ABSTRACT
The amyloid cascade hypothesis suggests that amyloid beta (Aß) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aß contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aß induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aß accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aß-induced tau uptake in AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Neurons , Receptor, Fibroblast Growth Factor, Type 3 , tau Proteins , tau Proteins/metabolism , Animals , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Receptor, Fibroblast Growth Factor, Type 3/genetics , Amyloid beta-Peptides/metabolism , Mice , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/etiology , Humans , Neurons/metabolism , Hippocampus/metabolism , Fibroblast Growth Factor 2/metabolism , Disease Models, Animal , Protein BindingABSTRACT
Limb amputation can lead to significant functional challenges in daily activities, prompting amputees to use prosthetic devices (PDs). However, the cognitive demands of PDs and usability issues have resulted in user rejections. This study aimed to create a Human Performance Model for Upper-Limb Prosthetic Devices (HPM-UP). The model used formulations of learnability, error rate, memory load, efficiency, and satisfaction to assess usability. The model was validated in an experiment with 30 healthy participants using a bypass prosthetic device. Findings indicated that the HPM-UP successfully predicted the usability of prosthetic devices, aligning with human subject data. This research proposes a quantitative approach to predict upper limb prosthetic device usability by quantifying each dimension and computationally connecting them. The model, available on Github and executable with Rstudio, could enable clinicians to assess and analyze the human performance of various commercial prostheses, aiding in recommending optimal devices for patients.
Subject(s)
Amputees , Artificial Limbs , Prosthesis Design , Upper Extremity , Humans , Upper Extremity/surgery , Male , Female , Adult , Amputees/psychology , Young AdultABSTRACT
This study experimentally investigated the effect of dogmatic and suggestive language in Christian-sourced excessive alcohol consumption messages among college-aged participants who identify as Christians or non-Christians, as well as the role of perceived similarity with the message source, on their self-reported freedom-threat, psychological reactance, and behavioral intentions to consume alcohol. The results from this study support psychological reactance theory and demonstrate the various message strategies to effectively communicate the negative health effects of excessive alcohol consumption to individuals who identify either as Christians or non-Christians.
Subject(s)
Alcohol Drinking , Christianity , Humans , Male , Christianity/psychology , Female , United States , Young Adult , Alcohol Drinking/psychology , Adult , Religion and Psychology , Students/psychology , Students/statistics & numerical data , IntentionABSTRACT
There has been growing emphasis on environmental pollutants, including heavy metals, pesticides, and nanoplastics, owing to the escalating significance of environmental pollution as a major global issue. Various toxicities induced by these compounds have been consistently reported, and many cell lines and animal models have been used in toxicity studies. Zebrafish are one of the most widely used animal models for verifying the toxic effects of environmental pollutants, owing to their many advantages. In this study, we provide brief guidelines for zebrafish maintenance and mating methods, toxicant treatments, survival measurements, and morphological abnormalities.
ABSTRACT
Mass spectrometry-based single-cell proteomics has undergone rapid progress and has become an active research area. However, because of the ultralow amount of proteins in single cells, it is still highly challenging to achieve efficient sample preparation and sensitive LC-MS detection. Here, we provide a detailed protocol for isobaric labeling-based single-cell proteomics relying on a microfluidic droplet-based sample processing technology. The protocol allows for processing both single cells and carrier samples in separate microchips using a commercially available platform (cellenONE) with high sample recovery and high throughput. We also provide an optimized LC-MS method for sensitive and robust data collection.
Subject(s)
Proteomics , Single-Cell Analysis , Proteomics/methods , Single-Cell Analysis/methods , Single-Cell Analysis/instrumentation , Humans , Chromatography, Liquid/methods , Mass Spectrometry/methods , Microfluidic Analytical Techniques/instrumentation , Microfluidic Analytical Techniques/methods , Microfluidics/methods , Microfluidics/instrumentation , Lab-On-A-Chip DevicesABSTRACT
Historically, the central nervous system (CNS) was regarded as 'immune-privileged', possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies.
Subject(s)
Blood-Brain Barrier , Brain , Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/pathology , Animals , Blood-Brain Barrier/immunology , Brain/immunology , Brain/pathology , Immune PrivilegeABSTRACT
Liver cancer stands as the fifth leading cause of cancer-related deaths globally. Hepatocellular carcinoma (HCC) comprises approximately 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients qualify for curative therapy, primarily due to the absence of reliable tools for early detection and prognosis of HCC. This underscores the critical need for molecular biomarkers for HCC management. Since proteins reflect disease status directly, proteomics has been utilized in biomarker developments for HCC. In particular, proteomics coupled with liquid chromatography-mass spectrometer (LC-MS) methods facilitate the process of discovering biomarker candidates for diagnosis, prognosis, and therapeutic strategies. In this work, we investigated LC-MS-based proteomics methods through recent reference reviews, with a particular focus on sample preparation and LC-MS methods appropriate for the discovery of HCC biomarkers and their clinical applications. We classified proteomics studies of HCC according to sample types, and we examined the coverage of protein biomarker candidates based on LC-MS methods in relation to study scales and goals. Comprehensively, we proposed protein biomarker candidates categorized by sample types and biomarker types for appropriate clinical use. In this review, we summarized recent LC-MS-based proteomics studies on HCC and proposed potential protein biomarkers. Our findings are expected to expand the understanding of HCC pathogenesis and enhance the efficiency of HCC diagnosis and prognosis, thereby contributing to improved patient outcomes.
ABSTRACT
Pyrethroid insecticides, such as beta-cyfluthrin, are used extensively globally, including in households and agriculture, and have been detected in the milk and urine of humans and cattle. Beta-cyfluthrin exhibits toxic effects, including neurotoxicity and male reproductive toxicity; however, few studies have investigated female reproductive toxicity despite its wide environmental distribution. The present study investigates effects of beta-cyfluthrin on implantation in porcine cells (pTr from the trophectoderm and pLE from the endometrial luminal epithelium). To identify the various physiological changes induced by beta-cyfluthrin, such as apoptosis and lipid peroxidation, flow cytometry analysis and immunofluorescence were performed with various reagents. In addition, the expression of genes and proteins associated with intracellular changes was confirmed using qRT-PCR and western blotting. Beta-cyfluthrin induced cell-cycle arrest and altered intracellular calcium flux. It also disrupted the mitochondrial function and promoted reactive oxygen species (ROS) production, leading to lipid peroxidation. Moreover, ROS induced by beta-cyfluthrin altered mitogen-activated protein kinase (MAPK) pathways and decreased cell migration capability. The expression levels of genes that are significant during early pregnancy were altered by beta-cyfluthrin in both cell lines. The changes resulted in apoptosis and diminished cell proliferation of pTr and pLE. Collectively, the results imply that beta-cyfluthrin disrupts the implantation process by affecting the physiology of the trophectoderm and endometrial luminal epithelial cells. The present study is the first to reveal the cellular mechanisms of beta-cyfluthrin on the female reproductive system and highlights the need for further in-depth research into its hazards.
Subject(s)
Epithelial Cells , Insecticides , Mitochondria , Nitriles , Pyrethrins , Reactive Oxygen Species , Signal Transduction , Animals , Reactive Oxygen Species/metabolism , Female , Pyrethrins/toxicity , Nitriles/toxicity , Swine , Insecticides/toxicity , Epithelial Cells/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Signal Transduction/drug effects , Embryo Implantation/drug effects , Uterus/drug effects , Apoptosis/drug effects , Trophoblasts/drug effectsABSTRACT
Previous health communication research has demonstrated the negative psychological and health effects of depicting thin-sized models in mass media advertisements including on social media sites such as Instagram. However, gym advertisements are one common source for the presentation of lean and thin-sized models on Instagram. Therefore, the current study guided by social comparison theory and signaling theory aimed to experimentally examine the effect of thin-sized models relative to plus-sized models as well as slogan-type (health and wellness versus physique-based) on women's appearance comparison, body satisfaction, perceived gym fit, and intentions to join the gym. A sample of 217 undergraduate students who identified as women were randomly assigned to one of four Instagram gym advertisement conditions varying in model body-size and slogan-type. Appearance comparisons, perceived gym fit, and intentions to join the gym were measured post advertisement exposure and body satisfaction was measured pre-and-post advertisement exposure. As expected, exposure to Instagram gym advertisements featuring thin-sized models resulted in greater appearance comparisons and lower body satisfaction than exposure to Instagram gym advertisements featuring plus-sized models. Moreover, the combination of plus-sized models with health and wellness slogans in Instagram gym advertisements resulted in greater gym fit perceptions although there was no effect of model body-size and slogan-type on intentions to join the gym. This study supports social comparison theory, signaling theory, and practically the findings indicate that Instagram gym advertisements that depict plus-sized models (versus thin) with health-and-wellness slogans (versus physique) generate fewer body image concerns and lead to greater gym fit perceptions.
ABSTRACT
Acifluorfen, a selective herbicide from the diphenyl ether family, targets broad leaf weeds. Diphenyl ether inhibits chlorophyll production in green plants by inhibiting protoporphyrinogen oxidase (PPO), causing cellular damage. Despite its known impacts on plants, the influence of acifluorfen on zebrafish embryo development remains unclear. In this study, we explored the LC50 of acifluorfen in early-stage wild-type zebrafish, determining it to be 54.99 mg/L. Subsequent examinations revealed morphological changes in zebrafish, including reduced body length. Using the cmlc2:dsRED transgenic model, we observed heart dysfunction in acifluorfen-exposed zebrafish, marked by an enlarged heart area, edema, and decreased heart rate. In response to dose-dependent acifluorfen exposure, the inhibition of angiogenesis in the brain was observed in transgenic zebrafish models (fli1a:eGFP). Organ malformations, specifically in the liver and pancreas, were noted, in lfabp:dsRED;elastase:eGFP transgenic models, indicating reduced organ size in acifluorfen-exposed zebrafish. Furthermore, acifluorfen heightened the expression of apoptosis-related genes (casp8, casp9, and tp53) in zebrafish embryos. We then determined whether acifluorfen affected the viability of zebrafish liver (ZFL) cells based on its effects on liver development in vivo. The results indicated that the proliferation of ZFL cells decreased significantly in a dose-dependent manner. Additionally, acifluorfen-treated ZFL cells exhibited a slight increase in apoptotic cells stained with annexin V and propidium iodide. In summary, these findings establish a baseline concentration for acifluorfen's effects on aquatic ecosystems and non-target organisms.
Subject(s)
Animals, Genetically Modified , Embryo, Nonmammalian , Herbicides , Zebrafish , Animals , Zebrafish/embryology , Embryo, Nonmammalian/drug effects , Herbicides/toxicity , Apoptosis/drug effects , Embryonic Development/drug effects , Water Pollutants, Chemical/toxicityABSTRACT
Existing evidence shows that currently used pesticides pose toxicological risks to exposed wildlife. Chemically, bifenox belongs to diphenyl ethers, a well-known group of herbicides. Its mechanism of action primarily involves inducing lipid peroxidation and blocking protoporphyrinogen oxidases. Toxicity of diphenyl ether herbicides has been elucidated in animal cells; however, in vivo toxicological evaluations of bifenox are required to determine its unexpected effects. This study aimed to determine the negative effects of bifenox, and its effects on higher eukaryotes. We found that early stages of zebrafish embryo exposed to bifenox demonstrated increased mortality and physiological defects, based on the LC50 value. Bifenox severely inhibited blood vessel growth by reducing key elements of complex connectivity; fluorescently tagged transgenic lines (fli1a:EGFP) showed morphological changes. Additionally, transgenic lines that selectively identified hepatocytes (fabp10a:DsRed) showed reduced fluorescence, indicating that bifenox may inhibit liver development. To evaluate the level of oxidative stress, we used 2',7'-dichlorofluorescein diacetate (DCFH-DA) probes in zebrafish embryos to identify the underlying mechanisms causing developmental damage. Our findings demonstrate that exposure to bifenox causes abnormalities in the hepatic and cardiovascular systems during zebrafish embryogenesis. Therefore, this study provides new information for the evaluation of toxicological risks of bifenox in vertebrates.
Subject(s)
Embryo, Nonmammalian , Reactive Oxygen Species , Signal Transduction , Zebrafish , Animals , Zebrafish/embryology , Embryo, Nonmammalian/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Oxidative Stress/drug effects , Animals, Genetically Modified , Herbicides/toxicity , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver/embryology , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/metabolism , Halogenated Diphenyl Ethers/toxicityABSTRACT
Environmental pollutants, including endocrine disruptors, heavy metals, nanomaterials, and pesticides, have been detected in various ecosystems and are of growing global concern. The potential for toxicity to non-target organisms has consistently been raised and is being studied using various animal models. In this review, we focus on pesticides frequently detected in the environment and investigate their potential exposure to livestock. Owing to the reproductive similarities between humans and pigs, various in vitro porcine models, such as porcine oocytes, trophectoderm cells, and luminal epithelial cells, are used to verify reproductive toxicity. These cell lines are being used to study the toxic mechanisms induced by various environmental toxicants, including organophosphate insecticides, pyrethroid insecticides, dinitroaniline herbicides, and diphenyl ether herbicides, which persist in the environment and threaten livestock health. Collectively, these results indicate that these pesticides can induce female reproductive toxicity in pigs and suggest the possibility of adverse effects on other livestock species. These results also indicate possible reproductive toxicity in humans, which requires further investigation.
Subject(s)
Environmental Pollutants , Reproduction , Animals , Female , Swine , Environmental Pollutants/toxicity , Reproduction/drug effects , Pesticides/toxicity , HumansABSTRACT
Meptyldinocap is a dinitrophenol fungicide used to control powdery mildew. Although other dinitrophenol pesticides have been found to exhibit reproductive toxicity, studies of meptyldinocaps are scarce. This study investigated the adverse effects of meptyldinocap on porcine trophectoderm (pTr) and porcine endometrial luminal epithelial (pLE) cells, which play crucial roles in implantation. We confirmed that meptyldinocap decreased cell viability, induced apoptosis, and inhibited proliferation by decreasing proliferation-related gene expression and inducing changes in the cell cycle. Furthermore, meptyldinocap treatment caused mitochondrial dysfunction, endoplasmic reticulum stress, and disruption of calcium homeostasis. Moreover, it induces alterations in mitogen-activated protein kinase signaling cascades and reduces the migration ability, leading to implantation failure. Our findings suggest that meptyldinocap reduces the cellular functions of pTr and pLE cells, which are important for the implantation process, and interferes with interactions between the two cell lines, potentially leading to implantation failure. We also propose a mechanism by which the understudied fungicide meptyldinocap exerts its cytotoxicity.
Subject(s)
Dinitrobenzenes , Fungicides, Industrial , Mitochondrial Diseases , Swine , Animals , Fungicides, Industrial/metabolism , Cell Proliferation , Apoptosis , Cell Cycle Checkpoints , Endoplasmic Reticulum Stress , Epithelial Cells , Dinitrophenols/metabolism , Dinitrophenols/pharmacology , Mitochondrial Diseases/metabolismABSTRACT
Electrochemical CO2 reduction on Cu is a promising approach to produce value-added chemicals using renewable feedstocks, yet various Cu preparations have led to differences in activity and selectivity toward single and multicarbon products. Here, we find, surprisingly, that the effective catalytic activity toward ethylene improves when there is a larger fraction of less active sites acting as reservoirs of *CO on the surface of Cu nanoparticle electrocatalysts. In an adaptation of chemical transient kinetics to electrocatalysis, we measure the dynamic response of a gas diffusion electrode (GDE) cell when the feed gas is abruptly switched between Ar (inert) and CO. When switching from Ar to CO, CO reduction (COR) begins promptly, but when switching from CO to Ar, COR can be maintained for several seconds (delay time) despite the absence of the CO reactant in the gas phase. A three-site microkinetic model captures the observed dynamic behavior and shows that Cu catalysts exhibiting delay times have a less active *CO reservoir that exhibits fast diffusion to active sites. The observed delay times and the estimated *CO reservoir sizes are affected by catalyst preparation, applied potential, and microenvironment (electrolyte cation identity, electrolyte pH, and CO partial pressure). Notably, we estimate that the *CO reservoir surface coverage can be as high as 88 ± 7% on oxide-derived Cu (OD-Cu) at high overpotentials (-1.52 V vs SHE) and this increases in reservoir coverage coincide with increased turnover frequencies to ethylene. We also estimate that *CO can travel substantial distances (up to 10s of nm) prior to desorption or reaction. It appears that active C-C coupling sites by themselves do not control selectivity to C2+ products in electrochemical COR; the supply of CO to those sites is also a crucial factor. More generally, the overall activity of Cu electrocatalysts cannot be approximated from linear combinations of individual site activities. Future designs must consider the diversity of the catalyst network and account for intersite transportation pathways.
ABSTRACT
Hexaconazole is a highly effective triazole fungicide that is frequently applied in various countries to elevate crop productivity. Given its long half-life and high water solubility, this fungicide is frequently detected in the environment, including water sources. Moreover, hexaconazole exerts hazardous effects on nontarget organisms. However, little is known about the toxic effects of hexaconazole on animal development. Thus, this study aimed to investigate the developmental toxicity of hexaconazole to zebrafish, a valuable animal model for toxicological studies, and elucidate the underlying mechanisms. Results showed that hexaconazole affected the viability and hatching rate of zebrafish at 96 h postfertilization. Hexaconazole-treated zebrafish showed phenotypic defects, such as reduced size of head and eyes and enlarged pericardiac edema. Moreover, hexaconazole induced apoptosis, DNA fragmentation, and inflammation in developing zebrafish. Various organ defects, including neurotoxicity, cardiovascular toxicity, and hepatotoxicity, were observed in transgenic zebrafish models olig2:dsRed, fli1:eGFP, and l-fabp:dsRed. Furthermore, hexaconazole treatment altered the Akt and MAPK signaling pathways, which possibly triggered the organ defects and other toxic mechanisms. This study demonstrated the developmental toxicity of hexaconazole to zebrafish and elucidated the underlying mechanisms.
Subject(s)
Fungicides, Industrial , Zebrafish , Animals , Zebrafish/metabolism , Fungicides, Industrial/toxicity , Proto-Oncogene Proteins c-akt/metabolism , Triazoles/toxicity , Inflammation/chemically induced , Apoptosis , Water/metabolism , Embryo, Nonmammalian/metabolismABSTRACT
Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)-mitochondrial axis is recognized as a representative interorganelle system. Several studies have confirmed that most proteins in the physically tethered sites between the ER and mitochondria, called mitochondria-associated ER membranes (MAMs), are vital for intracellular physiology. MAM proteins are involved in the regulation of calcium homeostasis, lipid metabolism, and mitochondrial dynamics and are associated with processes related to intracellular stress conditions, such as oxidative stress and unfolded protein responses. Accumulating evidence has shown that, owing to their extensive involvement in cellular homeostasis, alterations in the ER-mitochondrial axis are one of the etiological factors of tumors. An in-depth understanding of MAM proteins and their impact on cell physiology, particularly in cancers, may help elucidate their potential as diagnostic and therapeutic targets for cancers. For example, the modulation of MAM proteins is utilized not only to target diverse intracellular signaling pathways within cancer cells but also to increase the sensitivity of cancer cells to anticancer reagents and regulate immune cell activities. Therefore, the current review summarizes and discusses recent advances in research on the functional roles of MAM proteins and their characteristics in cancers from a diagnostic perspective. Additionally, this review provides insights into diverse therapeutic strategies that target MAM proteins in various cancer types.
Subject(s)
Mitochondrial Membranes , Neoplasms , Humans , Mitochondrial Membranes/metabolism , Mitochondria/metabolism , Endoplasmic Reticulum/metabolism , Neoplasms/diagnosis , Neoplasms/etiology , Neoplasms/therapy , Unfolded Protein Response , Endoplasmic Reticulum StressABSTRACT
Pyridaben is a widely used pyridazinone insecticide used to protect crops against insects and mites. The toxicity of pyridaben has been reported in mice, zebrafish, the human reproductive system, nervous system, and respiratory system. Pyridaben can also be ingested by dairy cattle through feed. However, the toxicity of pyridaben in cattle has not been investigated on. Thus, this study focuses on demonstrating the toxicity of pyridaben in the bovine mammary glands and with the generation milk in the bovine mammary epithelial cells, as it is crucial to the continuance of the amount and the quality of the milk produced. We started by analyzing the intracellular toxicity along with the impact of pyridaben on the cell cycle distribution and the transcription of associated genes. Pyridaben treatment induced cell cycle arrest accompanied the disruption in G1 and S phases with imbalanced cytosolic and mitochondrial calcium ion homeostasis, and caused a destruction of mitochondrial membrane potential. This eventually led to apoptosis of MAC-T cells. We also investigated in the impact that pyridaben has on MAPK signaling proteins, where phosphorylation of ERK1/2, JNK, and p38 were upregulateed. Moreover, examination of the effect of pyridaben in the inflammatory genes revealed hyperactivation of the inflammatory gene transcription. This is the first research to assess the negative outcomes that pyridaben could impose on dairy cattle and milk production.
Subject(s)
Calcium , MAP Kinase Signaling System , Pyridazines , Cattle , Animals , Humans , Mice , Calcium/metabolism , Up-Regulation , Zebrafish , Apoptosis , Epithelial Cells , Inflammation/metabolism , HomeostasisABSTRACT
As the population is ageing, the number of older adults with cognitive impairment (CI) is increasing. Automated vehicles (AVs) can improve independence and enhance the mobility of these individuals. This study aimed to: (1) understand the perception of older adults (with and without CI) and stakeholders providing services and supports regarding care and transportation about AVs, and (2) suggest potential solutions to improve the perception of AVs for older adults with mild or moderate CI. A survey was conducted with 435 older adults with and without CI and 188 stakeholders (e.g. caregivers). The results were analysed using partial least square - structural equation modelling and multiple correspondence analysis. The findings suggested relationships between older adults' level of cognitive impairment, mobility, knowledge of AVs, and perception of AVs. The results provided recommendations to improve older adults' perception of AVs including education and adaptive driving simulation-based training.Practitioner summary: This study investigated the perception of older adults and other stakeholders regarding AVs. The findings suggested relationships between older adults' level of cognitive impairment, mobility, knowledge of AVs, and perception of AVs. The results provided guidelines to improve older adults' perception of AVs.
Subject(s)
Automation , Cognitive Dysfunction , Humans , Aged , Male , Female , Aged, 80 and over , Surveys and Questionnaires , Automobiles , Middle Aged , Automobile Driving/psychology , PerceptionABSTRACT
Environmental pollution caused by pesticides is a growing concern. Pyridaben, a widely used organochlorine insecticide, is a representative water pollutant. Owing to its extensive usage, it has been detected in various aquatic ecosystems, including rivers and oceans. Pyridaben is highly toxic to aquatic organisms; however, the mechanism of its toxicity in the liver, which is important in toxicant metabolism, has not been studied. Therefore, we employed zebrafish and its well-characterized liver cell line, ZFL to assess pyridaben hepatotoxicity and explore its potential mechanisms of action. Pyridaben led to reduction of the liver size and fluorescence intensity of dsRed-labeled Tg (fabp10a:dsRed) zebrafish. It reduced the viability and proliferation of ZFL cells in vitro by inducing apoptosis and cell cycle arrest. These changes might be primarily linked to uncontrolled intracellular calcium flow in ZFL cells exposed to pyridaben. Additionally, it also downregulates the PI3K/Akt signaling cascade, leading to the inactivation of Gsk3ß and nuclear translocation of ß-catenin. Taken together, our findings suggest that pyridaben could have hepatotoxic effects on aquatic organisms. This study is the first to provide insight into the hepatotoxic mechanism of pyridaben using both in vivo and in vitro models.
Subject(s)
Proto-Oncogene Proteins c-akt , Zebrafish , Animals , Zebrafish/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Calcium/metabolism , Ecosystem , Hepatocytes/metabolism , Cell Cycle Checkpoints , HomeostasisABSTRACT
Psychiatric evaluation relies on subjective symptoms and behavioral observation, which sometimes leads to misdiagnosis. Despite previous efforts to utilize plasma proteins as objective markers, the depletion method is time-consuming. Therefore, this study aimed to enhance previous quantification methods and construct objective discriminative models for major psychiatric disorders using nondepleted plasma. Multiple reaction monitoring-mass spectrometry (MRM-MS) assays for quantifying 453 peptides in nondepleted plasma from 132 individuals [35 major depressive disorder (MDD), 47 bipolar disorder (BD), 23 schizophrenia (SCZ) patients, and 27 healthy controls (HC)] were developed. Pairwise discriminative models for MDD, BD, and SCZ, and a discriminative model between patients and HC were constructed by machine learning approaches. In addition, the proteins from nondepleted plasma-based discriminative models were compared with previously developed depleted plasma-based discriminative models. Discriminative models for MDD versus BD, BD versus SCZ, MDD versus SCZ, and patients versus HC were constructed with 11 to 13 proteins and showed reasonable performances (AUROC = 0.890-0.955). Most of the shared proteins between nondepleted and depleted plasma models had consistent directions of expression levels and were associated with neural signaling, inflammatory, and lipid metabolism pathways. These results suggest that multiprotein markers from nondepleted plasma have a potential role in psychiatric evaluation.