The relationship between sarcopenia and metabolic dysfunction-associated fatty liver disease among the young and middle-aged populations.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a new term for diagnosing fatty liver disease, which is considered to be a multi-systemic disease with multiple extrahepatic manifestations, including sarcopenia. The link between sarcopenia and MAFLD remains uncertain, especially among young and middle-aged adults. Thus, we examined the relationship between MAFLD and sarcopenia in young and middle-aged individuals in this study. METHODS: A total of 2214 individuals with laboratory tests, dual-energy X-ray absorptiometry and ultrasound transient elastography from NHANES 2017-2018 were selected for this study. MAFLD was diagnosed as fatty liver disease with any one of the situations: overweight/obesity, diabetes mellitus, presence of metabolic dysregulation. Sarcopenia was defined by appendicular lean mass adjusted for body mass index (BMI). Multivariable logistic regression and restricted cubic spline (RCS) model were applied to explore the relationship between MAFLD and sarcopenia, and the mediation analyses were also conducted. Moreover, subgroup analyses stratified by BMI and lifestyles were done. RESULTS: The prevalence of MAFLD was 47.85%, and nearly 8.05% of participants had sarcopenia. The prevalence of sarcopenia was higher in participants with MAFLD (12.75%; 95% CI 10.18-15.31%) than in the non-MAFLD (3.73%; 95% CI 2.16-5.31%). MAFLD was significantly positively associated with sarcopenia after adjustments [OR = 2.87 (95% CI: 1.62-5.09)]. Moreover, significant positive associations were observed between liver fibrosis and sarcopenia prevalence in MAFLD patients (OR = 2.16; 95% CI 1.13-4.15). The RCS curve revealed that MAFLD was linearly associated with sarcopenia. The relationship between the MAFLD and sarcopenia were mediated by C-reactive protein (mediation proportion: 15.9%) and high-density lipoprotein cholesterol (mediation proportion: 18.9%). Subgroup analyses confirmed the association between MAFLD and sarcopenia differed in different lifestyle groups. CONCLUSIONS: Both MAFLD prevalence and severity was significantly associated with sarcopenia. Thus, clinicians should advise comorbidity screening and lifestyle changes to young and middle-aged patients.

EISA-EXPOSOME: One Highly Sensitive and Autonomous Exposomic Platform with Enhanced in-Source Fragmentation/Annotation.

Lacking a highly sensitive exposome screening technique is one of the biggest challenges in moving exposomic research forward. Enhanced in-source fragmentation/annotation (EISA) has been developed to facilitate molecular identification in untargeted metabolomics and proteomics. In this work, with a mixture of 50 pesticides at three concentration levels (20, 4, and 0.8 ppb), we investigated the analytical performance of the EISA technique over the well-accepted targeted MS/MS mode (TMM) in the detection and identification of chemicals at low levels using a quadrupole time-of-flight (qTOF) instrument. Compared with the TMM method, the EISA technique can recognize additional 1, 20, and 23 chemicals, respectively, at the three concentration levels (20, 4, and 0.8 ppb, respectively) investigated. At the 0.8 ppb level, intensities of precursor ions and fragments observed using the EISA technique are 30-1,154 and 3-80 times higher, respectively, than those observed at the TMM mode. A higher matched fragment ratio (MFR) between the EISA technique and the TMM method was recognized for most chemicals. We further developed a chemical annotation informatics algorithm, EISA-EXPOSOME, which can automatically search each precursor ion (m/z) in the MS/MS library against the EISA MS1 spectra. This algorithm then calculated a weighted score to rank the candidate features by comparing the experimental fragment spectra to those in the library. The peak intensity, zigzag index, and retention time prediction model as well as the peak correlation coefficient were further adopted in the algorithm to filter false positives. The performance of EISA-EXPOSOME was demonstrated using a pooled dust extract with a pesticide mixture (n = 200) spiked at 5 ppb. One urine sample spiked with a contaminant mixture (n = 50) at the 5 ppb level was also used for the validation of the pipeline. Proof-of-principal application of EISA-EXPOSOME in the real sample was further evaluated on the pooled dust sample with a modified T3DB database (n = 1650). Our results show that the EISA-EXPOSOME algorithm can remarkably improve the detection and annotation coverage at trace levels beyond the traditional approach as well as facilitate the high throughput screening of suspected chemicals.

CIL-ExPMRM: An Ultrasensitive Chemical Isotope Labeling Assisted Pseudo-MRM Platform to Accelerate Exposomic Suspect Screening.

Exposome is the future of next-generation environmental health to establish the association between environmental exposure and diseases. However, due to low concentrations of exposure chemicals, exposome has been hampered by lacking an effective analytical platform to characterize its composition. In this study, by combining the benefit of chemical isotope labeling and pseudo-multiple reaction monitoring (CIL-pseudo-MRM), we have developed one highly sensitive and high-throughput platform (CIL-ExPMRM) by isotope labeling urinary exposure biomarkers. Dansyl chloride (DnsCl), N-methylphenylethylamine (MPEA), and their isotope-labeled forms were used to derivatize polar hydroxyl and carboxyl compounds, respectively. We have programmed a series of scripts to optimize MRM transition parameters, curate the MRM database (>70,000 compounds), predict accurate retention time (RT), and automize dynamic MRMs. This was followed by an automated MRM peak assignment, peak alignment, and statistical analysis. A computational pipeline was eventually incorporated into a user-friendly website interface, named CIL-ExPMRM (http://www.exposomemrm.com/). The performance of this platform has been validated with a relatively low false positive rate (10.7%) across instrumental platforms. CIL-ExPMRM has systematically overcome key bottlenecks of exposome studies to some extent and outperforms previous methods due to its independence of MS/MS availability, accurate RT prediction, and collision energy optimization, as well as the ultrasensitivity and automated robust intensity-based quantification. Overall, CIL-ExPMRM has great potential to advance the exposomic studies based on urinary biomarkers.

Liquid Crystal Monomer: A Potential PPARγ Antagonist.

Liquid crystal monomers (LCMs) are a large family of artificial ingredients that have been widely used in global liquid crystal display (LCD) industries. As a major constituent in LCDs as well as the end products of e-waste dismantling, LCMs are of growing research interest with regard to their environmental occurrences and biochemical consequences. Many studies have analyzed LCMs in multiple environmental matrices, yet limited research has investigated the toxic effects upon exposure to them. In this study, we combined in silico simulation and in vitro assay validation along with omics integration analysis to achieve a comprehensive toxicity elucidation as well as a systematic mechanism interpretation of LCMs for the first time. Briefly, the high-throughput virtual screen and reporter gene assay revealed that peroxisome proliferator-activated receptor gamma (PPARγ) was significantly antagonized by certain LCMs. Besides, LCMs induced global metabolome and transcriptome dysregulation in HK2 cells. Notably, fatty acid ß-oxidation was conspicuously dysregulated, which might be mediated through multiple pathways (IL-17, TNF, and NF-kB), whereas the activation of AMPK and ligand-dependent PPARγ antagonism may play particularly important parts. This study illustrated LCMs as a potential PPARγ antagonist and explored their toxicological mode of action on the trans-omics level, which provided an insightful overview in future chemical risk assessment.

Development and validation of a new nomogram to screen for MAFLD.

BACKGROUND AND AIM: Metabolic dysfunction-associated fatty liver disease (MAFLD) poses significant health and economic burdens on all nations. Thus, identifying patients at risk early and managing them appropriately is essential. This study's goal was to develop a new predictive model for MAFLD. Additionally, to improve the new model's clinical utility, researchers limited the variables to readily available simple clinical and laboratory measures. METHODS: Based on the National Health and Nutrition Examination Survey (NHANES) cycle 2017-2020.3, the study was a retrospective cross-sectional study involving 7300 participants. By least absolute shrinkage and selection operator (LASSO) regression, significant indicators independently associated with MAFLD were identified, and a predictive model called the MAFLD prediction nomogram (MPN) was developed. The study then compared the MPN with six existing predictive models for MAFLD. The model was evaluated by measuring the area under receiver operating characteristic curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) curve. RESULTS: In this study, researchers identified nine predictors from 33 variables, including age, race, arm circumference (AC), waist circumference (WC), body mass index (BMI), alanine aminotransferase (ALT)-to-aspartate aminotransferase (AST) ratio, triglyceride-glucose index (TyG), hypertension, and diabetes. The diagnostic accuracy of the MPN for MAFLD was significantly better than that of the other six existing models in both the training and validation cohorts (AUC 0.868, 95% confidence interval (CI) 0.858-0.877, and AUC 0.863, 95% CI 0.848-0.878, respectively). The MPN showed a higher net benefit than the other existing models. CONCLUSIONS: This nonimaging-assisted nomogram based on demographics, laboratory factors, anthropometrics, and comorbidities better predicted MAFLD than the other six existing predictive models. Using this model, the general population with MAFLD can be assessed rapidly.

Plastic Additives in Ambient Fine Particulate Matter in the Pearl River Delta, China: High-Throughput Characterization and Health Implications.

Elucidation of the chemical components of airborne fine particulate matter (PM2.5) facilitates the characterization of atmospheric contamination sources and associated human exposure risks. In the present study, we employed a high-throughput analytical approach to investigate the abundance and distribution of 163 plastic additives in ambient PM2.5 collected from 94 different sites across the Pearl River Delta region, China. These chemicals are from six categories, including organophosphate esters (OPEs), phthalate esters (PAEs), PAE replacements, bisphenol analogues, UV stabilizers, and antioxidants. Ninety-three of them exhibited a detection frequency greater than 50% in PM2.5, while the combined concentrations of target plastic additives ranged from 610 to 49,400 µg/g (median: 3500 µg/g) across sites. By category, concentrations of PAEs (median: 2710 µg/g) were one to three orders of magnitude greater than those of other groups, followed by PAE replacements (540 µg/g) and OPEs (76.2 µg/g). Chemical-dependent exposure risks to PM2.5-bound plastic additives were characterized via the estimated daily intake and hazard quotient (HQ) approaches, which resulted in two different risk prioritization systems. Although the HQ approach suggested no or very low health concerns when considering individual chemicals, the complexity of co-concurrent chemicals in PM2.5 raises the concern on potential health risks from exposure to airborne particles and a cocktail of chemical components.

Triphenyl Phosphate at Environmental Levels Retarded Ovary Development and Reduced Egg Production in Japanese Medaka (Oryzias latipes).

Since triphenyl phosphate (TPhP) elicits both antiestrogenic activities via blocking the estrogen receptor (ER) and estrogenic activity by elevating 17ß-estradiol (17ß-E2) synthesis, its adverse effect on female reproduction is uncertain. In this study, we exposed Japanese medaka to TPhP at 131, 363, and 1773 ng/L for 100 days following hatching. TPhP significantly induced ovary retardation in all exposure groups (incidence: from 11.9 to 37.8%) and reduced egg production by 38.9 and 50.9% in the 363 and 1773 ng/L exposure groups, respectively. Vitellogenin (vtg) transcription was significantly downregulated by 35.4-57.4% after TPhP exposure, explaining the ovary retardation. Considering that 17ß-E2 was only significantly decreased in the 1773 ng/L exposure group, ER antagonism could be the dominant contributor to the inhibition of vtg transcription and female reproductive toxicity of TPhP. As 4-hydroxyphenyl diphenyl phosphate, a metabolite of TPhP, was detected in livers with similar concentration [68.4-1237 ng/g lipid weight (lw)] to that of TPhP (485-1594 ng/g lw) and elicited medaka ER antagonistic activity (50% inhibitory concentration = 78.1 µM), TPhP and its metabolite should both contribute to the reproductive inhibition. We demonstrate that TPhP at environmentally relevant concentrations is toxic to female reproduction, which poses an ecological risk to wild fish at the population level.

Angiotensin II type 1 receptor blockers prevent aortic arterial stiffness in elderly patients with hypertension.

Backgrounds and aims: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of ARBs in aged patients with essential hypertension are not entirely investigated. Methods: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. Results: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared to patients without essential hypertension. In correlation analysis, PWV was associated positively with age, hypertension duration, and carotid atherosclerosis. However, there was no relationship between PWV and gender in aged patients with essential hypertension. In a perspective study, 6-12 months administration of ARBs (losartan, 50 mg/day; telmisartan, 40 mg/day; valsartan 80 mg/day; irbesartan, 150 mg/day) remarkably reduced PWV in aged patients with essential hypertension. Regression analyses of multiple factors indicated that the effects of ARBs on arterial stiffness were not associated with the reduction of blood pressure. Conclusion: ARB treatment is a negative risk factor of arterial stiffness in aged patients with essential hypertension.

Vitamin B6 prevents isocarbophos-induced vascular dementia in rats through N-methyl-D-aspartate receptor signaling.

BACKGROUND: We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown. METHODS: The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test. RESULTS: Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus. CONCLUSION: Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo.

BACKGROUND: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. METHODS: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. RESULTS: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. CONCLUSIONS: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.

Organophosphorus Flame Retardants in Pregnant Women and Their Transfer to Chorionic Villi.

The potential for prenatal exposure has recently raised concerns over the health risks of endocrine disruptors; however, knowledge about human prenatal exposure to organophosphorus flame retardants (OPFRs) is lacking. In this study, 2-ethylhexyl diphenyl phosphate (EHDPP), tributyl phosphate (TBP), triphenyl phosphate (TPHP), and tris(2-chloroethyl) phosphate (TCEP) were detected in the majority of chorionic villus samples, with median concentrations of 13.6, 18.8, 11.1, and 0.51 ng/g of dry weight (dw), respectively, significantly higher than those in the matching maternal decidua samples (5.96, 10.8, 1.44, and 0.26 ng/g of dw, respectively). The ratios of concentrations in chorionic villi (containing embryos) to those in maternal deciduae (CMRs) were 4.17, 3.82, 2.81, and 2.00 for EHDPP, TPHP, TBP, and TCEP, respectively, which correlated with their log Kow values (p = 0.003). The results of transthyretin (TTR) binding assays indicated that the stronger the binding ability to TTR, the higher the CMRs. The median concentrations of the metabolites diphenyl phosphate (DPHP), dibutyl phosphate (DBP), and bis(2-chloroethyl) phosphate (BCEP) were 4.11, 429, and 157 ng/g of dw in chorionic villi, higher than those in deciduae (1.64, 181, and 25.4 ng/g of dw, respectively). The ratios of DPHP/TPHP and DPHP/EHDPP were 0.20 and 0.43 in chorionic villi and 1.24 and 2.03 in deciduae, respectively, much lower than those of DBP/TBP and BCEP/TCEP (20.9 and 165.6 in chorionic villi and 13.1 and 35.3 in deciduae, respectively), suggesting that the difference in metabolism between the deciduae and chorionic villi would affect their maternal transfer.

Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step-down, step-through and morris water maze. Long-term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM-1 and VCAM-1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos-treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction.

Levels of Blood Organophosphorus Flame Retardants and Association with Changes in Human Sphingolipid Homeostasis.

While a recent toxicological study has shown that organophosphorus flame retardants (OPFRs) may disrupt sphingolipid homeostasis, epidemiologic evidence is currently lacking. In this study, a total of 257 participants were recruited from Shenzhen, China. Eleven OPFRs were for the first time simultaneously determined in the human blood samples by ultraperformance liquid chromatography and tandem mass spectrometry. Six OPFRs, tributyl phosphate (TNBP), 2-ethylhexyl diphenyl phosphate (EHDPP), tris(2-chloroisopropyl) phosphate (TCIPP), tris(2-butoxyethyl) phosphate (TBOEP), triethyl phosphate (TEP), and TPHP, were detectable in at least 90% of participants, with median concentrations of 37.8, 1.22, 0.71, 0.54, 0.49, and 0.43 ng/mL, respectively. Sphingomyelin (SM) levels in the highest quartile of EHDPP, TPHP, TNBP, TBOEP, TEP, and TCIPP were 45.3% [95% confidence interval; 38.1%, 53.0%], 51.9% (45.5%, 58.6%), 153.6% (145.1%, 162.3%), 20.6% (14.5%, 27.0%), 59.0% (52.1%, 66.2%), and 62.8% (55.2%, 70.6%) higher than those in the lowest quartile, respectively, after adjusting for covariates. Sphingosine 1-phosphate (S1P) levels in the highest quartile of EHDPP, TPHP, and TNBP were 36% (-39%, -33%), 16% (-19%, -14%), and 36% (-38%, -33%) lower than those in the lowest quartile, respectively. A similar pattern emerged when exposures were modeled continuously. We for the first time found the associations between OPFRs and changes in human sphingolipid homeostasis.

Occurrence and Maternal Transfer of Chlorinated Bisphenol A and Nonylphenol in Pregnant Women and Their Matching Embryos.

Prenatal exposure has recently raised concerns over the health risks of endocrine disruptors; however, little is known about their extent and the mechanisms of maternal transfer in the embryo stage. In this study, bisphenol A (BPA), nonylphenol (NP), and their six chlorinated derivatives were quantified in decidua samples from 25 pregnant women and their matching embryos, which were collected as chorionic villi samples. Monochloro-BPA (MCBPA), dichloro-BPA (DCBPA), monochloro-NP (MCNP), and dichloro-NP (DCNP) were detected in over 70% of the decidua or chorionic villi samples, while BPA, NP, trichloro-BPA (TCBPA), and tetrachloro-BPA (TeCBPA) were detected in less than half. The geometric mean (GM) concentrations of MCBPA, DCBPA, NP, MCNP, and DCNP in chorionic villi samples were 0.13, 0.17, 5.33, 4.52, and 2.44 ng/g dw, respectively, higher than those in maternal decidua samples, which were 0.10, 0.12, 3.27, 1.85, and 0.74 ng/g dw, respectively, while the GM concentration of BPA was lower in chorionic villi samples (0.09 ng/g dw) than in maternal decidua (0.10 ng/g dw). The ratios of the average lipid-normalized concentrations of chemicals in chorionic villi to those in maternal decidua (EMR) were calculated to be 1.53 for MCNP and 2.38 for DCNP, while those of BPA, MCBPA, DCBPA, and NP were lower than 1 (0.39-0.97). Such obvious difference in maternal transfer is probably due to their different affinities to plasma proteins, as exemplified by the correlation between EMR and the binding affinities to T4 transport proteins (TTR). This is the first report on the occurrence and maternal transfer of chlorinated derivatives of BPA and NP in human embryos and decidua.

Ubiquitous occurrence of chlorinated byproducts of bisphenol A and nonylphenol in bleached food contacting papers and their implications for human exposure.

The occurrence of bisphenol A (BPA), nonylphenol (NP), and their six chlorinated byproducts were investigated in 74 food contacting papers (FCPs) from China, the U.S.A., Japan, and Europe using a sensitive dansylation LC-MS/MS method. BPA (

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling.

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 µM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

Purpose: The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Methods: Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. Results: We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Conclusion: Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

Agricultural film-derived microplastics elevate the potential risk of pesticides in soil ecosystem: The inhibited leaching by altering soil pore.

The residue of mulch film is a crucial source of microplastics (MPs) in agricultural fields. The effects of mulch film-derived MPs on the environmental behavior of pesticides in agriculture remain unclear. In the present study, the effects of MPs of different sizes (5 mm, 1 mm, 30 µm, and 0.3 µm) at environmentally relevant concentrations on pesticide transport were evaluated, and the mechanism was explored with respect to adsorption and pore structure using fluorescence visualization, the extended Derjaguin-Landau-Verwey-Overbeek model, and microcomputed tomography. MPs were found to be retained in the soil due to size limitation, pore capture, and surface adhesion. The presence of mm-sized MPs (5 and 1 mm) at a concentration of 0.25 % inhibited the leaching behavior of atrazine, metolachlor, and tebuconazole. MPs did not significantly alter the pesticide adsorption ability of the soil. The reduced leaching originated from the impact of MPs on soil pore structure. Specifically, the porosity increased by 16.2-25.0 %, and the connectivity decreased by 34.5 %. These results demonstrate that mm-sized MPs inhibit pesticide leaching by obstructing the pores and altering the transport pathways, thereby potentially elevating environmental risks, particularly to the soil ecosystem.

Systematic health risks assessment of chiral fungicide famoxadone: Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior.

Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.

Sodium butyrate alleviates right ventricular hypertrophy in pulmonary arterial hypertension by inhibiting H19 and affecting the activation of let-7g-5p/IGF1 receptor/ERK.

Pulmonary arterial hypertension (PAH) is a complex and fatal cardio-pulmonary vascular disease. Decompensated right ventricular hypertrophy (RVH) caused by cardiomyocyte hypertrophy often leads to fatal heart failure, the leading cause of mortality among patients. Sodium butyrate (SB), a compound known to reduce cardiac hypertrophy, was examined for its potential effect and the underlying mechanism of SB on PAH-RVH. The in vivo study showed that SB alleviated RVH and cardiac dysfunction, as well as improved life span and survival rate in MCT-PAH rats. The in vivo and in vitro experiments showed that SB could attenuate cardiomyocyte hypertrophy by reversing the expressions of H19, let-7g-5p, insulin-like growth factor 1 receptor (IGF1 receptor), and pERK. H19 inhibition restored the level of let-7g-5p and prevented the overexpression of IGF1 receptor and pERK in hypertrophic cardiomyocytes. In addition, dual luciferase assay revealed that H19 demonstrated significant binding with let-7g-5p, acting as its endogenous RNA. Briefly, SB attenuated PAH-RVH by inhibiting the H19 overexpression, restoring the level of let-7g-5p, and hindering IGF1 receptor/ERK activation.