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Background: Fermentation is a widely used method of natural food preservation that has consequences on the nutritional value of the transformed food. Fermented dairy products are increasingly investigated in view of their ability to exert health benefits beyond their nutritional qualities.Objective: To explore the mechanisms underpinning the health benefits of fermented dairy intake, the present study followed the effects of milk fermentation, from changes in the product metabolome to consequences on the human serum metabolome after its ingestion.Methods: A randomized crossover study design was conducted in 14 healthy men [mean age: 24.6 y; mean body mass index (in kg/m2): 21.8]. At the beginning of each test phase, serum samples were taken 6 h postprandially after the ingestion of 800 g of a nonfermented milk or a probiotic yogurt. During the 2-wk test phases, subjects consumed 400 g of the assigned test product daily (200 g, 2 times/d). Serum samples were taken from fasting participants at the end of each test phase. The serum metabolome was assessed through the use of LC-MS-based untargeted metabolomics.Results: Postprandial serum metabolomes after milk or yogurt intake could be differentiated [orthogonal projections to latent structures discriminant analysis (OPLS-DA) Q2 = 0.74]. Yogurt intake was characterized by higher concentrations of 7 free amino acids (including proline, P = 0.03), reduced concentrations of 5 bile acids (including glycocholic acid, P = 0.04), and modulation of 4 indole derivative compounds (including indole lactic acid, P = 0.01). Fasting serum samples after 2 wk of daily intake of milk or yogurt could also be differentiated based on their metabolic profiles (OPLS-DA Q2 = 0.56) and were discussed in light of the postprandial results.Conclusion: Metabolic pathways related to amino acids, indole derivatives, and bile acids were modulated in healthy men by the intake of yogurt. Further investigation to explore novel health effects of fermented dairy products is warranted.This trial was registered at clinicaltrials.gov as NCT02230345. [ABSTRACT FROM AUTHOR]

Biomaterials with osteoinductivity are widely used for bone defect repair due to their unique structures and functions. Machine learning (ML) is pivotal in analyzing osteoinductivity and accelerating new material design. However, challenges include creating a comprehensive database of osteoinductive materials and dealing with low-quality, disparate data. As a standard for evaluating the osteoinductivity of biomaterials, ectopic ossification has been used. This paper compiles research findings from the past thirty years, resulting in a robust database validated by experts. To tackle issues of limited data samples, missing data, and high-dimensional sparsity, a data enhancement strategy is developed. This approach achieved an area under the curve (AUC) of 0.921, a precision of 0.839, and a recall of 0.833. Model interpretation identified key factors such as porosity, bone morphogenetic protein-2 (BMP-2), and hydroxyapatite (HA) proportion as crucial determinants of outcomes. Optimizing pore structure and material composition through partial dependence plot (PDP) analysis led to a new bone area ratio of 14.7 ± 7 % in animal experiments, surpassing the database average of 10.97 %. This highlights the significant potential of ML in the development and design of osteoinductive materials. This study leverages machine learning to analyze osteoinductive biomaterials, addressing challenges in database creation and data quality. Our data enhancement strategy significantly improved model performance. By optimizing pore structure and material composition, we increased new bone formation rates, showcasing the vast potential of machine learning in biomaterial design. [Display omitted] [ABSTRACT FROM AUTHOR]

Spinal cord compression is a source of pathology routinely seen in clinical practice. However, there remain unanswered questions surrounding both the understanding of pathogenesis and the best method of treatment. This arises from limited real-life testing of the mechanical properties of the spinal cord, either through cadaveric human specimens or animal testing, both of which suffer from methodological, as well as ethical, issues. To conduct a review of the literature on the mechanical properties of the spinal cord. A systematic review of the literature on the mechanical properties of the spinal cord is undertaken. All literature reporting the testing of the mechanical properties of the spinal cord. Reported physiological mechanical properties of the spinal cord. The methodological quality of the studies has been assessed within the ARRIVE guidelines using the CAMARADES framework and SYRCLE's risk of bias tool. This paper details the methodologies and results of the reported testing. We show that (1) the research quality of previous work does not follow published guidelines on animal treatment or risk of bias, (2) no standard protocol has been employed for sample preparation or mechanical testing, (3) this leads to a wide distribution of results for the tested mechanical properties, not applicable to the living human or animal, and (4) animal testing is not a good proxy for human application. The findings summarize the sum of current knowledge inherent to the mechanical properties of the spinal cord and may contribute to the development of a physical model which is applicable to the living human for analysis and testing in a controlled and repeatable fashion. Such a model would be the basis for further clinical research to improve outcomes from spinal cord compression. [ABSTRACT FROM AUTHOR]

[Display omitted] • We reviewed the literature on isolation of Toxoplasma gondii directly in cell culture. • Four experiments were reported to isolate T. gondii from different animals in Vero and HFF cell cultures. • We recommend an in vitro protocol to isolate T. gondii. • This method is simpler, more cost-effective, ethically more acceptable, and less time-sensitive. Toxoplasma gondii is an apicomplexan protozoan parasite that can infect mammals and birds. The infection can cause acute toxoplasmosis and death in susceptible hosts. Bioassay using cats and mice has been the standard for the isolation of T. gondii from infected hosts for the past several decades. However, bioassay is labor-intensive, expensive, and involves using laboratory animals. To search alternative approaches and o work towards replacement of animal experiments, we summarized the key literature and conducted four experiments to isolate T. gondii in vitro by cell culture. A few heart tissue samples from animals with the highest antibody titers in a given collection were used for T. gondii isolation. These experiments included samples from five out of 51 wild ducks, four of 46 wild turkeys, six of 24 white-tailed deer, as well as from six kangaroos that had died with acute toxoplasmosis in a zoo. These experiments resulted in three isolates from five chronically infected wild ducks (60%), four isolates from four chronically infected wild turkeys (100%), one isolate from six chronically infected white-tailed deer (17%), and four isolates from six kangaroos with acute toxoplasmosis (67%). In addition, five isolates from the five chronically infected wild ducks were obtained by bioassay in mice, showing a 100% success rate, which is higher than the 60% rate by direct cell culture. These T. gondii isolates were successfully propagated in human foreskin fibroblast (HFF) or Vero cells, and genotyped by multilocus PCR-RFLP markers. The results showed that it is practical to isolate T. gondii directly in cell culture. Although the cell culture approach may not be as sensitive as the bioassay, it does provide an alternative that is simple, cost-effective, ethically more acceptable, and less time-sensitive to isolate T. gondii. In this paper we propose a procedure that may be applied and further optimized for isolation of T. gondii. [ABSTRACT FROM AUTHOR]

• Evidence-based analysis of peri‑implant gas accumulation (PIGA). • Postoperative PIGA: common for musculoskeletal Mg implants. • Clinical relevance: potentially associated surgical complications. • Radiological techniques: for quantitative and longitudinal analysis. • Standardized evaluation needed for developing Mg implants. Historically, the rapid degradation and massive gas release from magnesium (Mg) implants resulted in severe emphysema and mechanical failure. With the advent of new alloys and surface treatment methods, optimized Mg implants have re-entered clinics since last decade with reliable performance. However, the optimization aims at slowing down the degradation process, rather than exemption of the gas release. This study involved a systematic evaluation of current preclinical and clinical evidence, regarding the physical signs, symptoms, radiological features, pathological findings and complications potentially associated with peri‑implant gas accumulation (PIGA) after musculoskeletal Mg implantation. The literature search identified 196 potentially relevant publications, and 51 papers were enrolled for further analysis, including 22 preclinical tests and 29 clinical studies published from 2005 to 2023. Various Mg-based materials have been evaluated in animal research, and the application of pure Mg and Mg alloys have been reported in clinical follow-ups involving multiple anatomical sites and musculoskeletal disorders. Soft tissue and intraosseous PIGA are common in both animal tests and clinical follow-ups, and potentially associated with certain adverse events. Radiological examinations especially micro-CT and clinical CT scans provide valuable information for quantitative and longitudinal analysis. While according to simulation tests involving Mg implantation and chemical processing, tissue fixation could lead to an increase in the volume of gas cavity, thus the results obtained from ex vivo imaging or histopathological evaluations should be interpreted with caution. There still lacks standardized procedures or consensus for both preclinical and clinical evaluation of PIGA. However, by providing focused insights into the topic, this evidence-based study will facilitate future animal tests and clinical evaluations, and support developing biocompatible Mg implants for the treatment of musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE 2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms. [Display omitted] • WJW treatment GUs potential mechanism is by inhibiting inflammation, oxidative stress injury and apoptosis signaling pathways. • Integrated network pharmacology and metabolomics identified the key targets of WJW in the treatment of GUs, namely TNF, AKT1, PTGS2 and MAPK1. • The active components in WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. • This paper provides a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms. [ABSTRACT FROM AUTHOR]

This paper re-examines research that studies economic rationality using experimental data generated by nonhuman animals (e.g. rats, pigeons, monkeys, etc.). The standard experimental methodology to elicit choices from nonhuman animals allows a researcher to test three types of economic rationality: standard deterministic utility maximization, average choice rationality, and random utility maximization. Most of the research has evaluated whether animals satisfy average choice rationality. We describe the difference between these models and check each type of rationality on capuchin monkey data from Chen et al.(2006). We reject standard deterministic utility maximization and random utility maximization for most subjects, but we cannot reject average choice rationality. This paper is the first to provide a statistical test for average choice rationality. [ABSTRACT FROM AUTHOR]

Despite aspirations to substitute animal experimentation with alternative methods and recent progress in the area of non-animal approaches, such as organoïds and organ(s)-on-a-chip technologies, there is no extensive replacement of animal-based research in biomedicine. In this paper, I will analyse this state of affairs with reference to key institutional and socio-epistemic barriers for the development and use of non-animal approaches in the context of biomedical research in Europe. I will argue that there exist several factors that inhibit change in this context. In particular, there is what I call "scientific inertia", i.e. a certain degree of conservatism in scientific practice regarding the development and use of non-animal approaches to replace animal experimentation. This type of inertia is facilitated by socio-epistemic characteristics of animal-based research in the life sciences and is a key factor in understanding the status quo in biomedical research. The underlying reasons for scientific inertia have not received sufficient attention in the literature to date because the phenomenon transcends traditional disciplinary boundaries in the study of animal experimentation. This paper addresses this issue and seeks to contribute to a better understanding of scientific inertia by using a methodology that looks at the interplay of institutional, epistemic, and regulatory aspects of animal-based research. [ABSTRACT FROM AUTHOR]

[Display omitted] In recent years, an increasing number of diverse Engineered Nano-Materials (ENMs), such as nanoparticles and nanotubes, have been included in many technological applications and consumer products. The desirable and unique properties of ENMs are accompanied by potential hazards whose impacts are difficult to predict either qualitatively or in a quantitative and predictive manner. Alongside established methods for experimental and computational characterisation, physics-based modelling tools like molecular dynamics are increasingly considered in Safe and Sustainability-by-design (SSbD) strategies that put user health and environmental impact at the centre of the design and development of new products. Hence, the further development of such tools can support safe and sustainable innovation and its regulation. This paper stems from a community effort and presents the outcome of a four-year-long discussion on the benefits, capabilities and limitations of adopting physics-based modelling for computing suitable features of nanomaterials that can be used for toxicity assessment of nanomaterials in combination with data-based models and experimental assessment of toxicity endpoints. We review modern multiscale physics-based models that generate advanced system-dependent (intrinsic) or time- and environment-dependent (extrinsic) descriptors/features of ENMs (primarily, but not limited to nanoparticles, NPs), with the former being related to the bare NPs and the latter to their dynamic fingerprinting upon entering biological media. The focus is on (i) effectively representing all nanoparticle attributes for multicomponent nanomaterials, (ii) generation and inclusion of intrinsic nanoform properties, (iii) inclusion of selected extrinsic properties, (iv) the necessity of considering distributions of structural advanced features rather than only averages. This review enables us to identify and highlight a number of key challenges associated with ENMs' data generation, curation, representation and use within machine learning or other advanced data-driven models to ultimately enhance toxicity assessment. Finally, the set up of dedicated databases as well as the development of grouping and read-across strategies based on the mode of action of ENMs using omics methods are identified as emerging methodologies for safety assessment and reduction of animal testing. [ABSTRACT FROM AUTHOR]

A mixed-signal four-channel biphasic current-mode functional electrical stimulator chip with a novel charge compensation circuit is presented in this paper. This chip can induce programmable biphasic current ranging from 10 μ A to 2.56 mA for each channel. However, a significant problem with functional electrical stimulation is charge balancing (CB) due to anodic and cathodic current mismatch for process variation. Therefore, a novel compensation module including both passive and active charge compensation schemes are adopted in this chip. The charge compensation module autonomously adjusts the supply and compensation current to achieve fast compensation and low-power consumption simultaneously. The proposed biphasic stimulator is designed and fabricated in a 0.18 μ m CMOS process with a die area of 2.27 mm × 1.99 mm. The measurement results from a test bench demonstrate the proposed circuit functionalities, and the standby power consumption of this chip is 193.7 μ W. Besides, animal experiments on mice for seizure suppression with deep brain stimulation were performed to verify the efficacy and safety of the developed stimulation chip. • A biphasic current-mode electrical stimulator with charge compensation is presented. • A novel module including both passive and active charge compensation schemes is adopted in this chip. • The proposed biphasic stimulator is designed and fabricated in a 0.18 μ m CMOS process. • Fast residual charge compensation and low power consumption module implemented. • Animal experiments were performed to verify the efficacy and safety of the developed stimulator. [ABSTRACT FROM AUTHOR]

The risk assessment of small particles (including nanoparticles) in products used in the food chain in the EU falls within the remit of the European Food Safety Authority (EFSA) and has been under thorough scientific considerations for over a decade. Now that more experience is gained with evaluating novel foods, food contact materials, food/feed additives and pesticides , the outlines for regulatory safety assessments and data requirements are established. This paper reviews the principles underlying safety testing of small particles, referring to two recently published EFSA guidance documents. Examples and observations from assessing existing materials are provided to facilitate to a wider readership adequate implementation of the regulatory requirements. The starting point for safety testing is the physicochemical characterisation of the pristine material, being an engineered nanomaterial, a nanostructured material or a conventional material that contains a fraction of small particles that may retain properties at the nanoscale. Key parameters and threshold values for establishing the presence of small particles, the techniques and methods for characterisation in complex matrices, as well as approaches for dietary exposure assessment are outlined. Where there is the likelihood of small particles remaining after gastrointestinal digestion , hazard identification and hazard characterisation are required with special provisions. In particular, certain nano-specific considerations are highlighted that have to be considered during toxicological testing with the aim to demonstrate consumer safety of products to be used in the food chain in Europe. • EFSA has established hypothesis driven guidance for nanoscale assessments. • This innovation is applicable to chemicals in EU food and feed safety assessments. • This ensures consumer protection, independently of nanomaterial definitions. • Alternatives to animal testing support these Next Generation Risk Assessments. • Cases of actual implementation in EFSA assessments are presented. [ABSTRACT FROM AUTHOR]

The Shenlian formula (SL) is a Chinese medicine formula used to curb the development of atherosclerosis (AS) and cardiovascular disease in clinical practice. However, owing to the complexity of compounds and their related multiple targets in traditional Chinese medicine (TCM), it remains difficult and urgent to elucidate the underlying mechanisms at a holistic level. To investigate the intrinsic mechanisms by which SL suppresses AS progression and to gain new insight into its clinical use. We proposed a network pharmacology-based workflow to evaluate the mechanism by which SL affects AS via data analysis, target prediction, PPI network construction, GO and KEGG analyses, and a "drug-core ingredient-potential target-key pathway" network. Then, non-targeted lipidomic analysis was performed to explore the differential lipid metabolites in AS rats, revealing the possible mechanism by which SL affects atherosclerotic progression. Moreover, an AS rabbit model was constructed and gavaged for SL intervention. Serum lipid profiles and inflammatory cytokine indices were tested as an indication of the mitigating effect of SL on AS. A total of 89 bioactive compounds and 298 targets related to SL and AS, which play essential roles in this process, were identified, and a component-target-disease network was constructed. GO and KEGG analyses revealed that SL regulated metabolic pathway, lipids and atherosclerosis, the PI3K-Akt pathway, the MAPK pathway and so on. In vivo experimental validation revealed that a total of 43 different lipid metabolites regulated by SL were identified by non-targeted lipidomics, and glycerophospholipid metabolism was found to be an important mechanism for SL to interfere with AS. SL reduced the plaque area and decreased the levels of inflammatory cytokines (TNF-α and IL-4) and blood lipids (TC, TG, LDL-C, and ApoB) in HFD-induced AS models. In addition, HDL and ApoA 1 levels are increased. PLA2 and Lipin1 are highly expressed in AS model, indicating their role in destabilizing glycerophosphatidylcholine metabolism and contributing to the onset and progression of ankylosing spondylitis. Moreover, SL intervention significantly reduced the level of pro-inflammatory cytokines; significantly down-regulated NF-kB/p65 expression, exhibiting anti-inflammatory activity. The Shenlian formula (SL) plays a pivotal role in the suppression of AS progression by targeting multiple pathways and mechanisms. This study provides novel insights into the essential genes and pathways associated with the prognosis and pathogenesis of AS. [Display omitted] • The innovation of this paper lies in clarifying the therapeutic effect of SL on atherosclerosis, especially the prediction of anti-atherosclerosis active ingredients and related targets by network pharmacology tools. • The network pharmacology prediction and lipid metabolism pathway were verified by In vivo experiments, in atherosclerosis model. • SL formula intervention significantly reduced the level of pro-inflammatory cytokines; significantly down-regulated NF-kB/p65 expression, exhibiting anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

The essential oil (EO) obtained from hemp (Cannabis sativa L.) biomass is rich of bioactive constituents and its oral administration can be valuable. In this paper two different hemp EOs were orally administered to CD1 mice. One EO, obtained from the fresh plant material, resulted rich in monoterpenes (monoterpene rich oil, MRO) and the other, obtained from the dried biomass, contained mainly sesquiterpenes and CBD (sesquiterpene rich oil, SRO). The blood levels of the most abundant constituents were evaluated in the animals 30 and 90 min after oral administration of hemp EOs. Furthermore, compounds were also measured in brain, liver, kidney, spleen, and cecum content to evaluate their tissue distribution at the same times. Results showed the easy absorption and the ability of the major hemp EOs constituents to reach brain, liver, and kidney. Oral administration of MRO resulted in blood levels of monoterpenes in the range 45–115 ng/g at 30 min and significant tissue distribution with the detection of monoterpenes in brain, liver, and kidney. Oral administration of SRO resulted in blood levels, at 30 min, in the range 70–80 ng/g of sesquiterpenes and 139 ng/g of CBD. The compounds are still detectable in blood and brain 90 min after oral administration and significant concentrations of terpenoids are observed in liver and kidney. MRO and SRO can be considered as valuable sources of these bioactive compounds and further investigations are needed to evaluate the potential uses of hemp EO as constituent of innovative drug formulations. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • We propose a decision logic to identify thyroid disruption in aquatic vertebrates. • The decision logic is evidence-based and includes internationally agreed guidelines. • Thyroid-mediated effect patterns must consider consistency and directions of changes. • The weight-of-evidence considers mode-of-action and population relevance assessments. • The decision logic supports regulatory assessments while minimising animal testing. According to the World Health Organisation and European Commission definitions, substances shall be considered as having endocrine disrupting properties if they show adverse effects, have endocrine activity and the adverse effects are a consequence of the endocrine activity (using a weight-of-evidence approach based on biological plausibility), unless the adverse effects are not relevant to humans or non-target organisms at the (sub)population level. To date, there is no decision logic on how to establish endocrine disruption via the thyroid modality in non-mammalian vertebrates. This paper describes an evidence-based decision logic compliant with the integrated approach to testing and assessment (IATA) concept, to identify thyroid-mediated effect patterns in aquatic vertebrates using amphibians as relevant models for thyroid disruption assessment. The decision logic includes existing test guidelines and methods and proposes detailed considerations on how to select relevant assays and interpret the findings. If the mammalian dataset used as the starting point indicates no thyroid concern, the Xenopus Eleutheroembryonic Thyroid Assay allows checking out thyroid-mediated activity in non-mammalian vertebrates, whereas the Amphibian Metamorphosis Assay or its extended, fixed termination stage variant inform on both thyroid-mediated activity and potentially population-relevant adversity. In evaluating findings, the response patterns of all assay endpoints are considered, including the direction of changes. Thyroid-mediated effect patterns identified at the individual level in the amphibian tests are followed by mode-of-action and population relevance assessments. Finally, all data are considered in an overarching weight-of-evidence evaluation. The logic has been designed generically and can be adapted, e.g. to accommodate fish tests once available for thyroid disruption assessments. It also ensures that all scientifically relevant information is considered, and that animal testing is minimised. The proposed decision logic can be included in regulatory assessments to facilitate the conclusion on whether substances meet the endocrine disruptor definition for the thyroid modality in non-mammalian vertebrates. [ABSTRACT FROM AUTHOR]

In this paper, the co-pyrolysis of blends of animal manure (AM) and high-density polyethylene (HDPE) waste was investigated using micro-thermal analysis techniques. Thermogravimetry coupled with Fourier-transform infrared spectroscopy was used to study the process kinetics and potential synergistic effects during co-pyrolysis. Dynamic co-pyrolysis experiments of animal manure (AM) and polyethylene (PE) blends in proportions of (90:10 %) and (80:20 %) were conducted at heating rates of 5, 10, 15, and 20 °C/min under an N 2 atmosphere. The process was analyzed and compared to the results obtained in the pyrolysis of pure components. AM and PE co-pyrolysis exhibited a synergic effect on the pyrolysis process, leading to a favorable change in the CPI pyrolysis initiation index. This was observed in the FTIR, shifting maximum devolatilization peaks by 14 °C towards lower temperatures and a lower activation energy of the main pyrolysis stage, with a decrease from 341.49±4.65 kJ/mol to 273.04±6.93 kJ/mol after the addition of 20 wt% PE to the blend. During co-pyrolysis, the main compounds observed in the FTIR absorption spectra were CO 2 , CO, CH 4 , NH 3 , and aromatic hydrocarbons from AM pyrolysis. Additionally, there was an increase in CH 4 and short-chain hydrocarbons due to the PE pyrolysis. • Co-processing of animal and plastic waste via pyrolysis using TG-FTIR was examined. • Addition of plastics to the animal waste changed CPI over 40 %. • 20 % addition of plastic lower energy activation of main pyrolysis stage by 25 %. • Four independent reaction kinetic models of the AM-PE co-pyrolysis were observed. [ABSTRACT FROM AUTHOR]

• In this paper, we found that senescent mice develop pathologies such as obesity lipid metabolism disorders. • The expression of miR-743b-3p was elevated in senescent mice, which inhibited the expression of PPM1K. • MiR-743b-3p regulates BCAA levels in senescent hepatocytes by targeting PPM1K causing abnormal lipid deposition. Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. In this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. We found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). These results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing. [Display omitted] [ABSTRACT FROM AUTHOR]

Animal experimentation has long been an integral part of biomedical and cosmetics research, with historical roots dating back to ancient Greece. During that period, physicians constrained by cultural taboos that forbade the use of human cadavers, turned to the dissection of animals for their anatomical studies. The use of specific animal models in research has often been justified by the remarkable biological similarities between animals and humans. However, there are instances where animal models, such as fish and frogs, are used, despite significant disparities in their anatomy and physiology compared to humans. In herbal medicine research, animal experimentation has found various applications. Numerous plant species from diverse global regions, including the United Kingdom, United States, China, India, and Africa, have been studied to identify their pharmacological properties and therapeutic indications. Nevertheless, the use of animals in these studies, while offering undeniable advantages, remains a subject of intense debate and contention, mainly arising from the ethical challenges it presents, as well as the substantial financial burden it imposes, and its inability to reliably predict human responses. This paper, therefore, proposes a comprehensive list of research methodologies that are ethical, practical, cost-effective, and consistent with the real ethos of herbal medicine. These alternative methods, which include in vitro studies, human cell cultures, computational modelling, culturally sensitive clinical trials, and ethnobotanical surveys, have the potential to provide cost-effective healthcare solutions, without subjecting animals to unnecessary suffering. [ABSTRACT FROM AUTHOR]

Taking as a point of departure the role that the category of frailty increasingly plays in the classification, sorting and management of ageing populations in contemporary societies, this paper focuses on the crafting and validation of mouse models of frailty. The paper suggests that such models embody therapeutic and techno-economic expectations of ageing research, particularly as these are re-invigorated by current attempts to manipulate or eradicate cell senescence. The paper brings together critical gerontology, social studies of science and more-than-human anthropology to contextualise and analyse ethnographic data collected during fieldwork in a biology of ageing laboratory. The paper proposes that to build a mouse model of frailty, researchers need to learn to 'think like a mouse', provisionally taking the animal's point of view, to then efface that link and reconfigure the scientific chain of reference that enables translation between humans and mouse models of frailty. • Frailty increasingly plays key role in the classification, sorting and management of ageing populations • Animal models of frailty embody technological promises of 'new geroscience' • Paper identifies two fold process in making and validating mouse models of frailty, involving having to learn to 'think like a mouse', to be able to qualify the model [ABSTRACT FROM AUTHOR]

The public health importance of myiasis [infestation with dipterous (fly) larvae] remains unknown. This disease is spread worldwide in animals and humans, but baseline data on its prevalence are limited. In particular, knowledge on human urogenital myiasis (UGM) is scattered. As such, a systematic search was undertaken of five English and five Persian databases for publications describing UGM cases in English or Persian published between 1975 and 2017. In total, 45 papers reporting 59 UGM cases from various regions of the world are included in this review. All included papers were from the English databases. The age of patients ranged from 5 to 89 years, and the mean age was 40.6 years. Thirty-six of the patients were female and 19 were male. The highest number of cases (n = 12) was reported from Brazil. The most common genera causing UGM were Psychoda spp. (23.7%) and Cochliomyia spp. (11.8%). The vagina was the most commonly reported anatomical location of UGM for women, and the urogenital tract was the most commonly reported location for men. Thirteen cases were reported from rural areas and eight cases from urban areas; the location of other cases was not specified. The incidence of UGM is likely to be substantially underestimated when evaluated based on published case reports. Epidemiological studies, such as questionnaires to medical doctors, could help to gather the necessary baseline data on the occurrence of UGM. [ABSTRACT FROM AUTHOR]

Stable delivery of liquids to microfluidic systems is essential for their reproducible functioning, especially when supplying flows to organs-on-chips – delicate living models that recreate human physiology on the microscale and thus can be used to reduce the need for animal testing. Most flow control systems are unable to sustain a robust and stable flow in longer experiments (>1 week), particularly those based on the ubiquitous syringe pump. Though easy to use, syringe pumps have no mechanism for actually measuring flow, let alone flow regulation with sensor feedback. We have developed a liquid delivery system based on the generation of flow by applying a constant air pressure to liquids in sealed containers. A flow of liquid is monitored by accurate measurement of mass flows (mg/min) using downstream Coriolis-based mass flow sensors. Measured mass flows provide fast feedback to integrated valves, with valves opening or closing slightly to increase or decrease solution flows to the organs-on-chips as required. This mass flow sensing principle is not affected by changes in the density, temperature, and viscosity of the liquids being displaced. This is in contrast to systems that use volumetric flow sensors, which require recalibration when these parameters change. The rationale behind using this principle for organs-on-chips, is that the stability provided by this flow control system allows for more control over growth of these mini-organs. We demonstrate the functionality of this system with three examples: 1) Fast stabilization (within seconds) under changing physical conditions; 2) Short-term stability (minutes to hours) of delivered flows in a microreactor with interconnected inlets; and 3) Long-term stability (>1 week) of cell medium flows to a living organ-on-a-chip. Two categories of organs-on-chips (OOCs) can be distinguished: 1) solid OOC are designed for three-dimensional cell or tissue constructs that interact with each other and their surroundings, and 2) barrier-type OOC contain a selective cellular barrier between two compartments as do many barriers in the body. The latter of these two types is the most challenging to culture and maintain as they are very sensitive to variations in flow and pressure surges. The flow control system presented in this work provides a great improvement compared to the use of syringe pumps and volumetric flow sensors in OOC studies. The novelty of this work lies in the long-term stability use of this system for organs-on-chips, maintaining stability for short to very long periods of time without compromising the barrier function of the organ-on-chip by pressure surges, bacterial contamination, or other undesired effects from the flow delivery system. • Stable flows are required for long-term (>1 week) organ-on-chip experiments. • This paper describes a flow control system based on Coriolis mass flow sensors. • Stable flows for long operation times, with varying conditions (viscosity, density). • Flow stability needed for optimal control of cell culture conditions. [ABSTRACT FROM AUTHOR]

• Proposed a parallel tapered seven-core fiber biosensor based on the vernier effect for AKT protein detection. • Ultra-low limit of detection of 44 pg/mL is achieved. • Detection of AKT protein in human embryonic kidney cell lysate compared with western blotting method. • The PTSCF biosensor has great stability, ultrahigh sensitivity and excellent specificity. The AKT protein is closely related to the cancer and diabetes. Rapid detection of AKT is very important in medical diagnosis. This paper proposed a parallel connected tapered seven-core fiber (PTSCF) biosensor to utilize vernier effect to improve sensitivity. Experimental results showed that 5.99 times improvements have been achieved in the refractive index sensing in the ranges of 1.333–1.337. By functionalizing AKT-Ab on the PTSCF sensor surface, a fast detection (<40 min) and an ultra-low limit of detection (LoD) of 0.044 ng/mL have been achieved for AKT protein solutions. The proposed PTSCF biosensor has been applied to detect AKT proteins in human embryonic kidney cell lysates and compared with those obtained by the western blotting (WB) method. Experimental results showed that the LoD of the PTSCF biosensor is 400-fold less than that of WB method. The proposed PTSCF biosensor holds great potential for applications in various medical fields, including intra-operative rapid detection, animal experiments, and pathological research. [ABSTRACT FROM AUTHOR]

In South Africa, there is currently no legislation that addresses animal experimentation directly. There is, however, a complex framework that consists of laws, national standards, and institutional guidelines governing the use of animals in scientific settings. Consequently, this paper starts by unpacking this framework, both legal and voluntary, in the South African context. Thereafter, it examines some criticisms against this framework. It subsequently proposes that an African ethic could respond to these criticisms, and so unpacks the central tenets of an African ethic in order to demonstrate how it may do this. Finally, it will argue that there are convincing moral reasons, from within an African framework, to significantly reduce, and even abolish, the use of animals in research, and that it should be enacted in legal regulations. [ABSTRACT FROM AUTHOR]

There were 116 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2015, which is a 14 % increase on the 102 articles published in 2014. The quality of the submissions continues to increase. The 2015 JCMR Impact Factor (which is published in June 2016) rose to 5.75 from 4.72 for 2014 (as published in June 2015), which is the highest impact factor ever recorded for JCMR. The 2015 impact factor means that the JCMR papers that were published in 2013 and 2014 were cited on average 5.75 times in 2015. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication. [ABSTRACT FROM AUTHOR]

Although some progress has been made in the last 3 decades to increase the number of women in clinical cardiology trials, review of recent cardiovascular literature demonstrates that women and underrepresented minority women are still underrepresented in most clinical cardiology trials. This is especially notable in trials of patients with coronary artery disease, heart failure with reduced ejection fraction, and arrhythmia studies, especially those involving devices and procedures. Despite the call from National Institutes of Health, Food and Drug Administration, Institute of Medicine, and various professional societies, the gap remains. This paper seeks to identify the barriers for low enrollment and retention from patient, clinician, research team, study design, and system perspectives, and offers recommendations to improve recruitment and retention in the current era. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cell metabolomics is a reliable and efficient tool to study PFAS toxicity. • Diverse cell types show non-specific and specific responses to PFAS. • Cell metabolomics approach revealed pathways associated with PFAS effects. • Cell metabolomics studies identified potential biomarkers linked to PFAS effects. Per- and polyfluoroalkyl substances (PFAS), ubiquitous environmental contaminants, pose significant challenges to ecosystems and human health. While cell cultures have emerged as new approach methodologies (NAMs) in ecotoxicity research, metabolomics is an emerging technique used to characterize the small-molecule metabolites present in cells and to understand their role in various biological processes. Integration of metabolomics with cell cultures, known as cell culture metabolomics, provides a novel and robust tool to unravel the complex molecular responses induced by PFAS exposure. In vitro testing also reduces reliance on animal testing, aligning with ethical and regulatory imperatives. The current review summarizes key findings from recent studies utilizing cell culture metabolomics to investigate PFAS toxicity, highlighting alterations in metabolic pathways, biomarker identification, and the potential linkages between metabolic perturbations. Additionally, the paper discusses different types of cell cultures and metabolomics methods used for studies of environmental contaminants and particularly PFAS. Future perspectives on the combination of metabolomics with other advanced technologies, such as single-cell metabolomics (SCM), imaging mass spectrometry (IMS), extracellular flux analysis (EFA), and multi-omics are also explored, which offers a holistic understanding of environmental contaminants. The synthesis of current knowledge and identification of research gaps provide a foundation for future investigations that aim to elucidate the complexities of PFAS-induced cellular responses and contribute to the development of effective strategies for mitigating their adverse effects on human health. [ABSTRACT FROM AUTHOR]

Sophora flavescens Ait.- Angelica sinensis (Oliv.) Diels drug pairing (SA) is a transformed drug pairing from Shengui pill, a traditional Chinese medicine prescription in the ninth volume of Traditional Chinese Medicine classic "Gu Jin Yi Jian", which is famous for clearing heat, moistening dryness, and promoting blood circulation. It is commonly used in the treatment of eczema, a skin condition that causes itching and inflammation. Despite its widespread use, there is still limited research on the mechanism of how SA treats eczema. This paper aims to fill this gap by conducting animal experiments to uncover the mechanism behind SA's therapeutic effects on eczema. Our findings provide a solid foundation for the clinical use of this TCM prescription. The basic purpose of this study is to clarify the therapeutic mechanism of Sophora flavescens-Angelica sinensis (SA) in the treatment and control of eczema. The chemical compositions of SA were analyzed using HPLC-Q-Orbitrap-MS. In vivo, a mouse model of eczema was created, and the serum levels of TNF-α and IL-1β were quantified using an enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (HE) staining was performed to assess the pathological state of the mouse skin, and immunohistochemical technique (IHC) was employed to estimate the contents of TNF-α, TLR4, and NF-κB semi-quantitatively. The expression levels of TLR4, MyD88, and NF-κB mRNA were determined through real-time quantitative polymerase chain reaction (qRT-PCR). Western Blotting was utilized to identify the protein levels of TLR4, MyD88, and NF-κB in mouse skin tissue. SA identified 18 active chemicals, some of which were shown in vivo to inhibit the TLR4/MyD88/NF-κB signaling pathway while reducing serum levels of TNF-α and IL-1β, making them ideal agents for the treatment of eczema. SA's anti-inflammatory properties are attributed to its ability to reduce serum levels of TNF-α and IL-1β, likewise inhibit the TLR4/MyD88/NF-κB signaling pathway. [Display omitted] • Application of SG in the treatment of acute eczema. • Study on the mechanism of SG in the treatment of acute eczema for the first time. • The experiments were carried out in vivo. • The results showed that SG could reduce the expression of IL-1β and TNF-α. • The anti-inflammation effect of SG is mediated by TLR4/MyD88/NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Cholestatic liver injury (CLI) is a pathologic process with the impairment of liver and bile secretion and excretion, resulting in an excessive accumulation of bile acids within the liver, which leads to damage to both bile ducts and hepatocytes. This process is often accompanied by inflammation. Cucumis melo L is a folk traditional herb for the treatment of cholestasis. Cucurbitacin B (CuB), an important active ingredient in Cucumis melo L, has significant anti-inflamamatory effects and plays an important role in diseases such as neuroinflammation, skin inflammation, and chronic hepatitis. Though numerous studies have confirmed the significant therapeutic effect of CuB on liver diseases, the impact of CuB on CLI remains uncertain. Consequently, the objective of this investigation is to elucidate the therapeutic properties and potential molecular mechanisms underlying the effects of CuB on CLI. The aim of this paper was to investigate the potential protective mechanism of CuB against CLI. First, the corresponding targets of CuB were obtained through the SwissTargetPrediction and SuperPre online platforms. Second, the DisGeNET database, GeneCards database, and OMIM database were utilized to screen therapeutic targets for CLI. Then, protein-protein interaction (PPI) was determined using the STRING 11.5 data platform. Next, the OmicShare platform was employed for the purpose of visualizing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The molecular docking technique was then utilized to evaluate the binding affinity existing between potential targets and CuB. Subsequently, the impacts of CuB on the LO2 cell injury model induced by Lithocholic acid (LCA) and the CLI model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were determined by evaluating inflammation in both in vivo and in vitro settings. The potential molecular mechanism was explored by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) techniques. A total of 122 CuB targets were collected and high affinity targets were identified through the PPI network, namely TLR4, STAT3, HIF1A, and NFKB1. GO and KEGG analyses indicated that the treatment of CLI with CuB chiefly involved the inflammatory pathway. In vitro study results showed that CuB alleviated LCA-induced LO2 cell damage. Meanwhile, CuB reduced elevated AST and ALT levels and the release of inflammatory factors in LO2 cells induced by LCA. In vivo study results showed that CuB could alleviate DDC-induced pathological changes in mouse liver, inhibit the activity of serum transaminase, and suppress the liver and systemic inflammatory reaction of mice. Mechanically, CuB downregulated the IL-6, STAT3, and HIF-1α expression and inhibited STAT3 phosphorylation. By combining network pharmacology with in vivo and i n vitro experiments, the results of this study suggested that CuB prevented the inflammatory response by inhibiting the IL-6/STAT3/HIF-1α signaling pathway, thereby demonstrating potential protective and therapeutic effects on CLI. These results establish a scientific foundation for the exploration and utilization of natural medicines for CLI. [Display omitted] • Targets of CuB treatment for cholestasis are enriched in the inflammatory pathway. • STAT3 and HIF-1α are key targets. • CuB alleviates cholestasis-induced liver damage and inflammatory reactions. • CuB prevents cholestasis by inhibiting the IL-6/STAT3/HIF-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ximenia caffra Sond. (Ximeniaceae), commonly known as “sour plum” is traditionally used, both topically and orally to treat a wide range of human diseases and ailments such as wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms, impotence and coughs. The bark and fruits are used by small-scale farmers as ethnoveterinary medicine to treat dermatophilosis, foot rot, saddle sores and control ectoparasites. Oil from X. caffra seed is traditionally used as a moisturiser, soap and shampoo for dry, fragile and damaged hair. Aim of the review The aim of this study was to comprehensively summarize the research that has been done on the botany, ethnomedicinal uses, phytochemistry and biological activities of X. caffra in different locations throughout its geographical range in the sub-Saharan African region so as to understand its importance and potential in primary healthcare systems. Materials and methods This study was carried out using a comprehensive and systematic literature search on the ethnomedicinal uses, phytochemistry and biological activities of the species throughout its distributional range. Literature sources included papers published in international journals, reports from international, regional and national organizations, conference papers, books and theses. PubMed and Scopus, search engines such as Google Scholar and online collection ScienceDirect were used. Results This study showed that X. caffra is used as traditional medicine in 83.3% of the countries in tropical Africa where it is indigenous. A total of 65 human and animal ailments and diseases are recorded for X. caffra, with a high degree of consensus for wounds, sexually transmitted infections (STIs), infertility, stomach ache, fever, eye problems, diarrhoea, bilharzia, menorrhagia, malaria, intestinal worms and coughs. Phytochemical investigation of X. caffra revealed that the species has various compounds including flavonoids, phenols, phytosterols, tannins and fatty acids. Different plant parts, aqueous and organic extracts exhibited anti-amoebic, antibacterial, antifungal, anti-inflammatory, antioxidant, antiparasitic, antiproliferative, HIV-1 reverse transcriptase (RT) inhibitory, insecticidal, non-mutagenic and toxicity activities. Conclusion In this review, the ethnomedicinal uses, phytochemistry, biological activities and toxicity of different extracts and compounds of X. caffra have been summarized. Although many of the ethnomedicinal uses of X. caffra have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. There are very few to nil experimental animal studies, randomized clinical trials and target-organ toxicity studies involving X. caffra and its derivatives that have been carried out so far. At the present moment, there is not sufficient evidence to interpret the specific chemical mechanisms associated with some of the documented biological activities of the species. Therefore, future studies should identify the bioactive components, details of the molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of X. caffra . [ABSTRACT FROM AUTHOR]

The literature (2012-4) describing experimental pig surgery was reviewed to estimate the extent to which neuromuscular block (NMB) is used, to examine methods for ensuring unconsciousness, and to identify the rationale for use of NMB and establish the anaesthetist's training. In the first stage of a two-stage review, NMB use was estimated using Web of Knowledge to identify articles describing NMB during pig surgeries. In the second stage, PubMed and Google Scholar were used to increase the number of articles for determining measures taken to prevent accidental awareness during general anaesthesia (AAGA). The corresponding authors of screened articles were emailed four times to establish the reason for using NMB and the anaesthetists' backgrounds (medical, veterinary, or technical). The first search revealed NMB use in 80 of 411 (20%) studies. Of the 153 articles analysed in the second stage, two described strategies to reduce AAGA. Some (6%) papers did not provide information on anaesthetic doses; citations supporting anaesthetic efficacy were found in only 13. Five of 69 papers using inhalation agents measured end-tidal anaesthetic concentrations based on human, not porcine, minimal alveolar concentrations. The methods in 13% of articles reporting anaesthetic depth assessment were incomplete or questionable, or both; four described using somatic motor reflexes. Corresponding authors of 121 articles reported that the principal reason for NMB was improved 'surgical visualization' (26%). Medical or veterinary anaesthetists supervised anaesthesia in 70% of studies; non-anaesthetists provided NMB, unsupervised, in 23. Nine respondents prioritized experimental expediency over pig welfare. In laboratory pig studies, AAGA may be prevalent; reported details of its attempted prevention are woefully inadequate. [ABSTRACT FROM AUTHOR]

There is growing evidence suggesting cannabinoids may provide suitable alternatives to conventional treatments in an increasing number of clinical settings. This review evaluates how cannabinoids are used to treat certain benign urological pathologies and to clarify the clinical value of this data. This review includes 62 papers and was undertaken per PRISMA's guidelines, it evidences the therapeutic potential of cannabinoids in the management of specific benign urological diseases, most notably neurogenic bladder dysfunction (clinical studies), renal disease (animal studies), and interstitial cystitis (animal studies). However, whilst cannabinoids are increasingly used, they cannot be considered reliable alternatives to more recognised treatments. [ABSTRACT FROM AUTHOR]

Oesophageal cancer is associated with high morbidity and mortality rates because it is highly invasive and prone to recurrence and metastasis, with a five-year survival rate of <20%. Therefore, there is an urgent need for new methods aimed at improving therapeutic intervention. Several studies have shown that targeted therapy may be effective for the treatment of oesophageal cancer. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase with kinase activity and scaffolding function, could be overexpressed in a variety of solid tumours, including oesophageal cancer. FAK participates in survival, proliferation, progression, adhesion, invasion, migration, epithelial-to-mesenchymal transition, angiogenesis, DNA damage repair, and other biological processes through multiple signalling pathways in cancer cells. It plays an important role in the occurrence and development of tumours and has been linked to the prognosis of oesophageal cancer. FAK has been suggested as a potential therapeutic target in oesophageal cancer; thus, the combination of FAK inhibitors with chemotherapy, radiotherapy, and immunotherapy is expected to prolong the survival of patients. This paper presents a brief overview of the structure of FAK and its potential role in oesophageal cancer, providing a rationale for the future application of FAK inhibitors in the treatment of the disease. [ABSTRACT FROM AUTHOR]

Methods and approaches that can be used in toxicology and safety assessment are changing at a faster pace than ever. Members of the International Life Sciences Institute (ILSI) Europe have formed an expert group to review possibilities, opportunities and challenges for the potential use of non-animal testing strategies in food safety and nutrition research, which can ultimately be used in support of regulatory submissions for pre-market authorisation. For the different areas of food improvement agents, genetically modified foods and novel foods, the acceptability of non-animal strategies is evaluated in comparison to legislative requirements in Europe. Current hazard and risk assessment tools that do not require additional animal testing are reviewed and emerging tools and methodologies considered, covering advanced in vitro methods, in silico and system biology approaches and high-throughput methods for mode-of-action assessment. The paper highlights the great potential for research strategies to be developed that reduce or avoid the use of animal tests, with the generation of more human-relevant data from multiple sources. It also shows the discordance in current legislation: on one hand saying non-animal strategies should be used, but on the other hand not providing sufficient guidance, leading in practice to lack of use of these non-animal testing strategies. This emphasizes the need for scientific developments and acceptability to be more reflected in legislation (e.g. guidance). What are we waiting for? • It is urgent to apply existing non-animal strategies in food safety assessment. • There is great potential for research strategies that reduce the use of animal tests. • Action is required by all stakeholders to be more challenging in applying non-animal approaches. • Acceptability of non-animal approaches needs to be more reflected in food safety legislation. [ABSTRACT FROM AUTHOR]

Introduction and Objectives The animal models for renal carcinogenesis have allowed researchers to better understand the physiopathological, genetic, molecular, and immunological mechanisms underlying the development of human renal cancers from the induction of precancerous lesions to the metastatic process. Our study aimed to review and discuss the characteristics of all the spontaneous animal models of renal carcinogenesis described in scientific literature to date and see how they could address future challenges in the field of personalized medicine. Methods and Materials We reviewed all the papers on PubMed which focus on spontaneous animal models of renal carcinogenesis. To do so, we used the keywords "spontaneous" AND "animal model" AND "renal cancer" in the PubMed search engine. We also conducted a search using the keywords "spontaneous" AND "animal model" AND "kidney cancer." PRISMA recommendations were used for the literature review. Results A total of 213 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "kidney cancer." 219 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "renal cancer." After pooling these 2 searches and removing the duplicate publications, 233 publications remained. Among these, 220 full-text articles were assessed for eligibility; 160 were removed because they were irrelevant to our topic, and the remaining 60 studies were included in our qualitative synthesis. Conclusions Many spontaneous animal models have been developed to study renal cancer. So far, these models have enabled the understanding of pathophysiological mechanisms underlying renal cancer. Though less appropriate than patient xenografts from the perspective of personalized medicine, we believe animal models can help medical professionals better understand the hows and whys of the genetic events underlying the intratumoral heterogeneity and spatial distribution of metastatic subclones. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase-5 inhibitors (PDE5Is) are used to treat erectile dysfunction (ED). Recently, the antidepressant-like effect of PDE5Is was demonstrated in animal models of depression. In clinical settings, PDE5Is were studied only for ED associated depression. Hence, there are no studies evaluating the effects of PDE5Is for the treatment of major depressive disorder (MDD) without ED. In this review article, we aimed to discuss the use of PDE5Is in the context of MDD, highlighting the roles of PDE genes in the development of MDD, the potential mechanisms by which PDE5Is can be beneficial for MDD and the potentials and limitations of PDE5Is repurposing to treat MDD.Methods: We used PubMed (MEDLINE) database to collect the studies cited in this review. Papers written in English language regardless the year of publication were selected.Results: A few preclinical studies support the antidepressant-like activity of PDE5Is. Clinical studies in men with ED and depression suggest that PDE5Is improve depressive symptoms. No clinical studies were conducted in subjects suffering from depression without ED. Antidepressant effect of PDE5Is may be explained by multiple mechanisms including inhibition of brain inflammation and modulation of neuroplasticity.Limitations: The low number of preclinical and absence of clinical studies to support the antidepressant effect of PDE5Is.Conclusions: No clinical trial was conducted to date evaluating PDE5Is in depressed patients without ED. PDE5Is' anti-inflammatory and neuroplasticity mechanisms may justify the potential antidepressant effect of these drugs. Despite this, clinical trials evaluating their efficacy in depressed patients need to be conducted. [ABSTRACT FROM AUTHOR]

Background: A test-and-not-treat (TaNT) strategy has been developed to prevent people with high concentrations of circulating Loa loa microfilariae (>20 000 microfilariae per mL) developing serious adverse events after ivermectin treatment during mass drug administration to eliminate onchocerciasis. An important question related to cost and programmatic issues is whether annual retesting is required for everyone. We therefore aimed to investigate changes in L loa microfilarial densities during TaNT campaigns run 18 months apart.Methods: In this observational cohort study, we assessed the participants of two TaNT campaigns for onchocerciasis. These campaigns, which were run by a research team, together with personnel from the Ministry of Health and community health workers, were done in six health areas (in 89 communities) in Okola health district (Cameroon); the first campaign was run between Aug 10, and Oct 29, 2015, and the second was run between March 7, and May 26, 2017. All individuals aged 5 years and older were invited to be screened for Loa loa microfilaraemia before being offered ivermectin (unless contraindicated). L loa microfilarial density was measured at the point of care using the LoaScope. All those with a L loa microfilarial density of 20 000 microfilariae per mL or less were offered treatment; in the first 2 weeks of the 2015 campaign, a higher exclusion threshold of 26 000 microfilariae per mL or less was used. At both rounds of the intervention, participants were registered with a paper form, in which personal information were collected. In 2017, we also recorded whether each individual reported participation in the 2015 campaign. The primary outcome, assessed in all participants, was whether L loa microfilarial density was above or below the exclusion threshold (ie, the criteria that guided the decision to treat).Findings: In the 2015 TaNT campaign, 26 415 people were censused versus 29 587 people in the 2017 TaNT campaign. All individuals aged 5 years and older without other contraindications to treatment (22 842 people in 2015 and 25 421 people in 2017) were invited to be screened for L loa microfilaraemia before being offered ivermectin. In 2015, 16 182 individuals were examined with the LoaScope, versus 18 697 individuals in the same communities in 2017. 344 (2·1%) individuals were excluded from ivermectin treatment because of a high L loa microfilarial density in 2015, versus 283 (1·5%) individuals in 2017 (p<0·0001). Records from 2017 could be matched to those from 2015 for 6983 individuals (43·2% of the 2015 participants). In this cohort, in 2017, 6981 (>99·9%) of 6983 individuals treated with ivermectin in 2015 had L loa microfilariae density below the level associated with neurological serious adverse events.Interpretation: Individuals treated with ivermectin do not need to be retested for L loa microfilaraemia before the next treatment, provided that they can be re-identified. This adjusted approach will enable substantial cost savings and facilitate reaching programmatic goals for elimination of onchocerciasis in areas that are co-endemic for loiasis.Funding: Bill & Melinda Gates Foundation, Division of Intramural Research (National Institute of Allergy and Infectious Diseases, US National Institutes of Health). [ABSTRACT FROM AUTHOR]

During clamping operation for minimally invasive intestinal surgery, patients often suffer from small intestine trauma. This phenomenon will lead to various complications, increase recovery time and cause pain for patients. In this paper, preliminary simulations of small intestine clamping operations in the minimally invasive surgery were made by conducting compression tests under different clamping stresses, durations and loading rates. A pathological grading system was designed after microscope observation to quantitatively evaluate the trauma of small intestine tissue. Results showed that different traumas: inflammatory cell infiltration, hyperemia, hemorrhage and rupture between serosa and muscularis, as well as villi destruction could be observed on the clamping sites of the small intestine tissue. When the clamping parameters (clamping stress, duration and loading rate) increased, the degree of the tissue trauma increased. There existed safe thresholds for clamping operations, at which severe trauma of small intestine tissues could be avoided in the clamping process. As the clamping parameters increased, the strain, that is the deformation of the small intestine tissue increased. The increase in the deformation would induce the aggravation of trauma degree. • Small intestine traumas under different clamping parameters were studied. • Pathological grading system was designed to quantitatively assess tissue damage. • Trauma degree was increasingly serious with the increasing clamping parameters. • Traumas were related to the variation of mechanical properties of soft tissue. • Safe thresholds were determined for prevention of severe trauma. [ABSTRACT FROM AUTHOR]

Erigeron breviscapus is a common medicine of eight ethnic minorities, including Miao, Naxi, and Yi. As early as the Ming Dynasty (AD 1368–1644), Lanmao's Materia Medica of Southern Yunnan (AD 1436) recorded that the medicine is used for the treatment of "Zuo tan you huan." In modern pharmacological research, Erigeron breviscapus injection is the most commonly used preparation in the treatment of ischemic stroke caused by acute cerebral infarction, but its mechanism of action in the treatment of ischemic stroke is not well understood. In this study, a metabonomics study based on ultraperformance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was used in investigating the effect of a traditional Chinese medicine preparation Erigeron breviscapus injection on the rat model of focal cerebral ischemia-reperfusion and the affinity of its main components with the targets of mitochondrial apoptotic pathways. This study used molecular docking technology to verify the effective binding ability of main effective components of Erigeron breviscapus injection to target proteins related to mitochondrial apoptosis pathway. This study developed a metabonomics method based on the ultra-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS) to evaluate the efficacy and study the mechanism of traditional Chinese medicine preparation. With pattern recognition analysis (principal component analysis and partial least squares-discriminate analysis) of urinary metabolites, a clear separation of focal cerebral ischemia-reperfusion model group and healthy control group was achieved. Erigeron breviscapus injection can significantly reduce the area of cerebral infarction, improve tissue morphological lesion in rats, and can increase the number of Nissl bodies. It may be a promoting factor by inhibiting hippocampal nerve cell apoptosis and Bax protein expression and by exerting effects against ischemia reperfusion after the induction of apoptosis. Thus, it plays a role in brain protection. Moreover, it can considerably promote the recovery of neurological deficiency signs in advance. Meanwhile, Erigeron breviscapus decreased malondialdehyde content and T-NOS activity. Its curative effect from strong to weak order: low dose > high dose > medium dose. The representative components of Erigeron breviscapus have good affinity with the active sites of mitochondrial apoptosis-related proteins. Metabolomics found that the potential biomarkers regulated by breviscapine are kynurequinolinic acid, succinylornithine, and leucine proline. It is speculated that it may participate in TRP–kynurequinolinic acid and succinylornithine–urea cycle–NO metabolic pathways. This paper revealed the potential biomarkers and metabolic pathways regulated by Erigeron breviscapus. It was speculated that the mechanism is related to its inhibition of mitochondrion-mediated apoptosis. Erigeron breviscapus could restore the metabolic profiles of the model animals to normal animal levels. The mechanism may be related to the potential biomarkers of quinolinic acid, succinylornithine, and leucine proline and the metabolic pathways involved. However, the exact mechanism by which Erigeron breviscapus inhibits mitochondrion-mediated apoptosis remains to be further explored. [Display omitted] • The metabolic profile of cerebral ischemia-reperfusion injury model rats regulated by Breviscapus injection were revealed. • A new method of metabolomics combined with pharmacodynamics to evaluate the effectiveness of ethnomedicine was explored. • Erigeron breviscapus has high research value. • Erigeron breviscapus is a common medicine of eight ethnic minorities, such as the Miao, Naxi and Yi nationalities. [ABSTRACT FROM AUTHOR]

Licorice can nourish Pi (spleen) and thereby strengthening the digestive system according to the theory of traditional Chinese medicine. Licorice has been generally used in the compound prescription to treat intestinal inflammatory disease. Licochalcone A (Lico A) is one of the characteristic molecules from licorice. T-UCRs, which are transcribed from ultraconserved regions, are a new class of long noncoding RNAs related to the renewal of intestinal epithelial renewal. This study aimed to investigate the effect and the uc.173-related mechanism of Lico A on intestinal epithelial renewal. IE-6 and Caco-2 cells were used to evaluate the effect of Lico A on apoptosis, proliferation, and migration of IECs. The intestinal organoid was used to investigate ex vivo effect and mechanism of Lico A promoting intestinal organoid development. C57BL/6J mice (both normal and uc.173-deficient ones) were used to examine the in vivo effect of Lico A on the renewal of intestinal mucosa. The expression of three T-UCRs related to the intestinal mucosa renewal was altered in Lico A-treated IECs. Lico A promoted the proliferation and inhibited the apoptosis of IECs through uc.173/miR-195 pathway. The development of intestinal organoids and the renewal of intestinal mucosa of mice subjected to the 48-h FAST were all promoted by the treatment of Lico A. Moreover, the growth arrest of uc.173-deficient intestinal organoids and the atrophy of intestinal mucosa in uc.173-deficient mice could be rescued by the Lico A administration. Results in this paper suggest that targeting T-UCRs may be the novel therapeutic approach for the promotion of epithelial regeneration, and through stimulating the regeneration of intestinal mucosa, Lico A may become a new therapeutic agent for the maintenance of intestinal epithelial integrity. Licochalcone A promotes intestinal epithelial renewal through uc.173. [Display omitted] • Licochalcone A from licorice affects the expression of three T-UCRs related to the regeneration of intestinal mucosa. • Licochalcone A promotes the development of intestinal organoids and in vivo renewal of intestinal mucosa. • Licochalcone A reverses uc. 173-induced delay in intestinal epithelial renewal both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Tight control of systemic oxygenation is a key component of mechanical ventilation of critically ill patients. Yet, closed-loop control remains challenging due to the non-linear, uncertain, and time-varying relationship between the inspired oxygen and the resulting patient's oxygen saturation, especially in cases of acute lung injury. This paper uses a Hammerstein model to combine a clinically validated static model incorporating ventilation-to-perfusion mismatch with uncertain linear dynamics to synthesize a robust closed-loop controller for regulating systemic oxygenation in subjects with acute lung injury. Data from an experimental lung injury model in five pigs, in combination with data augmentation, allowed modeling of the uncertainty in the system. Subsequently, gain-scheduled proportional–integral controllers were designed using the mixed-sensitivity H ∞ approach. The resulting closed-loop systems were analyzed for robust stability, and the performance was evaluated in a thousand synthetically generated subjects spanning the overall parameter space in various combinations. A mean rise time of less than three minutes was achieved for recovering from the severely hypoxemic state for simulated subjects with a range of ventilation-to-perfusion mismatch and arterial acid–base status. Furthermore, the results from a pilot animal experiment matched the simulated results well, and the system could respond to significant disturbances. The system was safe and reliable in both simulations and the pilot animal experiment. The methodological approach for uncertainty modeling and controller synthesis is an essential step toward the practical deployment of closed-loop control of systemic oxygenation in the acutely injured lung. [Display omitted] • Development of a Hammerstein model for systemic oxygenation in an acutely injured lung. • Parameter estimation and data augmentation to model the uncertainty of the system. • Robust controller synthesis and analysis of closed-loop oxygenation control. • Large uncertainties in open-loop gain and time constants limit controller performance, but stable controllers can be synthesized for the proposed subject populations. [ABSTRACT FROM AUTHOR]

Ultrasound shear wave elastography (SWE) is an imaging modality used for noninvasive, quantitative evaluation of tissue mechanical properties. SWE uses an acoustic radiation force to produce laterally propagating shear waves that can be tracked in spatial and temporal domains in order to obtain the wave velocity. One of the ways to study the viscoelasticity is through examining the shear wave velocity dispersion curves. In this paper, we present an alternative method to two-dimensional Fourier transform (2D-FT). Our unique approach (2P-CWT) considers shear wave propagation measured in two lateral locations only and uses wavelet transformation analysis. We used the complex Morlet wavelet function as the mother wavelet to filter two shear waves at different locations. We examined how the first signal position and the distance between the two locations affect the shear wave velocity dispersion estimation in 2P-CWT. We tested this new method on a digital phantom data created using the local interaction simulation approach (LISA) in viscoelastic media with and without added white Gaussian noise to the wave motion. Moreover, we tested data acquired from custom made tissue mimicking viscoelastic phantom experiments and ex vivo porcine liver measurements. We compared results from 2P-CWT with the 2D-FT technique. 2P-CWT provided dispersion curves estimation with lower errors over a wider frequency band in comparison to 2D-FT. Tests conducted showed that the two-point technique gives results with better accuracy in simulation results and can be used to measure phase velocity of viscoelastic materials. [ABSTRACT FROM AUTHOR]

Skin sensitisation, one of the most frequent forms of human immune toxicity, is authenticated to be a significant endpoint in the field of drug discovery and cosmetics. Due to the drawbacks of traditional animal testing methods, in silico methods have advanced to study skin sensitisation. In this study, mechanism-based binary and ternary classification models were constructed with a comprehensive data set. 1007 compounds were collected to develop five series of local and global models based on mechanisms. In each series, compounds were classified into five groups according to EC3 values, and applied as training sets, test sets and external validation sets. For each of the five series, 81 binary classification models and 81 ternary classification models were acquired via 9 molecular fingerprints and 9 machine learning methods using a novel KNIME workflow. Meanwhile, the applicability domains for the best 10 models were figured out to certify the rationality of prediction effect. In addition, 8 toxic substructures probably causing skin sensitisation were identified to speculate whether a compound is a skin sensitiser. The mechanism-based prediction models and the toxic substructures can be applied to predict the skin sensitising potential and potency of compounds. • The number of compounds collected in this study is the largest among all published papers about skin sensitisation so far. • The models can be applied to predict the skin sensitising potential and potency, and contribute to mechanism determination. • 8 toxic substructures probably causing skin sensitisation were identified. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance There are insufficient safe and effective treatments for chronic pain in pets. In cases such as osteoarthritis there is no commercially available cure and veterinarians use NSAIDs to manage pain. Pet owners may have to plan for a lifetime of plant-based treatment for the conditions that lead to chronic pain in pets. Phytopharmacotherapies have the advantage of being less toxic, cheap or free, readily available, are more likely to be safe for long-term use and have the potential to reset the immune system to normal functioning. Aim of the study To examine the recently published medicinal plant research that matches unpublished data on ethnoveterinary medicines (EVM) used for pets in Canada (British Columbia) to see if the EVM data can provide a lead to the development of necessary drugs. Materials and methods In 2003 semi-structured interviews were conducted with 60 participants who were organic farmers or holisitic medicinal/veterinary practitioners obtained using a purposive sample. A draft manual prepared from the data was then evaluated by participants at a participatory workshop that discussed the plant-based treatments. A copy of the final version of the manual was given to all research participants. In 2018, the recently published research matching the EVM data was reviewed to see if the EVM practices could serve as a lead for further research. Results and conclusion Medicinal plants are used to treat a range of conditions. The injuries treated in pets in British Columbia included abscesses (resulting from an initial injury), sprains and abrasions. Dogs were also treated with medicinal plants for rheumatoid arthritis, joint pain and articular cartilage injuries. More than 40 plants were used. Anal gland problems were treated with Allium sativum L., Aloe vera L., Calendula officinalis L., Plantago major L., Ulmus fulva Michx., Urtica dioica L. and Usnea longissima Ach. Arctium lappa , Hydrangea arborescens and Lactuca muralis were used for rheumatoid arthritis and joint pain in pets. Asthma was treated with: Linum usitatissimum L., Borago officinalis L., Verbascum thapsus L., Cucurbita pepo L., Lobelia inflata L., and Zingiber officinale Roscoe. Pets with heart problems were treated with Crataegus oxyacantha L., Cedronella canariensis (L.) Willd. ex Webb & Berth, Equisetum palustre L., Cypripedium calceolus L., Pinus ponderosa Douglas ex Lawson, Humulus lupulus L., Valeriana officinalis L., Lobelia inflata L., Stachys officinalis (L.) Trev., and Viscum album L. The following plants were used for epilepsy, motion sickness and anxiety- Avena sativa L., Valeriana officinalis , Lactuca muralis (L.) Fresen., Scutellaria lateriflora L., Satureja hortensis L., and Passiflora incarnata L. Plants used for cancer treatment included Phytolacca decandra , Ganoderma lucidum , Lentinula edodes , Rumex acetosella , Arctium lappa , Ulmus fulva , Rheum palmatum , Frangula purshiana , Zingiber officinale , Glycyrrhiza glabra , Ulmus fulva , Althea officinalis , Rheum palmatum , Rumex crispus and Plantago psyllium. Trifolium pratense was used for tumours in the prostate gland. Also used were Artemisia annua , Taraxacum officinale and Rumex crispu s. This review of plants used in EVM was possible because phytotherapy research of the plants described in this paper has continued because few new pharmaceutical drugs have been developed for chronic pain and because treatments like glucocorticoid therapy do not heal. Phytotherapuetic products are also being investigated to address the overuse of antibiotics. There have also been recent studies conducted on plant-based functional foods and health supplements for pets, however there are still gaps in the knowledge base for the plants Stillingia sylvatica , Verbascum thapsus , Yucca schidigera and Iris versicolor and these need further investigation. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Pulsatilla chinensis (Bunge) Regel is a valuable traditional Chinese medicine (TCM) which is widely used for the treatment of schistosomiasis, inflammatory, bacterial infections. In recent years, P chinensis has been reported to exhibit antitumor activities. However, the mechanisms underlying its toxic effects remain largely unresolved. This paper is designed to investigate the damage of long-term oral P. chinensis saponins (PRS) and to explore its potential damage mechanisms by serum metabonomics approach. Materials and methods The serum samples from control and PRS treated rats were analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) in positive ionization mode and negative ionization mode. Liver function index of ALT, AST and ALP, blood biochemistry and biomarkers were examined to identify specific changes of injury. Acquired data were subjected to principal component analysis (PCA) for differentiating the control and PRS treated groups. Then, serum metabolic profiling was analyzed and pathway analysis performed on the biomarkers reversed after PRS treated and further integration of metabolic networks. Results The results suggested that serum liver function indexes of ALT had significantly changed and stage increased. AST, ALP detection content show volatility changes. Changes in the 15 biomarkers found in the serum, such as acetaminophen glucuronide, 9 E, 11 E-linoleic acid, chenodeoxycholic acid, monoacylglycerides, sphingomyelin (SM), 7-ketodeoxycholic acid and 12-keto-deoxycholic acid, which were closely related to changes in liver injury. It could be seen clearly that with the change of the dosing time, the biomarkers in the serum have undergone obvious, regular and progressive changes through the score plot and corresponding loading plot. The underlying regulations of PRS-perturbed metabolic pathways were discussed according to the identified metabolites. Conclusion The present study proves the potential of UPLC-QTOF-MS based metabonomics in mapping metabolic response. Long-term oral administration of P. chinensis saponins can cause chronic liver injury, and its safety needs further attention. It is of great significance in safeguarding human health to explore the damage mechanism of Pulsatilla chinensis saponins on liver by serum metabolomics. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract (+)-usnic acid (UA) is an active natural phenolic acid ingredient originating from Chinese traditional Tibetan herb. Usnea acid is expected to become a new agent for anticancer and remarkable antitumor. To reveal its metabolic profile, metabolites identification of UA in vivo was studied using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) in this present study. The chromatographic separation was performed on a C 18 column with a mobile phase consisted of methanol and water with a flow rate of 0.4 ml/min. The mass spectral analysis conducted in a negative electrospray ionization mode combined with information-dependent acquirement technology (IDA) was used to trace all the potential UA metabolites. Several sensitive and specific multiple data-mining techniques especially key product ions (KPIs) filter were applied to hunt and identify metabolites rapidly. As a result, a total of 36 metabolites were detected after oral administration of UA, including 33, 8 and 16 in rat urine, plasma and bile, respectively. These results showed that the probable metabolite pathways of UA were oxidation, reduction, dihydroxylation, glycine conjugation, glucuronide conjugation, N -acetylcysteine conjugation and methylation. It is the first time to elucidate the profile of UA in vivo. These results not only provided the basis of UA pharmacological properties, but also gave the guidance in clinical medication. Moreover, the analysis strategy and methodology proposed in this paper could be widely used in characterization of other phenolic acids metabolites. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Although exposure to high levels of microbial bioaerosols can be linked to the deterioration of the human respiratory system, precise exposure levels responsible for such effects are still unknown. A previous systematic review concluded that there was not enough information in the studies in humans to derive an exposure-response relationship. Thus, the aim of this systematic review was to derive exposure limits for microbial bioaerosols based on health effects in experimental animal studies. A systematic search was done in MEDLINE (PubMed) for long-term in vivo exposure of the respiratory system via inhalation of a quantified microbial bioaerosol. A total of n = 301 studies were retrieved. Abstract screening using predefined inclusion and exclusion criteria was followed by full-text screening and standardized data extraction of study characteristics and measured outcomes. As a result, four suitable studies were identified where mice or guinea pigs were exposed for 4-12 weeks to a previously described mixture of fungal spores or conidia via inhalation. The number of macrophages, neutrophils, eosinophils and lymphocytes following subchronic exposure has been reported by all included papers and suggested a dose- and time-dependent relationship. Significant inflammation was observed following subacute exposure to Aspergillus fumigatus. However, the outcomes of the studies could not be directly compared due to the large degree of variation and poor description of the exposure conditions. It is our conclusion that more experimental research needs to be done with the specific aim of establishing a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest-Observed-Adverse-Effect Level (LOAEL) for exposure to microbial bioaerosols in ambient air. Expertise of both exposure and outcome assessment should be brought together to enable standardization of experimental animal studies with properly generated aerosols aiming to derive health-based exposure limits. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Involucrum castaneae (IC)is used in Chinese folk medicine to treat various lung diseases, as well as for its reducing phlegm and anti-inflammatory properties. Aim of the study The purpose of this experiment is to verify the effect of IC on airway inflammation, responsiveness in ovalbumin (OVA)-induced asthmatic guinea pigs. The main chemical components of IC were also analyzed. Materials and methods The potential of the ethanol extract of Involucrum castaneae (EEIC) to protect against OVA-induced allergic airway response in guinea pigs was investigated. The latency of asthma in guinea pigs were recorded after the allergic asthma induced. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of immunoglobulin E (IgE), interleukin-5 (IL-5), nerve growth factor (NGF) and interferon-γ (IFN-γ) in asthma allergy. Reverse transcription-PCR (RT-PCR) was used to detect the expression of IL-5 mRNA in asthmatic guinea pig lungs. Paraffin sections of lung tissue were used to analyze pathological changes. The total flavonoid content was determined and the chemical components were analyzed by LC-MS/MS. Results It was found that EEIC was able to reduce the number of eosinophil (EOS) in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) in the guinea pig model of OVA -induced asthma. Meanwhile, it also significantly reduced the levels of inflammation-related factors IgE and IL-5, decreased the expression of IL-5 mRNA in lung tissue, and increased the level of IFN-γ. Pathological examination of paraffin section of lung tissue showed that EEIC can reduce the thickening of bronchial smooth muscle and reduce the infiltration damage of tissues by various inflammatory cells. The presence of flavonoids, terpenoids and phenolic compounds in EEIC might be responsible for these activities. Conclusion IC alleviated airway inflammation and smooth muscle thickening in guinea pigs with OVA-sensitized allergic asthma. The paper explains the traditional efficacy and material basis of IC and lays a foundation for further development. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Highlights • Inadequate dosing schedule in preclinical studies erodes therapeutic index. • This erosion can prevent potentially effective drugs from entering clinical trials. • Dosing in animals must account for species difference to allow human translation. • Improved dosing practice to produce human-relevant exposure profiles is needed. Low pipeline output is a major problem for the pharmaceutical industry. Many compounds fail to enter clinical development, owing to toxicities in animals. Using pharmacology principles, this paper argues that the often-infrequent dosing in animal experiments despite a drug's short half-life produces a large fluctuation in drug concentration, which can severely erode the therapeutic index and safety margin for the anticipated clinical dose, consequently preventing potentially effective treatments from entering human trials. Aided by computer simulations under generalised conditions, the analysis was conducted in a quantitative framework with broad relevance. The findings call for more-translatable dosing practices through closer collaboration among scientists in multiple disciplines and better regulatory guidance for animal studies to better inform compound progression decisions. [ABSTRACT FROM AUTHOR]

Background: Photobiomodulation (PBM) with red and near-infrared light (NIR) -also known as Low-Level Light Therapy-is a low risk, inexpensive treatment-based on non-retinal exposure-under study for several neuropsychiatric conditions. The aim of this paper is to discuss the proposed mechanism of action and to perform a systematic review of pre-clinical and clinical studies on PBM for major depressive disorder (MDD).Methods: A search on MEDLINE and EMBASE databases was performed in July 2017. No time or language restrictions were used. Studies with a primary focus on MDD and presenting original data were included (n = 17). References on the mechanisms of action of PBM also included review articles and studies not focused on MDD.Results: Red and NIR light penetrate the skull and modulate brain cortex; an indirect effect of red and NIR light, when delivered non-transcranially, is also postulated. The main proposed mechanism for PBM is the enhancement of mitochondrial metabolism after absorption of NIR energy by the cytochrome C oxidase; however, actions on other pathways relevant to MDD are also reported. Studies on animal models indicate a benefit from PBM that is comparable to antidepressant medications. Clinical studies also indicate a significant antidepressant effect and good tolerability.Limitations: Clinical studies are heterogeneous for population and treatment parameters, and most lack an appropriate control.Conclusions: Preliminary evidence supports the potential of non-retinal PBM as a novel treatment for MDD. Future studies should clarify the ideal stimulation parameters as well as the overall efficacy, effectiveness and safety profile of this treatment. [ABSTRACT FROM AUTHOR]

Highlights • HS-GC method was used to analyze the TMA content in rat and human samples. • Trimethylamine as a predictor for postmortem interval estimation was studied. • The change trend of TMA content with the lengthening PMI was found. Abstract Trimethylamine (TMA), a simple amine in volatile compounds, indicating the spoilage degree of meat, related with the late postmortem interval (PMI) during the cadaver decomposition process. In this paper, a headspace gas chromatography (HS-GC) method has been successfully built to analyze the content of TMA in postmortem rat tissues (liver, myocardial and skeletal muscle tissues), which is used for PMI estimation with the wide range of PMI (0–720 h postmortem) at 16 °C ± 1 °C. Correspondingly, three equations about the relationship between the PMI and TMA content were established, in which they showed that the TMA content in all three tissues increased from the firstly detected time to 192 h and gradually decreased after 384 h. Furthermore, the TMA measurement in five human samples was carried out and the results (<35 h PMI) showed a good agreement about the change trend of TMA content between human and rat, which elucidated that this research might provide a new insight for the forensic scientist to band HS-GC technology together with TMA determination in the PMI estimation. [ABSTRACT FROM AUTHOR]

Duhuo Jisheng decoction is a traditional Chinese formula that has been widely used in clinical practice to treat osteoarthritis, which has the effects of removing invaded cold and dampness, relieving joint pain. However, it is difficult to determine the effective substances and mechanisms due to assorted herbs and components, and further research is needed. This study was designed to explore and verify the mechanism and targets of DHJSD in the treatment of OA via network analysis and experiments. In this study, the active ingredients of DHJSD were qualitatively analyzed by UPLC-QDA. Network analysis was used to identify common targets and pathways. Next, we explored the therapeutic mechanism of DHJSD through a rat model of knee osteoarthritis. HE staining was used to judge the establishment of the animal model. ELISA and Western blotting were used to verify the expression of key pathway proteins. In this study, seventeen chemical constituents in DHJSD were identified. According to the network analysis, we obtained the potential associated pathways of action. Then, molecular docking and SPR experiments showed that the sixteen identified components had high binding energies to IL-6. HE staining showed that the high-dose group of DHJSD had an obvious therapeutic effect on model rats. Compared with the model group, the levels of IL-1β, TNF-α, IL-6, MMP3, MMP13, ADAMTS4 and ADAMTS5 in serum and the expression of STAT3 and p-STAT3 protein in administration groups were significantly decreased. This result indicated that the IL-6/STAT3 signaling pathway was one of the important pathways regulated by DHJSD to improve OA. [Display omitted] • This paper first identified 17 compounds, found that DHJSD can treat OA by regulating IL-6/STAT3 pathway in vivo. [ABSTRACT FROM AUTHOR]