESULTS
After following the selection criteria, 9 articles were selected for comparison. The studies address the presence of biomarkers in the saliva of patients with periodontitis and their possible use in the monitoring and diagnosis of the disease. For the meta-analytic comparison, a sample size of 1,983 individuals was used. Statistical analyses showed that nitric oxide, IL-6, IL-1B and osteoprotegerin are substances that are significantly present in patients with periodontitis (P < 0.05).
CONCLUSIONS
IL-6, nitric oxide, IL-1B, TNF-α and osteoprotegerin are among the most present biomarkers in patients with periodontitis, and may be used in the future as a monitoring of periodontal disease. The present study also revealed that there was no statistically significant difference in the concentration of these biomarkers for clinical distinction from periodontitis.
Topics: Humans; Osteoprotegerin; Nitric Oxide; Interleukin-6; Periodontitis; Biomarkers; Saliva; Chronic Periodontitis
PubMed: 37026605
DOI: 10.4317/medoral.25876 -
International Journal of Molecular... Sep 2020The root bark of has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and... (Review)
Review
The root bark of has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin as one of 7 different isoprene flavonoid derivatives in the root bark of . However, the remarkable antioxidant capacity of morusin with the unexpected potential for health benefits over the other flavonoid derivatives has recently sparked scientific interest in the biochemical identification of target proteins and signaling pathways and further clinical relevance. In this review, we discuss recent advances in the understanding of the functional roles of morusin in multiple biological processes such as inflammation, apoptosis, metabolism and autophagy. We also highlight recent in vivo and in vitro evidence on the clinical potential of morusin treatment for multiple human pathologies including inflammatory diseases, neurological disorders, diabetes, cancer and the underlying mechanisms.
Topics: Antioxidants; Apoptosis; Autophagy; Butadienes; Flavonoids; Hemiterpenes; Humans; Inflammation; Morus; Plant Bark; Plant Extracts; Plant Roots; Signal Transduction; Stress, Physiological
PubMed: 32906784
DOI: 10.3390/ijms21186541 -
Nanomaterials (Basel, Switzerland) May 2022Mesoporous silica nanoparticles (MSNs) bearing methyl, thiol or glucose groups were synthesized, and their encapsulation and release behaviors for the anticancer drug...
Mesoporous silica nanoparticles (MSNs) bearing methyl, thiol or glucose groups were synthesized, and their encapsulation and release behaviors for the anticancer drug Doxorubicin (Dox) were investigated in comparison with nonporous homologous materials. The chemical modification of thiol-functional silica with a double bond glucoside was completed for the first time, by green thiol-ene photoaddition. The MSNs were characterized in terms of structure (FT-IR, Raman), morphology (TEM), porosity (nitrogen sorption-desorption) and Zeta potential measurements. The physical interactions responsible for the Dox encapsulation were investigated by analytic methods and MD simulations, and were correlated with the high loading efficiency of MSNs with thiol and glucose groups. High release at pH 5 was observed in most cases, with thiol-MSN exhibiting 98.25% cumulative release in sustained profile. At pH 7.4, the glucose-MSN showed 75.4% cumulative release, while the methyl-MSN exhibited a sustained release trend. The in vitro cytotoxicity was evaluated on NDHF, MeWo and HeLa cell lines by CellTiter-Glo assay, revealing strong cytotoxic effects in all of the loaded silica at low equivalent Dox concentration and selectivity for cancer cells. Atypical applications of each MSN as intravaginal, topical or oral Dox administration route could be proposed.
PubMed: 35683677
DOI: 10.3390/nano12111823 -
Journal of Molecular Modeling Mar 2023MNDO-based semi-empirical methods in quantum chemistry have found widespread application in the modelling of large and complex systems. A method for the analytic...
CONCEPT
MNDO-based semi-empirical methods in quantum chemistry have found widespread application in the modelling of large and complex systems. A method for the analytic evaluation of first and second derivatives of molecular properties against semi-empirical parameters in MNDO-based NDDO-descendant models is presented, and the resultant parameter Hessian is compared against the approximant currently used in parameterization for the PMx models.
METHODS
As a proof of concept, the exact parameter Hessian is employed in a limited reparameterization of MNDO for the elements C, H, N, O and F using 1206 molecules for reference data (heats of formation, ionization energies, dipole moments and reference geometries). The correctness of our MNDO implementation was verified by comparing the calculated molecular properties with the MOPAC program.
PubMed: 36977949
DOI: 10.1007/s00894-023-05499-3 -
Reproductive Biology and Endocrinology... Oct 2023With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged...
BACKGROUND
With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged oocytes. However, the molecular mechanism of aneuploidy in aged oocytes is far from understood. Histone acetyltransferase 1 (HAT1) has been reported to be essential for mammalian development and genome stability, and involved in multiple organ aging. Whether HAT1 is involved in ovarian aging and the detailed mechanisms remain to be elucidated.
METHODS
The level of HAT1 in aged mice ovaries was detected by immunohistochemical and immunoblotting. To explore the function of HAT1 in the process of mouse oocyte maturation, we used Anacardic Acid (AA) and small interfering RNAs (siRNA) to culture cumulus-oocyte complexes (COCs) from ICR female mice in vitro and gathered statistics of germinal vesicle breakdown (GVBD), the first polar body extrusion (PBE), meiotic defects, aneuploidy, 2-cell embryos formation, and blastocyst formation rate. Moreover, the human granulosa cell (GC)-like line KGN cells were used to investigate the mechanisms of HAT1 in this progress.
RESULTS
HAT1 was highly expressed in ovarian granulosa cells (GCs) from young mice and the expression of HAT1 was significantly decreased in aged GCs. AA and siRNAs mediated inhibition of HAT1 in GCs decreased the PBE rate, and increased meiotic defects and aneuploidy in oocytes. Further studies showed that HAT1 could acetylate Forkhead box transcription factor O1 (FoxO1), leading to the translocation of FoxO1 into the nucleus. Resultantly, the translocation of acetylated FoxO1 increased the expression of amphiregulin (AREG) in GCs, which plays a significant role in oocyte meiosis.
CONCLUSION
The present study suggests that decreased expression of HAT1 in GCs is a potential reason corresponding to oocyte age-related meiotic defects and provides a potential therapeutic target for clinical intervention to reduce aneuploid oocytes.
Topics: Animals; Female; Humans; Mice; Aneuploidy; Granulosa Cells; Histone Acetyltransferases; Mammals; Meiosis; Mice, Inbred ICR; Oocytes
PubMed: 37907924
DOI: 10.1186/s12958-023-01147-w -
ACS Chemical Biology Mar 2022Determining cell death mechanisms occurring in patient and animal tissues is a longstanding goal that requires suitable biomarkers and accurate quantification. However,...
Determining cell death mechanisms occurring in patient and animal tissues is a longstanding goal that requires suitable biomarkers and accurate quantification. However, effective methods remain elusive. To develop more powerful and unbiased analytic frameworks, we developed a machine learning approach for automated cell death classification. Image sets were collected of HT-1080 fibrosarcoma cells undergoing ferroptosis or apoptosis and stained with an anti-transferrin receptor 1 (TfR1) antibody, together with nuclear and F-actin staining. Features were extracted using high-content-analysis software, and a classifier was constructed by fitting a multinomial logistic lasso regression model to the data. The prediction accuracy of the classifier within three classes (control, ferroptosis, apoptosis) was 93%. Thus, TfR1 staining, combined with nuclear and F-actin staining, can reliably detect both apoptotic and ferroptotis cells when cell features are analyzed in an unbiased manner using machine learning, providing a method for unbiased analysis of modes of cell death.
Topics: Actins; Apoptosis; Biomarkers; Ferroptosis; Humans; Machine Learning; Receptors, Transferrin
PubMed: 35230809
DOI: 10.1021/acschembio.1c00953