Microplastics (MPs) pose emerging threats to human health, with growing concerns about liver toxicity and other harmful effects from plastic particles. While aquatic species exhibit hepatic vulnerability to micro/nanoplastics, the role of submicroplastics (100 nm-1 μm) in mammalian non-alcoholic fatty liver disease (NAFLD) progression remains unclear. We investigated the effects of a 12-week exposure to 0.5 μm polystyrene MPs (submicroplastics) in drinking water, administering this to ApoE-deficient mice fed either a chow diet (CD) or a Western diet (WD). Submicroplastics accumulated predominantly in the liver and were excreted in the feces. Histologically, submicroplastics significantly increased NAFLD activity scores, hepatic steatosis (Oil Red O-positive area), and fibrosis (Masson-positive area), with maximal severity in the WD+MPs group. Also, the MPs exposure group had increases in positive areas for F4/80 and inflammatory markers TNF-α, IL-1β and IL-6 expression under both diets. Concurrently, submicroplastics inhibited antioxidant defenses by lowering levels of superoxide dismutase and glutathione, while also increasing the lipid peroxidation marker malondialdehyde. WD-fed mice exhibited pronounced MPs-induced lipid dysregulation, including elevated hepatic triglycerides, total cholesterol, and free fatty acids (FAs). Mechanistically, submicroplastics upregulated FA synthesis regulators (ACC, FASN, SREBP1) while downregulating FA oxidation mediators (CPT1A, ACOX1, PPARα) in the livers under a WD. Our findings demonstrate that chronic submicroplastics-exposure exacerbates the progression of NAFLD in ApoE-deficient mice by disturbing lipid metabolism, enhancing oxidative stress, and amplifying inflammatory responses. This study provides experimental evidence linking environmental plastic pollution to accelerated metabolic liver disease, thereby highlighting the urgent need for plastic exposure control strategies.

We live in a world increasingly dominated by plastic, leading to the generation of microplastic particles that pose significant global health concerns. Microplastics can enter the body via ingestion, inhalation, and direct contact, accumulating in various tissues and potentially causing harm. Despite this, the specific cellular mechanisms and signaling pathways involved remain poorly understood. Macrophages are essential in absorbing, distributing, and eliminating microplastics, playing a key role in the body's defense mechanisms. Recent evidence highlights oxidative stress signaling as a key pathway in microplastic-induced macrophage dysfunction. The accumulation of microplastics generates reactive oxygen species (ROS), disrupting normal macrophage functions and exacerbating inflammation and organ damage. This review serves as the first comprehensive examination of the interplay between microplastics, macrophages, and oxidative stress. It discusses how oxidative stress mediates macrophage responses to microplastics and explores the interactions with gut microbiota. Additionally, it reviews the organ damage resulting from alterations in macrophage function mediated by microplastics and offers a novel perspective on the defense, assessment, and treatment of microplastic-induced harm from the viewpoint of macrophages.

Macrophage polarization plays a pivotal role in immune homeostasis and disease progression across inflammatory, neoplastic, and metabolic disorders. Saponins, which are natural compounds with steroidal/triterpenoid structures, demonstrate therapeutic potential through immunomodulatory, anti-inflammatory, and anti-tumor activities. This study aims to highlight the potential of key saponins-such as ginsenosides, astragaloside IV, dioscin, platycodin D, pulsatilla saponins, and panax notoginseng saponins-in modulating macrophage polarization and enhancing conventional therapies, particularly in oncology. We conducted structured searches in PubMed, Google Scholar, and SciFinder (2013-2024) using controlled vocabulary, including "saponins," "macrophage polarization," and "therapeutic effects." Our findings demonstrate that saponins significantly modulate immune responses and improve treatment efficacy. However, clinical translation is hindered by challenges such as poor bioavailability and safety concerns, which limit systemic exposure and therapeutic utility. To overcome these barriers, innovative delivery strategies, including nanoemulsions and engineered exosomes, are essential for enhancing pharmacokinetics and therapeutic index. Future research should prioritize elucidating the molecular mechanisms underlying saponin-mediated macrophage polarization, identifying novel therapeutic targets, and optimizing drug formulations. Addressing these challenges will enable the restoration of immune balance and more effective management of diverse diseases.

The increasing prevalence of nanoplastics (NPs) in the environment, particularly polystyrene (PS) nanoparticles, raises concerns regarding their potential impact on human and animal health. Given their small size, NPs can cross biological barriers and accumulate in organs, including those critical for immune functions. This study investigates the effects of short-term oral exposure to 100 and 500 nm PS NPs on the adaptive immune responses during viral infections in vivo, using vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV) as models. Male and female C57BL/6 mice were orally exposed to PS NP for a period of 28 days, during which they were infected with either VSV or LCMV to study the humoral and cellular responses, respectively. The humoral responses were assessed by measuring total and VSV-specific antibody levels, and splenic immune populations. T cell phenotypes, activation, exhaustion and functionality towards LCMV epitopes were studied as readouts of the cellular responses. Our results demonstrate that short-term NP exposure does not significantly affect the generation or neutralizing capacity of antibodies against VSV, nor the cellular responses directed against LCMV. These findings indicate that, under these conditions, PS NP exposure does not significantly compromise the adaptive immune responses during viral infections, underscoring the value of in vivo models.

The inevitable exposure of humans to micro/nanoplastics has become a pressing global environmental issue, with growing concerns regarding their impact on health. While the direct effects of micro/nanoplastics on human health remain largely unknown, increasing attention is being given to their potential role as carriers of environmental pollutants and organic substances. This study investigates the direct toxicity of 500 nm polystyrene nanoplastics (NPs) on human hepatocytes (HepG2) in vitro, both alone and in combination with cadmium (Cd), a hazardous heavy metal and a prevalent environmental pollutant. One-hour exposure to 100 µg/mL of NPs causes a significant increase in ROS production (+25% compared to control) but cell viability remains unaffected even at concentrations much higher than environmental levels. Interestingly, NPs significantly reduce Cd cytotoxicity at LC50 concentrations (cell viability compared to control: 55.4% for 50 µM Cd, 66.9% for 50 µM Cd + 10 µg/mL NPs, 68.4% for 50 µM Cd + 100 µg/mL NPs). Additionally, NPs do not alter the cellular lipid content after short-term exposure (24 h). However, when Cd and fatty acids are added to the medium, NPs appear to sequester fatty acids, reducing their availability and impairing their uptake by cells in a dose-dependent manner. We confirmed by Dynamic Light Scattering and Scanning Electron Microscopy the interaction between NPs, Cd and free fatty acids. Although polystyrene NPs exhibited minimal cytotoxicity in our experimental model, collectively our findings suggest that predicting the effects of cell exposure to NPs is extremely challenging, due to the potential interaction between NPs, environmental pollutants and specific components of the biological matrix.

Nano-plastics (NPs) are emerging hazardous environmental contaminants that pose health risks with size-dependent toxic effects and are potential risk factors for hepatocellular carcinoma (HCC) and lipid metabolism disorders including non-alcoholic fatty liver disease (NAFLD). However, their underlying molecular mechanisms remain unclear. To shed more light on the causes of these risks, we developed a digestive system microphysiological platform (DS-MPP) for simulating dynamic internal-exposure of multi-size NPs in the gastrointestinal tract and liver. Multi-omics analysis based on DS-MPP revealed hepatic cells are more sensitive to 72 μg/day NPs than gastrointestinal mucosa cells. Specifically, 50 nm NPs disrupt phospholipid metabolism, promote diacylglycerol (DG) accumulation, convert more DG to phosphatidic acid (PA) than triacylglycerol (TG), thus facilitating endocytic vesicles production. Meanwhile, it can active tumorigenesis related pathway mTOR, inducing HCC marked by CAB39. Moreover, 500 nm NPs promote NAFLD by inducing insulin resistance pathways and decreasing PLD1 expression. Our results demonstrate the mechanism of disease and metabolic disorders induced by NPs vary depending on particle size. DS-MPP is a reliable platform for evaluating risk of dynamic NPs exposure and elucidating mechanisms of related metabolic diseases. This platform provides a promising method for health risk assessment caused by environmental pollutants.

Microplastics (MPs) are environmental pollutants attracting widespread attention due to their environmental omnipresence and potential health effects. MPs undergo ageing in the environment and our previous research found that aged Polystyrene microplastics (PS-MPs) affected lipid metabolism in healthy female mice, but not males. In this study, we examined the effects of aged PS-MP exposure on lipid metabolism in mice with Metabolic Associated Fatty Liver Disease (MAFLD). 14 female and 14 male mice were furnished with a high-fat diet (HFD) for eight weeks to create MAFLD model mice. They were then orally administered aged PS-MPs for four weeks, and changes in the AMP-activated protein kinase signalling pathway were examined in order to determine PS-MP's effect on hepatic metabolism. The outcomes showed that though serum estradiol, inflammatory gene expression and ROS levels increased significantly in both male and female HFD-aged PS-MP groups, hepatic steatosis was attenuated only in the female group. Furthermore, serum ERα, ERβ, AMPKα, acetyl-CoA carboxylase, sterol regulatory element binding protein-1c, and Fas expressions were significantly increased in the MAFLD mice groups compared to the control group. Combining serum E2 levels, AMPK pathway changes, oxidative stress markers, and inflammatory gene levels, aged PS-MPs may stimulate E2 production and mobilize the liver AMPK signalling pathway of both male and female MAFLD mice. However, lipid metabolism is only affected in female MAFLD mice, suggesting other possible mechanisms besides the AMPK pathway may be at play. These results provide a new perspective on the potential health effects of MP exposure in individuals with metabolic disorders such as MAFLD.

Nano- and microplastics (NMPs) have become a serious global environmental threat that causes damage to mammalian organs. In this work, we investigated the potential molecular mechanism underlying the development of liver fibrosis induced by long-term exposure to three different sized polystyrene (PS)-NMPs (80 nm, 0.5 µm and 5 µm) in mice. Liver fibrosis levels were evaluated in mice after chronic exposure to PS-NMPs. Liver inflammation was mainly increased in chronic exposure to 80 nm and 0.5 µm PS-NMPs. Liver lipid deposition was significantly enhanced after PS-NMPs exposure. However, oxidative stress was not changed under PS-NMPs exposure. GO enrichment and KEGG pathway analyses revealed that the DEGs and shared DEGs were mainly enriched in the metabolism of lipids. The mRNA expression levels of genes related to fatty acid oxidation, synthesis and transport were dramatically induced by PS-NMPs exposure. Four hub genes, Acot3, Abcc3, Nr1i3 and Fmo2, were identified by CytoHubba analysis of shared DEGs. The mRNA expression levels of three hub genes, Acot3, Abcc3 and Nr1i3, were significantly augmented under chronic PS-NMPs exposure. Our results suggest that Acot3, Abcc3 and Nr1i3 are potential molecules involved in the development of liver fibrosis under chronic exposure to PS-NMPs.

In recent years, awareness regarding micro-nanoplastics' (MNPs) potential effects on human health has progressively increased. Despite a large body of evidence regarding the origin and distribution of MNPs in the environment, their impact on human health remains to be determined. In this context, there is a major need to address their potential carcinogenic risks, since MNPs could hypothetically mediate direct and indirect carcinogenic effects, the latter mediated by particle-linked chemical carcinogens. Currently, evidence in this field is scarce and heterogeneous, but the reported increased incidence of malignant tumors among younger populations, together with the ubiquitous environmental abundance of MNPs, are rising a global concern regarding the possible role of MNPs in the development and progression of cancer. In this review, we provide an overview of the currently available evidence in eco-toxicology, as well as methods for the identification and characterization of environmental MNP particulates and their health-associated risks, with a focus on cancer. In addition, we suggest possible routes for future research in order to unravel the carcinogenetic potential of MNP exposure and to understand prognostic and preventive implications of intratumoral MNPs.

Plastic pollution has become a global pollution problem that cannot be ignored. As the main destination of human oral intake, the toxic effects of plastic on the digestive system represented by the intestine and liver are the focus of current research. Marine-derived DHA-PS has a variety of biological activities, mainly focusing on improving brain function and regulating lipid metabolism. However, whether it has an improvement effect on PS-NPs-induced hepato-intestinal injury and the underlying mechanism remain unclear.

A murine liver injury model was established by gavage of PS-NPs for six weeks. By integrating approaches from lipidomics, transcriptomics, and gut microbiota analysis, the molecular mechanism by which DHA-PS alleviates PS-NPs-induced murine hepatotoxicity was explored through the "gut-liver axis".

Our findings reveal that prolonged exposure to PS-NPs results in significant murine liver damage and dysfunction, characterized by increased oxidative stress and inflammation, along with exacerbated hepatic lipid accumulation. Mechanistically, PS-NPs disrupt the hepatic SIRT1-AMPK pathway by suppressing the expression of SIRT1, AMPKα, and PPARα, while enhancing the expression of SREBP-1c, ultimately leading to disordered hepatic lipid metabolism. The sphingolipid and glycerophospholipid metabolic pathways were particularly affected. Additionally, in agreement with transcriptomic analyses, PS-NPs activate the hepatic TLR4/NF-κB pathway. At the same time, exposure to PS-NPs decreases the expression of ZO-1, occludin, and claudin-1, diminishes the relative abundance of beneficial gut bacteria (norank_f_Muribaculaceae, Akkermansia, and norank_f_norank_o_Clostridia_UCG-014), and increases the prevalence of pathogenic gut bacteria (Coriobacteriaceae_UCG-002 and Desulfovibrio), exacerbating liver injury through the gut-liver axis. However, administering DHA-PS (50 mg/kg) effectively alleviated these injuries.

This study was the first to employ multi-omics techniques to elucidate the potential mechanisms underlying hepatotoxicity induced by PS-NPs, thereby supporting the use of DHA-PS as a dietary supplement to mitigate the effects of nanoplastic pollutants.

Polyethylene terephthalate nanoplastics (PET-NPs) are one of the most frequently distributed nanoplastics in daily life. Betaine is thought to be a promising hepatoprotective agent. The current investigation focused on whether orally administered PET-NPs caused hepatotoxicity and ameliorative effect of betaine. Forty adult male Swiss albino mice were randomly split into four groups: group I control, group II betaine (1000 mg/kg I/P), group III PET-NPs (200 mg/kg orally), and group IV betaine plus PET-NPs at doses similar to group II& III respectively. After 30 days, blood sample were collected then animals were euthanized and liver specimens were dissected out for biochemical and histopathological examination. PET-NPs induced a significant elevation in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA), as well as an increase in the inflammatory genes a proto-oncogene (c-FOS) and cyclooxygenase 2 (COX2) (p ≤ 0.05), with a substantial decrease in glutathione (GSH) (p ≤ 0.05). Furthermore, on the level of histopathological analysis PET-NPs caused alterations in hepatic tissue architecture as vascular dilatation and congestion with hepatocytes degeneration, bile duct epithelial hyperplasia and inflammatory cell infiltrations While on the level of immunohistochemistry, PET-NPs trigger positive tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-ҠB) expression in comparison to control. Meanwhile, betaine treatment reduced the deleterious effects of PET-NPs. To summarize, PET-NPs may cause hepatotoxicity in mice, with a belief that betaine could mitigate the detrimental impact.

Background: Humans cannot avoid plastic exposure due to its ubiquitous presence in the natural environment. The waste generated is poorly biodegradable and exists in the form of MPs, which can enter the human body primarily through the digestive tract, respiratory tract, or damaged skin and accumulate in various tissues by crossing biological membrane barriers. There is an increasing amount of research on the health effects of MPs. Most literature reports focus on the impact of plastics on the respiratory, digestive, reproductive, hormonal, nervous, and immune systems, as well as the metabolic effects of MPs accumulation leading to epidemics of obesity, diabetes, hypertension, and non-alcoholic fatty liver disease. MPs, as xenobiotics, undergo ADMET processes in the body, i.e., absorption, distribution, metabolism, and excretion, which are not fully understood. Of particular concern are the carcinogenic chemicals added to plastics during manufacturing or adsorbed from the environment, such as chlorinated paraffins, phthalates, phenols, and bisphenols, which can be released when absorbed by the body. The continuous increase in NMP exposure has accelerated during the SARS-CoV-2 pandemic when there was a need to use single-use plastic products in daily life. Therefore, there is an urgent need to diagnose problems related to the health effects of MP exposure and detection. Methods: We collected eligible publications mainly from PubMed published between 2017 and 2024. Results: In this review, we summarize the current knowledge on potential sources and routes of exposure, translocation pathways, identification methods, and carcinogenic potential confirmed by in vitro and in vivo studies. Additionally, we discuss the limitations of studies such as contamination during sample preparation and instrumental limitations constraints affecting imaging quality and MPs detection sensitivity. Conclusions: The assessment of MP content in samples should be performed according to the appropriate procedure and analytical technique to ensure Quality and Control (QA/QC). It was confirmed that MPs can be absorbed and accumulated in distant tissues, leading to an inflammatory response and initiation of signaling pathways responsible for malignant transformation.

Micro- and nanoplastic pollution has emerged as a significant global concern due to their extensive presence in the environment and potential adverse effects on human health. Nanoplastics can enter the human circulatory system and accumulate in the liver, disrupting hepatic metabolism and causing hepatotoxicity. However, the precise mechanism remains uncertain. Lipophagy is an alternative mechanism of lipid metabolism involving autophagy. This study aims to explore how polystyrene nanoplastics (PSNPs) influence lipid metabolism in hepatocytes via lipophagy. Initially, it was found that PSNPs were internalized by human hepatocytes, resulting in decreased cell viability. PSNPs were found to induce the accumulation of lipid droplets (LDs), with autophagy inhibition exacerbating this accumulation. Then, PSNPs were proved to activate lipophagy by recruiting LDs into autophagosomes and block the lipophagic flux by impairing lysosomal function, inhibiting LD degradation. Ultimately, PSNPs were shown to activate lipophagy through the AMPK/ULK1 pathway, and knocking down AMPK exacerbated lipid accumulation in hepatocytes. Overall, these results indicated that PSNPs triggered lipophagy via the AMPK/ULK1 pathway and blocked lipophagic flux, leading to lipid accumulation in hepatocytes. Thus, this study identifies a novel mechanism underlying nanoplastic-induced lipid accumulation, providing a foundation for the toxicity study and risk assessments of nanoplastics.

Studies have shown that microplastics (MPs) and nanoplastics (NPs) could accumulate in the human body and pose a potential threat to human health. The purpose of this study is to evaluate the biodistribution and toxicity of MPs/NPs with different particle sizes comprehensively and thoroughly.

The purpose of this study was to investigate the biodistribution and in vivo toxicity of polystyrene (PS) MPs/NPs with different sizes (50 nm, 100 nm, and 500 nm). The BALB/c mice were given 100 μL of PS50, PS100 and PS500 at the dosage of 1 mg/kg BW or 10 mg/kg BW, respectively, by gavage once a day. After 28 consecutive days of treatment, the biodistribution of differently sized PS MPs/NPs was determined through cryosection fluorescence microscopy and fluorescent microplate reader analysis, and the subsequent effects of differently sized PS MPs/NPs on histopathology, hematology and blood biochemistry were also evaluated.

The results showed that the three different sizes of PS MPs/NPs were distributed in the organs of mice, mainly in the liver, spleen, and intestine. At the same time, the smaller the particle size, the more they accumulate in the body and more easily penetrate the tissue. During the whole observation period, no abnormal behavior and weight change were observed. The results of H&E staining showed that no severe histopathological abnormalities were observed in the main organs in the low-dose exposure group, while. Exposure of three sizes of PS MPs/NPs could cause some changes in hematological parameters or biochemical parameters related to heart, liver, and kidney function; meanwhile, there were size- and dose-dependencies.

The biological distribution and toxicity of plastic particles in mice were more obvious with the decrease of particle size and the increase of concentration of plastic particles. Compared with MPs, NPs were easier to enter the tissues and produce changes in liver, kidney, and heart functions. Therefore, more attention should be paid to the toxicity of NPs.

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.

Continuous exposure to plastic pollutants may have serious consequences on human health. However, most toxicity assessments focus on non-environmentally relevant particles and rarely investigate long-term effects such as cancer induction. The present study assessed the carcinogenic potential of two secondary nanoplastics: polyethylene terephthalate (PET) particles generated from plastic bottles, and a biodegradable polylactic acid material, as respective examples of environmentally existing particles and new bioplastics. Pristine polystyrene nanoplastics were also included for comparison. A broad concentration range (6.25-200 μg/mL) of each nanoplastic was tested in both the initiation and promotion conditions of the regulatory assessment-accepted in vitro Bhas 42 cell transformation assay. Parallel cultures allowed confirmation of the efficient cellular internalisation of the three nanoplastics. Cell growth was enhanced by polystyrene in the initiation assay, and by PET in both conditions. Moreover, the number of transformed foci was significantly increased only by the highest PET concentration in the promotion assay, which also showed dose-dependency, indicating that nano PET can act as a non-genotoxic tumour promotor. Together, these findings support the carcinogenic risk assessment of nanoplastics and raise concerns regarding whether real-life co-exposure of PET nanoplastics and other environmental pollutants may result in synergistic transformation capacities.

Nanoplastics (NPs) are increasingly pervasive in the environment, raising concerns about their potential health implications, particularly within aquatic ecosystems. This study investigated the impact of polystyrene nanoparticles (PSN) on zebrafish liver metabolism using liquid chromatography hybrid quadrupole time of flight mass spectrometry (LC-QTOF-MS) based non-targeted metabolomics. Zebrafish were exposed to 50 nm PSN for 28 days at low (L-PSN) and high (H-PSN) concentrations (0.1 and 10 mg/L, respectively) via water. The results revealed significant alterations in key metabolic pathways in low and high exposure groups. The liver metabolites showed different metabolic responses with L-PSN and H-PSN. A total of 2078 metabolite features were identified from the raw data obtained in both positive and negative ion modes, with 190 metabolites deemed statistically significant in both L-PSN and H-PSN groups. Disruptions in lipid metabolism, inflammation, oxidative stress, DNA damage, and amino acid synthesis were identified. Notably, L-PSN exposure induced changes in DNA building blocks, membrane-associated biomarkers, and immune-related metabolites, while H-PSN exposure was associated with oxidative stress, altered antioxidant metabolites, and liver injury. For the first time, L-PSN was found depolymerized in the liver by cytochrome P450 enzymes. Utilizing an analytical approach to the adverse outcome pathway (AOP), impaired lipid metabolism and oxidative stress have been identified as potentially conserved key events (KEs) associated with PSN exposure. These KEs further induced liver inflammation, steatosis, and fibrosis at the tissue and organ level. Ultimately, this could significantly impact biological health. The study highlights the PSN-induced effects on zebrafish liver metabolism, emphasizing the need for a better understanding of the risks associated with NPs contamination in aquatic ecosystems.

Polystyrene nanoparticles are emerging as contaminants in freshwater environments, posing potential risks to amphibians exposed to extended periods of water contamination. Using tadpoles as a model, this study aimed to evaluate the toxicity of PS NPs. Pyrolysis-gas chromatography-tandem mass spectrometry (Py-GCMS) analysis revealed a concentration-dependent increase in polystyrene nanoparticles (PS NPs) levels in tadpoles with escalating exposure concentrations. Following exposure to 100 nm fluorescent microspheres, fluorescence was observed in the intestines and gills, peaking at 48 hours. Histopathological analysis identified degenerative necrosis and inflammation in the liver, along with atrophic necrosis of glomeruli and tubules in the kidneys. These results indicate a discernible impact of PS NPs on antioxidant levels, including reduced superoxide dismutase and catalase activities, elevated glutathione content, and increased malondialdehyde levels. Electron microscopy observations revealed the infiltration of PS NPs into Kupffer's cells and hepatocytes, leading to visible lesions such as nuclear condensation and mitochondrial disruption. The primary objective of this research was to elucidate the adverse effects of prolonged PS NPs exposure on amphibians.

Microplastics (MP) derived from the weathering of polymers, or synthesized in this size range, have become widespread environmental contaminants and have found their way into water supplies and the food chain. Despite this awareness, little is known about the health consequences of MP ingestion. We have previously shown that the consumption of polystyrene (PS) beads was associated with intestinal dysbiosis and diabetes and obesity in mice. To further evaluate the systemic metabolic effects of PS on the gut-liver-adipose tissue axis, we supplied C57BL/6J mice with normal water or that containing 2 sizes of PS beads (0.5 and 5 µm) at a concentration of 1 µg/ml. After 13 weeks, we evaluated indices of metabolism and liver function. As observed previously, mice drinking the PS-containing water had a potentiated weight gain and adipose expansion. Here we found that this was associated with an increased abundance of adipose F4/80+ macrophages. These exposures did not cause nonalcoholic fatty liver disease but were associated with decreased liver:body weight ratios and an enrichment in hepatic farnesoid X receptor and liver X receptor signaling. PS also increased hepatic cholesterol and altered both hepatic and cecal bile acids. Mice consuming PS beads and treated with the berry anthocyanin, delphinidin, demonstrated an attenuated weight gain compared with those mice receiving a control intervention and also exhibited a downregulation of cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor (PPAR) signaling pathways. This study highlights the obesogenic role of PS in perturbing the gut-liver-adipose axis and altering nuclear receptor signaling and intermediary metabolism. Dietary interventions may limit the adverse metabolic effects of PS consumption.

Global health concerns about micro- and nanoplastics are increasing. The newly discovered beige adipocytes play a vital role in energy homeostasis through their high thermogenic capacity upon activation. However, the effects of micro- and nanoplastics on beige adipocytes have not yet been studied. We investigated whether the effects of oral exposure to polystyrene nanoparticles (PS-NPs) on systemic metabolic performance can be induced by disrupting beige adipocyte function, and the potential mechanism. In the present study, C57BL/6J male mice were fed a high-fat diet (HFD) with or without PS-NPs exposure for 12 weeks to investigate the differences in metabolic performance. We also isolated stromal vascular fraction from C57BL/6J male mice to differentiate and prepare primary beige adipocyte cultures. Primary beige adipocytes were treated with PS-NPs on the sixth day of differentiation. The results showed that oral intake of PS-NPs exacerbated metabolic disorders of mice under HFD, including suppressed energy expenditure, increased fat mass and liver steatosis, decreased insulin sensitivity, disrupted glucose homeostasis, and decreased cold-tolerance capability compared with the control group. Intriguingly, we observed that, after a 12-week exposure, PS-NPs accumulated in the inguinal white adipose tissue (iWAT), a fat depot rich in beige adipocytes, further suppressing thermogenic gene programs, particularly the level of uncoupling protein 1 (UCP1), a master regulator in the browning process of beige adipocytes. These effects ultimately led to decreased energy expenditure and subsequent disorders of glucolipid metabolism. Mechanistically, we revealed that PS-NPs disrupt mitochondrial function and induce oxidative damage and inflammation in beige adipocytes to inhibit their function. These negative metabolic effects of PS-NPs were ameliorated by antioxidant supplementation. Our study is the first to demonstrate that PS-NPs exposure exacerbates metabolic disorder in HFD-fed mice by disrupting beige adipocyte function.

Micro- and nanoplastics are vast anthropogenic pollutants in our direct surroundings with a robust environmental stability and a potential for a long-lasting and increasing global circulation. This has raised concerns among the public and policy makers for human health upon exposure to these particles. The micro- and nanoplastic burden on humans is currently under debate, along with criticism on the experimental approaches used in hazard assessment. The present review presents an overview of the human-relevant aspects associated with the current micro-and nanoplastic burden. We focus on environmental circulation and the estimation of exposure quantities to humans, along with a state-of-the-art overview of particle accumulation in over 15 human organs and other specimen. Additionally, data regarding particle characteristics used in toxicity testing was extracted from 91 studies and discussed considering their environmental and human relevance.

The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs-induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS-NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 μg/day). Results showed that inhaled PS-NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time-dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-β, α-SMA, and Col1a1 identified that inhaled PS-NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS-NPs-induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS-NPs-induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS-NPs on the liver, identified that continuous inhaled PS-NPs could cause liver injury and fibrosis, and PS-NPs- ferroptosis provided a novel mechanistic explanation.

With continuous population and economic growth in the 21st century, plastic pollution is a major global issue. However, the health concern of microplastics/ nanoplastics (MPs/NPs) decomposed from plastic wastes has drawn public attention only in the recent decade. This article summarizes recent works dedicated to understanding the impact of MPs/NPs on the liver-the largest digestive organ, which is one of the primary routes that MPs/NPs enter human bodies. The interrelated mechanisms including oxidative stress, hepatocyte energy re-distribution, cell death and autophagy, as well as immune responses and inflammation, were also featured. In addition, the disturbance of microbiome and gut-liver axis, and the association with clinical diseases such as metabolic dysfunction-associated fatty liver disease, steatohepatitis, liver fibrosis, and cirrhosis were briefly discussed. Finally, we discussed potential directions in regard to this trending topic, highlighted current challenges in research, and proposed possible solutions.

Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.

Microplastics (MPs) are ubiquitous in environmental compartments and consumer products. Although liver is frequently reported to be a target organ of MP accumulation in mammals, few studies have focused on MP hepatoxicity in humans. In this study, we used normal human liver cells, THLE-2, to assess the acute and chronic toxicity of polystyrene (PS) MPs with sizes of 0.1 and 1 μm. The results showed that after 48 h of exposure, both kinds of PS MPs could enter THLE-2 cells and cause no obviously acute cytotoxicity at <20 μg/mL. In contrast, metabolomic analysis revealed that 90 days of PS MPs exposure at environmentally relevant dose (0.2 μg/mL) could significantly alter the metabolic profiles of the cells, especially the nanosized MPs. KEGG pathway analysis showed that the ATP-binding cassette (ABC) transporter pathway was the most significantly changed pathway. Cell functional tests confirmed that chronic PS MP treatment could inhibit the activity of the ABC efflux transporter and further increase the cytotoxicity of arsenic, indicating that the PS MPs had a chemosensitizing effect. These findings underline the chronic risk of MPs to human liver.

Microplastics (MPs) have been detected in various human tissues, including the liver, placenta, and blood. However, studies about MPs in the human locomotor system are limited. This study evaluated the presence of MPs in the synovium of 45 patients undergoing hip or knee arthroplasty using micro-Fourier transform infrared spectroscopy, scanning electron microscopy, and Raman microscopy and investigated their association with clinical indicators and local cellular responses. A total of 343 MPs of nine common types were identified, with a mean abundance of 5.24 ± 2.07 particles/g and ranging from 1.16 to 10.77 particles/g. Although there was no clear correlation between MP abundance and demographics, MP abundance was higher in hip samples than in knee samples. In addition, a potential association was observed between MP abundance and specific clinical diagnoses. Transcriptomic analysis revealed that a three-fold increase in MP abundance corresponded to enhanced local cellular stress responses, particularly heat shock protein reactions. Our findings demonstrate the presence of MPs in human joints and suggest that further studies are needed to explore the intricate associations between MPs and anatomical location, clinical diagnosis, and local cellular responses.

Co-existing of polystyrene-nano plastics (PSNPs) and arsenic (As) in the environment caused a horrendous risk to human health. However, the potential mechanism of PSNPs and As combination induced testicular toxicity in mammals has not been elucidated. Therefore, we first explore the testicular toxicity and the potential mechanism in male Kunming mice exposed to As or/and PSNPs. Results revealed that compared to the As or PSNPs group, the combined group showed more significant testicular toxicity. Specifically, As and PSNPs combination induced irregular spermatozoa array and blood-testis barrier disruption. Simultaneously, As and PSNPs co-exposure also exacerbated oxidative stress, including increasing the MDA content, and down-regulating expression of Nrf-2, HO-1, SOD-1, and Trx. PSNPs and As combination also triggered testicular apoptosis, containing changes in apoptotic factors (P53, Bax, Bcl-2, Cytc, Caspase-8, Caspase-9, and Caspase-3). Furthermore, co-exposed to As and PSNPs aggravated inflammatory damage characterized by targeted phosphorylation of NF-κB and degradation of I-κB. In summary, our results strongly confirmed As + PSNPs co-exposure induced the synergistic toxicity of testis through excessive oxidative stress, apoptosis, and inflammation, which could offer a new sight into the mechanism of environmental pollutants co-exposure induced male reproductive toxicity.

Plastic pollution has become a significant global problem over the years, leading to the continuous decomposition and accumulation of micro/nanoplastics (MNPLs) in the environment. As a result, human exposure to these MNPLs is inevitable. The liver, in particular, is highly susceptible to potential MNPL toxicity. In this study, we systematically reviewed the current literature on MNPLs-induced hepatotoxicity and collected data on toxic events occurring at different biological levels. Then, to better understand the cause-mechanism causality, we developed an Adverse Outcome Pathway (AOP) framework for MNPLs-induced hepatotoxicity. The AOP framework provided insights into the mechanism of MNPL-induced hepatotoxicity and highlighted potential health risks such as liver dysfunction and inflammation, metabolism disorders and liver fibrosis. Moreover, we discussed the potential application of emerging toxicological models in the hepatotoxicity study. Liver organoids and liver-on-chips, which can simulate the structure and function of the liver in vitro, offer a promising alternative platform for toxicity testing and risk assessment. We proposed combining the AOP framework with these emerging toxicological models to improve our understanding of the hepatotoxic effects of MNPLs. Overall, this study performed a preliminary exploration of novel toxicological methodologies to assess the hepatotoxicity of MNPLs, providing a deeper understanding of environmental toxicology.

Prolyl endopeptidase (PREP) is a serine endopeptidase that participates in many pathological processes including inflammation, oxidative stress, and autophagy. Our previous studies found that PREP knockout exhibited multiple benefits in high-fat diet (HFD) or methionine choline-deficient diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD). However, cumulative studies have suggested that PREP performs complex functions during disease development. Therefore, further understanding the role of PREP in MAFLD development is the foundation of PREP intervention.

In this study, an HFD-induced MAFLD model at different time points (4, 8, 12, and 16 weeks) was used to explore dynamic changes in the PREP proline-glycine-proline (PGP)/N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) system. To explore its potential value in MAFLD treatment, saline, or the PREP inhibitor, KYP-2047, was administered to HFD-induced MAFLD mice from the 10th to 16th weeks.

PREP activity and expression were increased in HFD-mice compared with control mice from the 12th week onwards, and increased PREP mainly resulted in the activation of the matrix metalloproteinase 8/9 (MMP8/9)-PREP-PGP axis rather than the thymosin β4-meprin α/PREP-AcSDKP axis. In addition, KYP-2047 reduced HFD-induced liver injury and oxidative stress, improved lipid metabolism through the suppression of lipogenic genes and the induction of β-oxidation-related genes, and attenuated hepatic inflammation by decreasing MMP8/9 and PGP. Moreover, KYP2047 restored HFD-induced impaired autophagy and this was verified in HepG2 cells.

These findings suggest that increased PREP activity/expression during MAFLD development might be a key factor in the transition from simple steatosis to steatohepatitis, and KYP-2047 might possess therapeutic potential for MAFLD treatment.

Accumulating evidence shows widespread contamination of water sources and food with microplastics. Although the liver is one of the main sites of bioaccumulation within the human body, it is still unclear whether microplastics produce damaging effects. In particular, the hepatic consequences of ingesting polyethylene (PE) microplastics in mammals are unknown. In this study, female mice were fed with food contaminated with 36 and 116 µm diameter PE microbeads at a dosage of 100 µg/g of food for 6 and 9 weeks. Mice were exposed to each type of microbead, or co-exposed to the 2 types of microbeads. Mouse liver showed altered levels of genes involved in uptake, synthesis, and β-oxidation of fatty acids. Ingestion of PE microbeads disturbed the detoxification response, promoted oxidative imbalance, increased inflammatory foci and cytokine expression, and enhanced proliferation in liver. Since relative expression of the hepatic stellate cell marker Pdgfa and collagen deposition were increased following PE exposure, we assessed the effect of PE ingestion in a mouse model of CCl4-induced fibrosis and showed that PE dietary exposure exacerbated liver fibrogenesis. These findings provide the first demonstration of the adverse hepatic effects of PE ingestion in mammals and highlight the need for further health risk assessment in humans.

As emerging pollutants in the environment, nanoplastics (NPs) can cross biological barriers and be enriched in organisms, posing a greatest threat to the health of livestock and humans. However, the size-dependent toxic effects of NPs in higher mammals remain largely unknown. To determine the size-dependent potential toxicities of NPs, we exposed mouse (AML-12) and human (L02) liver cell lines in vitro, and 6-week-old C57BL/6 mice (well-known preclinical model) in vivo to five different sizes of polystyrene NPs (PS-NPs) (20, 50, 100, 200 and 500 nm). We found that ultra-small NPs (20 nm) induced the highest cytotoxicity in mouse and human liver cell lines, causing oxidative stress and mitochondrial membrane potential loss on AML-12 cells. Unexpectedly in vivo, after long-term oral exposure to PS-NPs (75 mg/kg), medium NPs (200 nm) and large NPs (500 nm) induced significant hepatotoxicity, evidenced by increased oxidative stress, liver dysfunction, and lipid metabolism disorders. Most importantly, medium or large NPs generated local immunotoxic effects via recruiting and activating more numbers of neutrophils and monocytes in the liver or intestine, which potentially resulted in increased proinflammatory cytokine secretion and the tissue damage. The discrepancy in in vitro-in vivo toxic results might be attributed to the different properties of biodistribution and tissue accumulation of different sized NPs in vivo. Our study provides new insights regarding the hepatotoxicity and immunotoxicity of NPs on human and livestock health, warranting us to take immense measures to prevent these NPs-associated health damage.

Plastic waste has been produced at a rapidly growing rate over the past several decades. The environmental impacts of plastic waste on marine and terrestrial ecosystems have been recognized for years. Recently, researchers found that micro- and nanoplastics (MNPs), micron (100 nm - 5 mm) and nanometer (1 - 100 nm) scale particles and fibers produced by degradation and fragmentation of plastic waste in the environment, have become an important emerging environmental and food chain contaminant with uncertain consequences for human health. This review provides a comprehensive summary of recent findings from studies of potential toxicity and adverse health impacts of MNPs in terrestrial mammals, including studies in both in vitro cellular and in vivo mammalian models. Also reviewed here are recently released biomonitoring studies that have characterized the bioaccumulation, biodistribution, and excretion of MNPs in humans. The majority MNPs in the environment to which humans are most likely to be exposed, are of irregular shapes, varied sizes, and mixed compositions, and are defined as secondary MNPs. However, the MNPs used in most toxicity studies to date were commercially available primary MNPs of polystyrene (PS), polyethylene (PE), polyvinyl chloride (PVC), polyethylene terephthalate (PET), and other polymers. The emerging in vitro and in vivo evidence reviewed here suggests that MNP toxicity and bioactivity are largely determined by MNP particle physico-chemical characteristics, including size, shape, polymer type, and surface properties. For human exposure, MNPs have been identified in human blood, urine, feces, and placenta, which pose potential health risks. The evidence to date suggests that the mechanisms underlying MNP toxicity at the cellular level are primarily driven by oxidative stress. Nonetheless, large knowledge gaps in our understanding of MNP toxicity and the potential health impacts of MNP exposures still exist and much further study is needed to bridge those gaps. This includes human population exposure studies to determine the environmentally relevant MNP polymers and exposure concentrations and durations for toxicity studies, as well as toxicity studies employing environmentally relevant MNPs, with surface chemistries and other physico-chemical properties consistent with MNP particles in the environment. It is especially important to obtain comprehensive toxicological data for these MNPs to understand the range and extent of potential adverse impacts of microplastic pollutants on humans and other organisms.

With the massive manufacture and use of plastics, plastic pollution-related environmental impacts have raised great concern in recent years. As byproducts of plastic fragmentation and degradation, microplastics (MPs) and nanoplastics (NPs) have been identified as novel pollutants that posed a threat to the ecosystem and humans. Since MPs/NPs could be transported via the food chain and retained in the water, the digestive system should be one of the major targets of MPs/NPs-related toxicity. Although considerable evidence has supported the digestive toxicity of MPs/NPs, the proposed mechanisms remained ambiguous due to the variety of study types, models, and endpoints. This review provided a mechanism-based perspective on MPs/NPs-induced digestive effects by adopting the adverse outcome pathway framework as a promising tool. The overproduction of reactive oxygen species was identified as the molecular initiating event in MPs/NPs-mediated injury to the digestive system. A series of detrimental effects including oxidative stress, apoptosis, inflammation, dysbiosis, and metabolic disorders were summarized as key events. Finally, the occurrence of these effects eventually led to an adverse outcome, suggesting a possible increase in the incidence of digestive morbidity and mortality.

This study aims to explore the effect of liver stem cells (LSCs)-derived exosomes and the miR-142a-5p carried by them on the process of fibrosis by regulating macrophages polarization.

In this study, CCL₄ was used to establish liver fibrosis model. The morphology and purity of exosomes (EVs) were verified by transmission electron microscopy, western blotting (WB) and nanoparticle tracing analysis (NTA). Real-time quantitative PCR (qRT-PCR), WB and enzyme-linked immunoadsorption (ELISA) were used to detect liver fibrosis markers, macrophage polarization markers and liver injury markers. Histopathological assays were used to verify the liver injury morphology in different groups. The cell co-culture model and liver fibrosis model were constructed to verify the expression of miR-142a-5p and ctsb.

Immunofluorescence of LSCs markers CK-18, epithelial cell adhesion molecule (EpCam), and AFP showed that these markers were up-regulated in LSCs. In addition, we evaluated the ability of LSCs to excrete EVs by labeling LSCs-EVs with PKH67. We found that CCL₄ and EVs were simultaneously treated at 50 and 100 μg doses, and both doses of EVs could reduce the degree of liver fibrosis in mice. We tested markers of M1 or M2 macrophage polarization and found that EVs reduced M1 marker expression and promoted M2 marker expression. Further, ELISA was used to detect the secreted factors related to M1 and M2 in tissue lysates, which also verified the above views. Further analysis showed that the expression of miR-142a-5p increased significantly with the increase of EVs treatment concentration and time. Further, in vitro and in vivo LSCs-EVs regulate macrophage polarization through miR-142a-5p/ctsb pathway and affect the process of liver fibrosis.

Our data suggest that EVs-derived miR-142-5p from LSCs improves the progression of liver fibrosis by regulating macrophage polarization through ctsb.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and represents an increasing public health issue given the limited treatment options and its association with several other metabolic and inflammatory disorders. The epidemic, still growing prevalence of NAFLD worldwide cannot be merely explained by changes in diet and lifestyle that occurred in the last few decades, nor from their association with genetic and epigenetic risk factors. It is conceivable that environmental pollutants, which act as endocrine and metabolic disruptors, may contribute to the spreading of this pathology due to their ability to enter the food chain and be ingested through contaminated food and water. Given the strict interplay between nutrients and the regulation of hepatic metabolism and reproductive functions in females, pollutant-induced metabolic dysfunctions may be of particular relevance for the female liver, dampening sex differences in NAFLD prevalence. Dietary intake of environmental pollutants can be particularly detrimental during gestation, when endocrine-disrupting chemicals may interfere with the programming of liver metabolism, accounting for the developmental origin of NAFLD in offspring. This review summarizes cause-effect evidence between environmental pollutants and increased incidence of NAFLD and emphasizes the need for further studies in this field.

In this study, the role of autophagy in hepatic fibrosis and its effects on macrophage polarization and exosomes (EVs) were verified by establishing hepatic fibrosis model and co-culture model, providing evidence for treatment.

In this study, CCL₄ was used to establish hepatic fibrosis model. The morphology and purity of exosomes (EVs) were verified by transmission electron microscopy, western blotting (WB), and nanoparticle tracing analysis (NTA). Real-time quantitative PCR (qRT-PCR), WB and enzyme-linked immunoadsorption (ELISA) were used to detect hepatic fibrosis markers, macrophage polarization markers and liver injury markers. Histopathological assays were used to verify the liver injury morphology in different groups. The cell co-culture model and hepatic fibrosis model were constructed to verify the expression of miR-423-5p.

Hepatic fibrosis model showed that CCL₄ promoted early autophagy increase but inhibited autophagy flux in liver. mRFP-GFP-LC3 detection showed that both LPS group and Baf group inhibited autophagy flux. This inhibitory effect was reversed by Rap combination therapy. The M1/M2 markers of macrophage polarization were further tested, and it was found that LPS and Baf could promote M1 polarization and inhibit M2 polarization. Rap processing reverses this phenomenon. These data suggest that autophagy can regulate the polarization process of liver macrophages. WB and NTA showed that LPS induced EVs generation. In addition, LPS-induced EVs could promote HSC proliferation, cell cycle, migration, and the expression of fibrosis markers. Macrophage-EVs could affect the fibrosis process of stellate cells through the secretion of miR-423a-5p expression. The hepatic fibrosis model was further established to verify the regulation of autophagy and EVs on the fibrosis process.

This study was showed that autophagy could regulate fibrosis by promoting HSC activation by regulating macrophage polarization and exosome secretion.

Ischemia-reperfusion (IR) injury is an inevitable complication of liver transplantation and partial hepatectomy. Although the hazards of environmental microplastics (EMPs) have been well explored, data underlying their impact on IR-induced hepatotoxicity and how to alleviate these damages remain largely undefined. In this study, the involvement of melatonin (MT) in modulating EMPs toxicity in the liver undergoing ischemia-reperfusion injury was investigated. Male Wistar rats were exposed to MPs for 7 days and then subjected to 1 h of partial warm ischemia (70 %) followed by 24 h of reperfusion. We analyzed some parameters as the oxidative stress, the stability of cytoskeleton as well as inflammation, and autophagy. Our data suggested that EMPs elicited liver injury in ischemic animals. Data revealed several histological alterations caused by EMP and IRI, including cellular disorientation, cell necrosis, and microvacuolar steatosis, as well as inflammatory cell infiltration. EMPs increased blood transaminase (AST and ALT) and oxidative stress levels in the ischemic liver. In addition, RT-qPCR, immunofluorescence, and western blot analyses highlighted an increased expression of α-tubulin, IL-18, NFkB, and LC3. However, the ability of MT to reduce MPs and IRI toxicity was consistent with a significant decrease in the evaluated markers. The combined data not only document that melatonin is an effective agent to protect against hepatic IRI but also reduces cellular dysfunction caused by EMPs.