Function of serine/arginine-rich splicing factors in hematopoiesis and hematopoietic malignancies.

The serine/arginine-rich splicing factors (SRSFs) play an important role in regulating the alternative splicing of precursor RNA (pre-RNA). During this procedure, introns are removed from the pre-RNA, while the exons are accurately joined together to produce mature mRNA. In addition, SRSFs also involved in DNA replication and transcription, mRNA stability and nuclear export, and protein translation. It is reported that SRSFs participate in hematopoiesis, development, and other important biological process. They are also associated with the development of several diseases, particularly cancers. While the basic physiological functions and the important roles of SRSFs in solid cancer have been extensively reviewed, a comprehensive summary of their significant functions in normal hematopoiesis and hematopoietic malignancies is currently absent. Hence, this review presents a summary of their roles in normal hematopoiesis and hematopoietic malignancies.

Ubiquity of Synthetic Phenolic Antioxidants in Children's Cerebrospinal Fluid from South China: First Evidence for Their Penetration across the Blood-Cerebrospinal Fluid Barrier.

Synthetic phenolic antioxidants (SPAs) and relevant transformation products (TPs) are potentially neurotoxic pollutants to which humans are widely exposed. However, their penetration behavior across the brain barrier and associated exposure to the central nervous system (CNS) remain unknown. This study is the first to investigate a wide range of 30 SPAs and TPs, including emerging SPAs, in matched serum and cerebrospinal fluid (CSF) samples from children in Guangzhou, China. Sixty-two children of either sex aged <14 years with nonbloody CSF and complete clinical information were included. The findings demonstrated the ubiquitous occurrence of many SPAs and TPs, particularly BHT, 2,4-di-tert-butylphenol (DBP), AO 1010, AO 1076, BHT-Q, and BHT-quinol, not only in serum but also in the CSF. Median total concentrations of SPAs and TPs were up to 22.0 and 2.63 ng/mL in serum and 14.5 and 2.11 ng/mL in CSF, respectively. On calculating the penetration efficiencies across the blood-CSF barrier (BCSFB) (RCSF/serum, CCSF/Cserum) for selected SPAs and TPs, their RCSF/serum values (median 0.52-1.41) were highly related to their physicochemical properties, indicating that passive diffusion may be the potential mechanism of BCSFB penetration. In addition, the RCSF/serum values were positively correlated with the barrier permeability index RAlb (AlbuminCSF/Albuminserum), indicating that barrier integrity is an important determinant of BCSFB penetration. Overall, these results will improve our perception of human internal exposure to SPAs and lay a solid foundation for assessing the risk of CNS exposure to various SPAs.

Urinary Metabolites of Polycyclic Aromatic Hydrocarbons of Rural Population in Northwestern China: Oxidative Stress and Health Risk Assessment.

Polycyclic aromatic hydrocarbon (PAH) exposure is suspected to be linked to oxidative damage. Herein, ten PAH human exposure biomarkers [hydroxylated PAH metabolites (OH-PAHs)] and five oxidative stress biomarkers (OSBs) were detected in urine samples collected from participants living in a rural area (n = 181) in Northwestern China. The median molar concentration of ΣOH-PAHs in urine was 47.0 pmol mL-1. The 2-hydroxynaphthalene (2-OHNap; median: 2.21 ng mL-1) was the dominant OH-PAH. The risk assessment of PAH exposure found that hazard index (HI) values were <1, indicating that the PAH exposure of rural people in Jingyuan would not generate significant cumulative risks. Smokers (median: 0.033) obtained higher HI values than nonsmokers (median: 0.015, p < 0.01), suggesting that smokers face a higher health risk from PAH exposure than nonsmokers. Pearson correlation and multivariate linear regression analysis revealed that ΣOH-PAH concentrations were significant factors in increasing the oxidative damage to deoxyribonucleic acid (DNA) (8-hydroxy-2'-deoxyguanosine, 8-OHdG), ribonucleic acid (RNA) (8-oxo-7,8-dihydroguanine, 8-oxoGua), and protein (o, o'-dityrosine, diY) (p < 0.05). Among all PAH metabolites, only 1-hydroxypyrene (1-OHPyr) could positively affect the expression of all five OSBs (p < 0.05), suggesting that urinary 1-OHPyr might be a reliable biomarker for PAH exposure and a useful indicator for assessing the impacts of PAH exposure on oxidative stress. This study is focused on the relation between PAH exposure and oxidative damage and lays a foundation for the study of the health effect mechanism of PAHs.

Environmental exposure to melamine and its derivatives and kidney outcomes in children.

Melamine caused acute nephrotoxicity in a past food adulteration incident, but it is unclear whether and how widespread ambient exposure to melamine and related compounds might affect pediatric kidney health. We assessed cross-sectional associations between childhood exposure to melamine and its derivatives and biomarkers of kidney injury and health and explored potential heterogeneity by sex suggested by sex-dependent differences in renal physiology. We measured melamine and its derivatives ammeline, ammelide, and cyanuric acid (CYA) in spot urine samples collected from 192 children from an urban site (Seattle, WA) and 187 children from a rural site (Yakima, WA) aged 4-8 years in the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) Study. In addition, biomarkers of kidney injury were measured in the same urine samples, including albumin, total protein, KIM-1, NAG, NGAL, and EGF. We utilized linear regressions to examine associations between individual chemical exposures and kidney biomarkers. Interaction terms examined association modification by sex, as well as potential interactions between melamine and CYA. Despite comparable exposures, girls had higher levels of many kidney injury biomarkers compared to boys. A ten-fold higher melamine concentration was associated with a 18% (95% CI: 5.6%, 31%) higher EGF in the full sample, while ten-fold higher melamine was associated with a 76% (14.1%, 173%) higher KIM-1 in boys but not in girls (-10.1% (-40.6%, 36.1%), interaction p = 0.026). Melamine exhibited significant negative interactions with CYA in association with total protein and NAG that appeared to be specific to girls. Our results suggest possible associations between melamine exposure and markers of kidney injury that may be more pronounced in boys. These findings provide novel insights into melamine and related derivative compound health effects at low levels of exposure in children and emphasize the role of sex in mediating the relationship between nephrotoxicant exposure and kidney injury.

Phthalate Biomarkers Composition in Relation to Fatty Liver: Evidence from Epidemiologic and in vivo studies.

Phthalates, classified as environmental endocrine disruptors, pose potential toxicity risks to human health. Metabolic dysfunction-associated fatty liver disease is one of the most widespread liver diseases globally. Compared to studies focusing on metabolic disorders in relation to pollutants exposure, the impact of individual factors such as fatty liver on the in vivo metabolism of pollutants is always overlooked. Therefore, this study measured concentrations and composition of phthalate monoesters (mPAEs) in human urine samples, particularly those from fatty liver patients. Furthermore, we induced fatty liver in male Wistar rats by formulating a high-fat diet for twelve weeks. After administering a single dose of DEHP at 500 mg/kg bw through gavage, we compared the levels of di-2-ethylhexyl phthalate (DEHP), its metabolites (mDEHPs) and three hepatic metabolic enzymes, namely cytochrome P450 enzymes (CYP450), UDP glucuronosyltransferase 1 (UGT1), and carboxylesterase 1 (CarE1), between the normal and fatty liver rat groups. Compared to healthy individuals (n = 75), fatty liver patients (n = 104) exhibited significantly lower urinary concentrations of ∑mPAEs (median: 106 vs. 166 ng/mL), but with a higher proportion of mono-2-ethylhexyl phthalate in ∑mDEHPs (25.7 % vs. 9.9 %) (p < 0.05). In the animal experiment, we found that fatty liver in rats prolonged the elimination half-life of DEHP (24.61 h vs. 18.89 h) and increased the contents of CYP450, CarE1, and UGT1, implying the common but differentiated metabolism of DEHP as excess lipid accumulation in liver cells. This study provides valuable information on how to distinguish populations in biomonitoring studies across a diverse population and in assigning exposure classifications of phthalates or similar chemicals in epidemiologic studies.

Contents of ɑ-dicarbonyl compounds in commercial black tea and affected by the processing.

The species and contents of ɑ-dicarbonyls in commercial black tea were examined, along with the effects of the manufacturing process and drying temperature on the formation of ɑ-dicarbonyls. Ten ɑ-dicarbonyls were quantified in commercial and in-process black tea samples by using UPLC-MS/MS and their derived quinoxalines. The ɑ-dicarbonyls content in commercial black tea decreased significantly (p < 0.05) in the following order: 3-deoxyglucosone > glucosone > 3-deoxypentosone = threosone > galactosone ≥ methylglyoxal = glyoxal ≥ 3-deoxygalactosone = 3-deoxythreosone = diacetyl. Except for 3-deoxyglucosone and 3-deoxygalactosone, a further eight ɑ-dicarbonyls were identified in all manufacturing steps of black tea. Except for the drying step, the rolling and fermenting played important roles in the formation of ɑ-dicarbonyls. The total contents of ɑ-dicarbonyls in black tea infusion ranged from 16.48 to 75.32 µg/g based on our detected ten ɑ-dicarbonyls.

Aromatic amine antioxidants (AAs) and p-phenylenediamines-quinones (PPD-Qs) in e-waste recycling industry park: Occupational exposure and liver X receptors (LXRs) disruption potential.

Recently, evidence of aromatic amine antioxidants (AAs) existence in the dust of the electronic waste (e-waste) dismantling area has been exposed. However, there are limited studies investigating occupational exposure and toxicity associated with AAs and their transformation products (p-phenylenediamines-quinones, i.e., PPD-Qs). In this study, 115 dust and 42 hand wipe samples collected from an e-waste recycling industrial park in central China were analyzed for 19 AAs and 6 PPD-Qs. Notably, the median concentration of ∑6PPD-Qs (1,110 ng/g and 1,970 ng/m2) was significantly higher (p < 0.05, Mann-Whitney U test) than that of ∑6PPDs (147 ng/g and 34.0 ng/m2) in dust and hand wipes. Among the detected analytes, 4-phenylaminodiphenylamine quinone (DPPD-Q) (median: 781 ng/g) and 1,4-Bis(2-naphthylamino) benzene quinone (DNPD-Q) (median: 156 ng/g), were particularly prominent, which were first detected in the e-waste dismantling area. Occupational exposure assessments and nuclear receptor interference ability, conducted through estimated daily intake (EDI) and molecular docking analysis, respectively, indicated significant occupational exposure to PPD-Qs and suggested prioritized Liver X receptors (LXRs) disruption potential of PPDs and PPD-Qs. The study provides the first evidence of considerable levels of AAs and PPD-Qs in the e-waste-related hand wipe samples and underscores the importance of assessing occupational exposure and associated toxicity effects.

Enhancing multiple myeloma staging: a novel cell death risk model approach.

The prognostication of survival trajectories in multiple myeloma (MM) patients presents a substantial clinical challenge. Leveraging transcriptomic and clinical profiles from an expansive cohort of 2,088 MM patients, sourced from the Gene Expression Omnibus and The Cancer Genome Atlas repositories, we applied a sophisticated nested lasso regression technique to construct a prognostic model predicated on 28 gene pairings intrinsic to cell death pathways, thereby deriving a quantifiable risk stratification metric. Employing a threshold of 0.15, we dichotomized the MM samples into discrete high-risk and low-risk categories. Notably, the delineated high-risk cohort exhibited a statistically significant diminution in survival duration, a finding which consistently replicated across both training and external validation datasets. The prognostic acumen of our cell death signature was further corroborated by TIME ROC analyses, with the model demonstrating robust performance, evidenced by AUC metrics consistently surpassing the 0.6 benchmark across the evaluated arrays. Further analytical rigor was applied through multivariate COX regression analyses, which ratified the cell death risk model as an independent prognostic determinant. In an innovative stratagem, we amalgamated this risk stratification with the established International Staging System (ISS), culminating in the genesis of a novel, refined ISS categorization. This tripartite classification system was subjected to comparative analysis against extant prognostic models, whereupon it manifested superior predictive precision, as reflected by an elevated C-index. In summation, our endeavors have yielded a clinically viable gene pairing model predicated on cellular mortality, which, when synthesized with the ISS, engenders an augmented prognostic tool that exhibits pronounced predictive prowess in the context of multiple myeloma.

End-of-life vehicle dismantling activity emits large quantities of phthalates and their alternatives: New insights on environmental sources and co-exposure risks.

Automotive interiors have been identified as significant sources of various chemicals, yet their occupational hazards for end-of-life vehicle (ELV) dismantlers remain poorly characterized. Herein, eight classes of plasticizers, including 11 phthalates esters (PAEs) and 16 non-phthalates esters (NPAEs), were detected in dust samples from inside and outside ELV dismantling workshops. Moreover, indoor dust from ordinary households and university dormitories was compared. The indoor dust from the ELV dismantling workshops contained the highest concentrations of plasticizers (median: 594 µg/g), followed by ordinary households (296 µg/g), university dormitories (186 µg/g), and outdoor dust (157 µg/g). PAEs remained the dominant plasticizers, averaging 11.7-fold higher than their NPAE alternatives. Specifically, diisononyl phthalate and trioctyl trimellitate were notably elevated in workshop dust, being 15.5 and 4.78 times higher, respectively, than in ordinary household dust, potentially indicating their association with ELV dismantling activities. The estimated daily intake of occupational ELV dismantling workers was up to five times higher than that of the general population. Moreover, certain dominant NPAEs demonstrated nuclear receptor interference abilities comparable to typical PAEs, suggesting potential toxic effects. This study is the first to demonstrate that ELV dismantling activities contribute to the co-emission of PAEs and NPAEs, posing a substantial risk of exposure to workers, which warrants further investigation.

The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.