Brownsnyder2899

Mathematical modeling of mixture effects indicated potentially more than additive behavior using a model for compounds with similar modes of action. The present data underline the usefulness of AOP-guided in vitro testing for the identification of mixture effects and highlight the need for further research on chemical mixtures and harmonization of data interpretation of mixture effects.Vanadium dioxide nanoparticles (VO2 NPs) have been massively produced and widely applied due to their excellent metal-insulator transition property, making it extremely urgent to evaluate their safety, especially for low-dose long-term respiratory occupational exposure. Here, we report a comprehensive cytotoxicity and genotoxicity study on VO2 NPs to lung cell lines A549 and BEAS-2B following a long-term exposure. A commercial VO2 NP, S-VO2, was used to treat BEAS-2B (0.15-0.6 μg/mL) and A549 (0.3-1.2 μg/mL) cells for four exposure cycles, and each exposure cycle lasted for 4 consecutive days; then various bioassays were performed after each cycle. Significant proliferation inhibition was observed in both cell lines after long-term exposure of S-VO2 at low doses that did not cause apparent acute cytotoxicity; however, the genotoxicity of S-VO2, characterized by DNA damage and micronuclei, was only observed in A549 cells. These adverse effects of S-VO2 were exposure time-, dose- and cell-dependent, and closely related to the solubility of S-VO2. The oxidative stress in cells, i.e., enhanced reactive oxygen species (ROS) generation and suppressed reduced glutathione, was the main toxicity mechanism of S-VO2. The ROS-associated mitochondrial damage and DNA damage led to the genotoxicity, and cell proliferation retard, resulting in the cellular viability loss. Our results highlight the importance and urgent necessity of the investigation on the long-term toxicity of VO2 NPs.The incidence and mortality of cancer are rapidly growing all over the world. Nowadays, antineoplastic antimetabolites still play a key role in the chemotherapy of cancer. However, the interindividual variations in the efficacy and toxicity of antineoplastic antimetabolites are nonnegligible challenges to their clinical applications. Although many studies have focused on genetic variation, the reasons for these interindividual variations have still not been fully understood. Gut microbiota is reported to be associated with the efficacy and toxicity of antineoplastic antimetabolites. In this review, we summarize the interaction of antineoplastic antimetabolites on gut microbiota and the influences of shifted gut microbiota profiles on the efficacy and toxicity of antineoplastic antimetabolites. The factors affecting the efficacy and toxicity of antineoplastic antimetabolites via gut microbiota are also discussed. In addition, we present our viewpoints that regulating the gut microbiota may increase the efficacy and decrease the toxicity of antineoplastic antimetabolites. This will help us better understand the new mechanism via gut microbiota and promote individualized use of antineoplastic antimetabolites.

Phyto-preparations and phyto-compounds, by their natural origin, easy availability, cost-effectiveness, and fruitful traditional uses based on accumulated experiences, have been extensively explored to mitigate the global burden of obesity.

The review aimed to analyse and critically summarize the prospect of future anti-obesity drug leads from the extant array of phytochemicals for mitigation of obesity, using adipose related targets (adipocyte formation, lipid metabolism, and thermogenesis) and non-adipose targets (hepatic lipid metabolism, appetite, satiety, and pancreatic lipase activity). Phytochemicals as inhibitors of adipocyte differentiation, modulators of lipid metabolism, and thermogenic activators of adipocytes are specifically discussed with their non-adipose anti-obesogenic targets.

PubMed, Google Scholar, Scopus, and SciFinder were accessed to collect data on traditional medicinal plants, compounds derived from plants, their reported anti-obesity mechanisms, and therapeutic targets. The ta derived compounds hold high therapeutic potential to tackle obesity and associated risks. This review has been able to generate fresh perspectives on the anti-diabetic/anti-hyperglycemic/anti-obesity effect of phytochemicals. It has also brought into the focus that many phytochemicals demonstrating in vitro anti-obesogenic effects are yet to undergo in vivo investigation which could lead to potential phyto-molecules for dedicated anti-obesity action.

Due to high molecular diversity and a greater ratio of benefit to risk, plant derived compounds hold high therapeutic potential to tackle obesity and associated risks. This review has been able to generate fresh perspectives on the anti-diabetic/anti-hyperglycemic/anti-obesity effect of phytochemicals. It has also brought into the focus that many phytochemicals demonstrating in vitro anti-obesogenic effects are yet to undergo in vivo investigation which could lead to potential phyto-molecules for dedicated anti-obesity action.

Alzheimer's disease (AD) is the main cause of dementia, and according to traditional Chinese medicine (TCM), it is leaded by the deficiency of essence, qi, and blood. Allii sativi bulbus, acrid and warm, is traditionally used as the important adjuvant and conductant drug to distribute essence-qi throughout the body, fortify the spleen and harmonize the stomach. Garlic (Allium sativum L., Alliaceae) has also been reported to display potential anti-AD effect both in vitro and in vivo studies, while no systematic review of these studies has been conducted.

This review aims to provide a comprehensive evaluation of the effect and underlying mechanism of garlic extract against cognitive impairment and AD neuropathology through meta-analysis and sensitivity analysis.

Eligible studies were searched from PubMed, Web of Science and EMBASE from February to March in 2020, and 13 studies describing the effect of garlic extract in AD animal models (551 mice and 88 rats) were identified.

Analysis of these studies showed that garlic extract could reduce cerebral Aβ levels [Aβ

SMD -8.62(-11.75, -5.49), p<0.00001 and Aβ

SMD -11.70(-18.01, -5.39), p=0.0003], and increase the number of right crossings in MWM [SMD 2.87(1.48, 4.26), p<0.0001] in AD animals. However, moderate risk of bias (quality score ranged from 40% to 60%) is revealed by SYRCLE's checklist, mainly because of the lacks of sample size calculation, random allocation and blind assessment.

This review shows that garlic extract may be effective in alleviating cognitive impairment and neuropathology in AD animal models. High quality AD animal studies with enough sample size and more comprehensive evaluation of outcomes are needed to further confirm the results.

This review shows that garlic extract may be effective in alleviating cognitive impairment and neuropathology in AD animal models. CX-5461 research buy High quality AD animal studies with enough sample size and more comprehensive evaluation of outcomes are needed to further confirm the results.Because ganciclovir resistance mutations in the cytomegalovirus UL97 gene most commonly occur at codons 460, 520 and 590-607, diagnostic genotyping for drug resistance has often omitted the analysis of codons below 440. However, the UL97 kinase inhibitor maribavir selects for distinctive resistance mutations at codons 409 and 411, and ganciclovir/maribavir resistance mutations have also been described in the ATP binding region starting at codon 335. Expanded genotypic testing of UL97 codons 335-440 in 1535 clinical specimens disclosed 10 uncharacterized sequence variants that were phenotyped for ganciclovir and maribavir susceptibility. Notable findings included low-grade ganciclovir resistance conferred by amino acid substitutions K359N and E362D, decreased maribavir susceptibility of L348V, and maribavir hypersensitivity of V345I and E362D. Recently published substitutions F342Y and K359E/Q were also confirmed. The data indicate that mutations in the UL97 ATP binding region may arise in clinical specimens to affect the interpretation of ganciclovir and maribavir resistance. This region should now be included in the standard diagnostic genotyping of UL97, especially with the introduction of maribavir into therapeutic use.It should now be recognized that codes are central to life and to understanding its more complex forms, including human culture. Recognizing the 'conventional' nature of codes provides solid grounds for rejecting efforts to reduce life to biochemistry and justifies according a place to semantics in life. The question I want to consider is whether this is enough. Focussing on Eigen's paradox of how a complex code could originate, I will argue that along with Barbieri's efforts to account for the origins of life based on the ribosome and then to account for the refined codes through a process of ambiguity reduction, something more is required. Barbieri has not provided an adequate account of emergence, or the basis for providing such an account. I will argue that Stanley Salthe has clarified to some extent the nature of emergence by conceptualizing it as the interpolation of new enabling constraints. Clearly, codes can be seen as enabling constraints. How this actually happens, though, is still not explained. Stuart Kauffman has grappled with this issue and shown that it radically challenges the assumptions of mainstream science going back to Newton. He has attempted to reintroduce real possibilities or potentialities into his ontology, and argued that radically new developments in nature are associated with realizing adjacent possibles. This is still not adequate. What is also involved, I will suggest, utilizing concepts developed by the French natural philosopher Gilbert Simondon, is 'transduction' as part of 'ontogenesis' of individuals in a process of 'individuation', that is, the emergence of 'individuals' from preindividual fields or milieux.Papillary thyroid cancer (PTC), whose incidence has been increasing in the last years, occurs more frequently in women. Experimental studies suggested that estrogen could be an important risk factor for the higher female incidence. In fact, it has been demonstrated that 17β-estradiol (E2) could increase proliferation and dedifferentiation in thyroid follicular cells. Genomic estrogen responses are typically mediated through classical estrogen receptors, the α and β isoforms, which have been described in normal and abnormal human thyroid tissue. Nevertheless, effects mediated through G protein estrogen receptor 1 (GPR30/GPER/GPER1), described in some thyroid cancer cell lines, could be partially responsible for the regulation of growth in normal cells. In this study, GPER1 gene and protein expression are described in non-malignant and in papillary thyroid cancer (PTC), as well as its association with clinical features of patients with PTC. The GPER1 expression was lower in PTC as compared to paired non-malignant thyroid tissues in fresh samples of PTC and in silico analysis of GEO and TCGA databases. In PTC cases of TCGA database, low GPER1 mRNA expression was independently associated with metastatic lymph nodes, female gender, and BRAF mutation. Besides, GPER1 mRNA levels were positively correlated with mRNA levels of thyroid differentiation genes. These results support the hypothesis that GPER1 have a role in PTC tumorigenesis and might be a potential target for its therapy. Further studies are needed to determine the functionality of these receptors in normal and diseased thyroid.