New Sight of Renal Toxicity Caused by UV-Aged Polystyrene Nanoplastics: Induced Ferroptosis via Adsorption of Transferrin.

Secondary nanoplastics (NPs) caused by degradation and aging due to environmental factors are the main source of human exposure, and alterations in the physicochemical and biological properties of NPs induced by environmental factors cannot be overlooked. In this study, pristine polystyrene (PS) NPs to obtain ultraviolet (UV)-aged PS NPs (aPS NPs) as secondary NPs is artificially aged. In a mouse oral exposure model, the nephrotoxicity of PS NPs and aPS NPs is compared, and the results showed that aPS NPs exposure induced more serious destruction of kidney tissue structure and function, along with characteristic changes in ferroptosis. Subsequent in vitro experiments revealed that aPS NPs-induced cell death in human renal tubular epithelial cells involved ferroptosis, which is supported by the use of ferrostatin-1, a ferroptosis inhibitor. Notably, it is discovered that aPS NPs can enhance the binding of serum transferrin (TF) to its receptor on the cell membrane by forming an aPS-TF complex, leading to an increase in intracellular Fe2+ and then exacerbation of oxidative stress and lipid peroxidation, which render cells more sensitive to ferroptosis. These findings indicated that UV irradiation can alter the physicochemical and biological properties of NPs, enhancing their kidney biological toxicity risk by inducing ferroptosis.

Circulating Tumor Cell Phenotype Detection and Epithelial-Mesenchymal Transition Tracking Based on Dual Biomarker Co-Recognition in an Integrated PDMS Chip.

Circulating tumor cells (CTCs) are widely considered as a reliable and promising class of markers in the field of liquid biopsy. As CTCs undergo epithelial-mesenchymal transition (EMT), phenotype detection of heterogeneous CTCs based on EMT markers is of great significance. In this report, an integrated analytical strategy that can simultaneously capture and differentially detect epithelial- and mesenchymal-expressed CTCs in bloods of non-small cell lung cancer (NSCLS) patients is proposed. First, a commercial biomimetic polycarbonate (PCTE) microfiltration membrane is employed as the capture interface for heterogenous CTCs. Meanwhile, differential detection of the captured CTCs is realized by preparing two distinct CdTe quantum dots (QDs) with red and green emissions, attached with EpCAM and Vimentin aptamers, respectively. For combined analysis, a polydimethylsiloxane (PDMS) chip with simple structure is designed, which integrates the membrane capture and QDs-based phenotype detection of CTCs. This chip not only implements the analysis of the number of CTCs down to 2 cells mL-1, but enables EMT process tracking according to the specific signals of the two QDs. Finally, this method is successfully applied to inspect the correlations of numbers or proportions of heterogenous CTCs in 94 NSCLS patients with disease stage and whether there is distant metastasis.

Enhanced hepatic metabolic perturbation of polystyrene nanoplastics by UV irradiation-induced hydroxyl radical generation.

The environmental behavior of and risks associated with nanoplastics (NPs) have attracted considerable attention. However, compared to pristine NPs, environmental factors such as ultraviolet (UV) irradiation that lead to changes in the toxicity of NPs have rarely been studied. We evaluated the changes in morphology and physicochemical properties of polystyrene (PS) NPs before and after UV irradiation, and compared their hepatotoxicity in mice. The results showed that UV irradiation caused particle size reduction and increased the carbonyl index (CI) and negative charge on the particle surface. UV-aged PS NPs (aPS NPs) could induce the generation of hydroxyl radicals (·OH), but also further promoted the generation of ·OH in the Fenton reaction system. Hepatic pathological damage was more severe in mice exposed to aPS NPs, accompanied by a large number of vacuoles and hepatocyte balloon-like changes and more marked perturbations in blood glucose and serum lipoprotein, alanine aminotransferase and aspartate aminotransferase levels. In addition, exposure to PS NPs and aPS NPs, especially aPS NPs, triggered oxidative stress and significantly damaged the antioxidant capacity of mice liver. Compared with PS NPs, exposure to aPS NPs increased the number of altered metabolites in hepatic and corresponding metabolic pathways, especially glutathione metabolism. Our research suggests that UV irradiation can disrupt the redox balance in organisms by promoting the production of ·OH, enhancing PS NPs-induced liver damage and metabolic disorders. This study will help us understand the health risks of NPs and to avoid underestimation of the risks of NPs in nature.

Effective Screening Descriptor for MXenes to Enhance Sulfur Reduction in Lithium-Sulfur Batteries.

MXenes, two-dimensional transition (2D) metal carbides/nitrides, have shown promise as cathodic catalysts for accelerating the conversion of lithium polysulfides (LiPSs) in lithium-sulfur (Li-S) batteries due to their diverse redox-active sites and rapid electron transfer. However, efficiently screening the optimal cathodic catalysts out of thousands of MXenes is challenging. To address this, we developed a model that accurately predicts the thermodynamic energy barrier of the rate-limiting step in Li-S batteries. Our model relates the local chemical reactivity of the MXene sites to the p-band center of the terminations and the electronegativity of subsurface transition metals. The accuracy of the model was verified through density functional theory calculations and contrast experiments in pure and Zn-doping MXenes qualitatively. By utilizing this model, we screened a large library of MXenes (27 types of five-atom-layer MXenes) and identified Ti2CS2, Mo2CS2, and W2CS2 as potential cathodic catalysts for Li-S batteries.

Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia.

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. METHODS: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. RESULTS: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. CONCLUSIONS: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

PM2.5 induces alterations in gene expression profile of platelet-derived extracellular vesicles and mediates cardiovascular injury in rats.

Platelet-derived extracellular vesicles (P-EVs), as the most abundant vesicles in blood, have been proven to play cardinal roles in cardiovascular injury. RNAs (especially miRNAs) carried by P-EVs can be transferred to the receptor, which plays a critical role in regulating vascular endothelial function. PM2.5 is one of the most well-known risk factors that cause cardiovascular disease. Therefore, the objective of the current study was to explore whether exposure to PM2.5 would alter the gene expression profile of P-EVs, and to further elucidate the role of RNAs (especially miRNAs) carried by P-EVs in cardiovascular injury induced by PM2.5 exposure. P-EVs were isolated from the platelet-rich plasma which was exposed and unexposed to PM2.5, and the differentially expressed target genes were evaluated using whole-transcriptome gene sequencing. Rats were treated with P-EVs under different exposure conditions (a protein concentration of 50 µg/mL) and an equal volume of normal saline. The pathological damage of the thoracic aorta and cardiac tissue was evaluated and the coagulation function of the rats was detected. The differentially expressed genes were shown to be mainly concentrated in inflammation, angiogenesis, and apoptosis-related pathways. Moreover, P-EVs extracted from PM2.5-exposed plasma had the potential to trigger an inflammatory response, impair vascular endothelial function, disrupt the normal coagulation process, and promote a prothrombotic state. Our study indicated that PM2.5 induces cardiovascular injury in rats by interfering with the gene expression of P-EVs. It will provide new targets for studying the mechanism involved in PM2.5-induced cardiovascular injury.

Short term exposure to polystyrene nanoplastics in mice evokes self-regulation of glycolipid metabolism.

With the detection of nano-plastics (NPs) in daily essentials and drinking water, the potential harm of NPs to human health has become the focus of global attention. Studies have shown that long term exposure to NPs can lead to disorders of glucose and lipid metabolism in organisms, while the effects of short term exposure are rarely reported. Moreover, environmental factors cause the aging of NPs, and it is unclear whether this has an effect on their toxicity. In this study, we use 100 nm polystyrene (PS) NPs and ultraviolet (UV) aging PS (aPS) NPs to gavage mice for 7 days at an exposure dose of 50 mg/kg/day. To evaluate the effects of exposure on mice hepatic glucose lipid metabolism, we performed blood biochemical, pathological and metabolomic analyses. The results showed that exposure to PS NPs and aPS NPs increased serum glucose, disrupted serum lipoprotein levels, and up-regulated the expression levels of phosphatidylinositol 3-kinase (PI3K)/ phosphoprotein kinase B (p-AKT)/Glucose transporter 4 (GLUT4) proteins in the glucose metabolism pathway. The expression levels of key proteins sterol regulatory element binding protein-1 (SREBP-1)/peroxisome proliferator-activated receptor-γ (PPARγ)/adipose triglyceride lipase (ATGL) in the lipid metabolism signaling pathway were significantly increased. These findings suggest that short term exposure to PS NPs and aPS NPs induces glycolipid metabolism disturbance in mice, which may subsequently awaken the mice to self-regulate the serum levels of various lipoproteins and the expression of related key proteins. Compared with PS NPs, the aPS NPs interfered more strongly with glucose metabolism, and the corresponding self-regulation in mice was also more obvious. These findings not only provide a basis for environmental factors to increase the health risk of NPs but also provided a reference for the selection of test substances for further studies on the toxicity of NPs.

Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis.

OBJECTIVE: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. METHODS: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. RESULTS: A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. CONCLUSION: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy.

Interindividual differences in drug response have always existed in clinical treatment. Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) play an important role in the process of pharmacokinetics. The effects of genetic polymorphism and nuclear receptors on the expression of drug metabolism enzymes and transporters can only explain some individual differences in clinical treatment. Several key ADME genes have been demonstrated to be regulated by epigenetic mechanisms that can potentially affect inter-individual variability in medical treatment. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug response. Among them, the most studied are anti-tumor drugs, followed by anti-tuberculous and anti-platelet drugs. Therefore, we provide an epigenetics perspective on variability in drug response. The review summarizes the correlation between ADME gene expression and DNA methylation, including the exact methylation locations, and focuses on the corresponding drug disposition and effects to illuminate interindividual differences in clinical medication.

Gold nanocluster-based ratiometric fluorescent probe for biosensing of Hg2+ ions in living organisms.

Gold nanoclusters (Au NCs) have become a new alternative to conventional fluorescent probes in biosensing and imaging. Herein, a gold nanocluster-based nanocomplex displaying single-excitation and dual-emission fluorescence property was fabricated by the conjugation of red-emitting glutathione-protected gold nanoclusters (Au-GSH NCs) and green-emitting fluorescein isothiocyanate (FITC) molecules. The inorganic-organic nanocomplex possesses good ratiometric fluorescence sensing ability with one emission peak showing a sensitive fluorescence response towards Hg2+ ions and the other acting as the internal reference. The nanocomplex was demonstrated to have high stability, excellent biocompatibility, high intracellular penetrability and good biological imaging ability. It was employed as a sensitive nanosensor for rapid sensing and imaging of Hg2+ ions in living cells and zebrafish with high contrast.

Rapid degradation of p-arsanilic acid and simultaneous removal of the released arsenic species by Co-Fe@C activated peroxydisulfate process.

In this study, a bimetallic composite catalyst (Co-Fe@C) was fabricated with calcination at high temperature (800 °C) by using Co-MIL-101 (Fe) as the precursor. The characterization results showed that the resulted Co-Fe@C composite mainly consisted of carbon, FeCo alloys, Fe3O4, Co3O4 and FeO, and owned evident magnetism. In addition, the Co-Fe@C was employed to activate the peroxydisulfate (PDS) to degrade a representative organic pollutant (p-arsanilic acid, p-ASA) and the main factors were optimized, which involved 0.2 g L-1 of catalyst dosage, 1.0 g L-1 of PDS dosage and 5.0 of initial pH. Under the optimal condition, Co-Fe@C/PDS system could completely degrade p-ASA (20 mg L-1) in 5 min. In the Co-Fe@C/PDS system, SO4-·, Fe(IV) and ·OH were the main species during p-ASA degradation. Under the attack of these species, p-ASA was first decomposed into phenols and then transformed into the organics acids and finally mineralized into CO2 and H2O through a series of reactions like hydroxylation, dearsenification, deamination and benzene ring opening. Importantly, most of the released inorganic arsenic species (93.40%) could be efficiently adsorbed by the catalyst.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

BACKGROUND: Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES: The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS: Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS: Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2  = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2  = 46%, p < .00001) had significantly higher voriconazole Cmin (µg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2  = 0%, p = .0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2  = 22%, p = .003). Similarly, the Cmin /D (µg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2  = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2  = 0%, p = .003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2  = 0%, p < .00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2  = 50%, p = .005). CONCLUSIONS: Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

A modified method for preparation of fluorescent MantGDP bound CDC42.

Small GTPase cycled between the GDP-bound inactive state and GTP-bound active state, catalyzed by guanine nucleotide exchange factors (GEFs). Guanine nucleotide exchange assay was a direct way to investigate the specificity, activity, and kinetics of GEFs. The N-methylanthraniloyl derivative of GDP (mantGDP), which was bound to small GTPase, served as a substitution for labeled small GTPase involved in bioluminescent, colorimetric, or radioactive methods due to its safety and sensitivity. In this study, we present an economical and efficient approach to prepare qualified mantGDP-bound CDC42, a member of the Rho GTPase family. In our protocol, with a Kd value of 0.048 µM, alkaline phosphatase hydrolysis of CDC42 increased mantGDP binding affinity to CDC42, allowing mant-nucleotide associating onto CDC42 more easily. Only 1.5-fold molar excess of mantGDP was required to prepare mantGDP-bound CDC42 without nonhydrolyzable GTP analog and high performance liquid chromatography. The mantGDP-bound CDC42 was verified to be efficient for measuring the guanine nucleotide exchange activity of VAV2.

The Legionella pneumophila effector WipA disrupts host F-actin polymerisation by hijacking phosphotyrosine signalling.

The major virulence determinant of Legionella pneumophila is the type IVB secretion system (T4BSS), which delivers approximately 330 effector proteins into the host cell to modulate various cellular processes. However, the functions of most effector proteins remain unclear. WipA, an effector, was the first phosphotyrosine phosphatase of Legionella with unknown function. In this study, we found that WipA induced relatively strong growth defects in yeast in a phosphatase activity-dependent manner. Phosphoproteomics data showed that WipA was likely involved into endocytosis, FcγR-mediated phagocytosis, tight junction, and regulation of actin cytoskeleton pathways. Western blotting further confirmed WipA dephosphorylates several proteins associated with actin polymerisation, such as p-N-WASP, p-ARP3, p-ACK1, and p-NCK1. Thus, we hypothesised that WipA targets N-WASP/ARP2/3 complex signalling pathway, leading to disturbance of actin polymerisation. Indeed, we demonstrated that WipA inhibits host F-actin polymerisation by reducing the G-actin to F-actin transition during L. penumophila infection. Furthermore, the intracellular proliferation of wipA/legK2 double mutant was significantly impaired at the late stage of infection, although the absence of WipA does not confer any further effect on actin polymerisation to the legK2 mutant. Collectively, this study provides unique insights into the WipA-mediated regulation of host actin polymerisation and assists us to elucidate the pathogenic mechanisms of L. pnuemophila infection.

Characterization of guanine nucleotide exchange activity of DH domain of human FGD2.

FGD2, a member of FGD family, contains a Dbl homology domain (DH) and two pleckstrin homology domains segregated by a FYVE domain. The DH domain has been deduced to be responsible for guanine nucleotide exchange of CDC42 to activate downstream factors. Our aim was to build a prokaryotic expression system for the DH domain and to examine its guanine nucleotide exchange activity toward CDC42 in vitro. A recombinant vector, which was successfully constructed based on pGEX-6P-1, was employed to express the DH domain of human FGD2 (FGD2-DH) in E. coli BL21 (DE3). Purified FGD2-DH behaved as a homogeneous monomer with an estimated molecular weight that corresponded to the theoretical molecular weight and was predicted to be an α-helix protein by circular dichroism spectroscopy. FGD2-DH displayed weak guanine nucleotide exchange activity in vitro and very weak interactions with CDC42 following glutaraldehyde cross-linking.

Rapid visualized isothermal nucleic acid testing of Vibrio parahaemolyticus by polymerase spiral reaction.

The aim of this study was to develop an effective and specific visual method to rapidly detect and identify Vibrio parahaemolyticus (V. parahaemolyticus) based on the polymerase spiral reaction (PSR). The method utilized only two pairs of primers designed specifically to target the conserved tlh gene sequence of V. parahaemolyticus. Nucleic acid amplification can be achieved under isothermal conditions using DNA polymerase. The reaction could be accomplished in < 40 min with high specificity and sensitivity. The limits of detection of V. parahaemolyticus in purified genomic DNA and pure culture were 300 fg/µL and 2.4 CFU/mL per reaction, respectively, which were 100-fold more sensitive than with conventional PCR. The model food samples showed consistent specificity and sensitivity to the pure bacterial culture. With these encouraging results, it is expected that the novel, effortless and reliable isothermal nucleic acid testing assay developed in this study has potential to be applied to screening for V. parahaemolyticus in seafood samples.

Zwitterionic Design Principle of Nickel(II) Catalysts for Carbonylative Polymerization of Cyclic Ethers.

Zwitterionic structure is necessary for NiII complexes to catalyze carbonylative polymerization (COP) of cyclic ethers. The cationic charge at the NiII center imparts sufficient electrophilicity to the Ni-acyl bond for it to react with cyclic ethers to give an acyl-cyclic ether oxonium intermediate, while the ligand-centered anionic charge ensures that the resultant oxonium cation is ion-paired with the Ni0 nucleophile. The current catalysts give non-alternating copolymers of carbon monoxide and cyclic ethers and are the most effective when both ethylene oxide and tetrahydrofuran are present as the cyclic ether monomers.

Monitoring of Bactrocera dorsalis (Diptera: Tephritidae) resistance to cyantraniliprole in the south of China.

The oriental fruit fly, Bactrocera dorsalis (Hendel), is a globally important economic insect pest that has evolved resistance to various types of insecticides. Cyantraniliprole (DuPont Cyazypyr) is a new anthranilic diamide insecticide registered to control lepidopteran and sucking insects. The susceptibility of field-collected populations of B. dorsalis to cyantraniliprole was assessed via a diet incorporation bioassay in adults. Based on the obtained LC50 values (ranging from 3.29 to 15.83 microg/g), all the testing populations, including ZZ (Fujian province), HH (Yunnan province), JM (Guangdong province), SY (Hainan province), HZ (Zhejiang province), YL (Guangxi province), SH (Shanghai), WH (Hubei province), and CS (Hunan province), were susceptible to cyantraniliprole, with the samples of WH (Hubei province) being the most tolerant (by 4.80-fold). Two (SY, Hainan province; CS, Hunan province) of the nine field-collected populations of B. dorsalis showed a similar susceptibility to cyantraniliprole, while the remaining populations displayed narrow variations in tolerance compared with the laboratory strain. Synergist assays were performed to determine the potential detoxification mechanisms. Piperonyl butoxide showed significant synergism effects in lab, CS, and resistant strain. S,S,S-tributylphorotrithioate and diethyl maleate also showed obvious synergism effects in resistant strain. A 19.44-fold increase in resistance to cyantraniliprole was observed after 14 generations of selection in the laboratory. The present work clarifies the baseline susceptibility and primary mechanisms of B. dorsalis to cyantraniliprole in the south China and established a cyantraniliprole-resistant strain as well. A sound resistance management strategy is also discussed in relation to the risk of susceptibility.

UV-aged polystyrene nanoplastics aggravate intestinal barrier damage by overproduction of ROS.

UV irradiation significantly alters nanoplastics (NPs) physicochemical properties, thus affecting their biological toxicity. This study is the first to assess the influence of virgin and UV-aged polystyrene NPs (v-PS NPs, a-PS NPs) on the intestinal barrier of ICR mice. We found that a-PS NPs can cause more severe intestinal barrier damage compared with v-PS NPs. The reason may be attributed to that a-PS NPs produced more ROS in intestinal tissue. Moreover, the strong oxidizing property of hydroxyl radicals (·OH) generated from the a-PS NPs can damage cell membranes through lipid peroxidation, thereby leading to a low clearance rate of ·OH due to the impaired intestinal tissue function, in turn, causing more ROS to accumulate and inducing severe oxidative damage. This research underscores the crucial role of ·OH in mediating oxidative damage from UV-aged nanoparticles, emphasizing the need to consider environmental factors in assessing NPs toxicity.

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.