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IntroductionThe balance of trace elements plays an important role in diabetic kidney disease (DKD) patients. However, studies on the differences in urinary trace elements across different DKD stages are scarce. This study aimed to explore the associations between nine essential trace elements and DKD.Research design and methodsThis cross-sectional analysis included 830 diabetic patients. Participants were classified into non-DKD (NDKD) and DKD, the latter was further grouped into mid and end DKD based on estimated glomerular filtration rate (eGFR), and the case and control were matched based on age and sex. The concentration of urinary trace elements was measured with inductively coupled plasma mass spectrometry.ResultsUrinary concentrations of copper (Cu) and manganese (Mn) in DKD patients were significantly higher than that of NDKD patients, whereas that of iron (Fe), cobalt, selenium, and nickel (Ni) of DKD were lower. Positive correlations between urinary Mn/Cu and the risk of mid-stage and end-stage DKD were revealed by conditional logistic regression, while Fe and Ni were negatively associated with the risk of DKD. In mixed effect analyses, no significant trend was found for joint trace element exposure and risk of mid DKD, while negative associations between combined effects of trace elements and the risk of end DKD were observed.ConclusionsThis study revealed different associations between trace elements and the risk of mid and end DKD using both single and mixture effect modeling. The results suggested that the urinary trace element profile might be associated with the progression of DKD, which provides important insights for understanding the pathogenesis of DKD and developing individualized nutritive management strategies.

Perfluorohexane sulfonate (PFHxS) is a frequently detected per- and polyfluoroalkyl substance in most populations, including in individuals who are pregnant, a period critical for early life development. Despite epidemiological evidence of exposure, developmental toxicity, particularly at realistic human exposures, remains understudied. We evaluated the effect of gestational exposure to human-relevant body burden of PFHxS on fetal and placental development and explored mechanisms of action combining alternative splicing (AS) and gene expression (GE) analyses. Pregnant ICR mice were exposed to 0, 0.03, and from gestational day 7 to day 17 via oral gavage. Upon euthanasia, PFHxS distribution was measured using liquid chromatography-tandem mass spectrometry. Maternal and fetal phenotypes were recorded, and histopathology was examined for placenta impairment. Multiomics was adopted by combining AS and GE analyses to unveil disruptions in mRNA quality and quantity. The key metabolite transporters were validated by quantitative real-time PCR (qRT-PCR) for quantification and three-dimensional (3D) structural simulation by AlphaFold2. Targeted metabolomics based on liquid chromatography-tandem mass spectrometry was used to detect amino acid and amides levels in the placenta. Pups developmentally exposed to PFHxS exhibited signs of intrauterine growth restriction (IUGR), characterized by smaller fetal weight and body length ( ) compared to control mice. PFHxS concentration in maternal plasma was . PFHxS trans-placenta distribution suggested dose-dependent transfer through placental barrier. Histopathology of placenta of exposed dams showed placental dysplasia, manifested with an attenuated labyrinthine layer area and deescalated blood sinus counts and placental vascular development index marker CD34. Combined GE and AS analyses pinpointed differences in genes associated with key biological processes of placental development, proliferation, metabolism, and transport in placenta of exposed dams compared to that of control dams. Further detection of placental key transporter gene expression, protein structure simulation, and amino acid and amide metabolites levels suggested that PFHxS exposure during pregnancy led to impairment of placental amino acid transportation. The findings from this study suggest that exposure to human-relevant very-low-dose PFHxS during pregnancy in mice caused IUGR, likely via downregulating of placental amino acid transporters, thereby impairing placental amino acid transportation, resulting in impairment of placental development. Our findings confirm epidemiological findings and call for future attention on the health risk of this persistent yet ubiquitous chemical in the early developmental stage and provide a new approach for understanding gene expression from both quantitative and qualitative omics approaches in toxicological studies. https://doi.org/10.1289/EHP13217.

Background Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), significantly impacting the global burden of diabetes mellitus (DM). Testosterone has been implicated in the pathophysiology of DN, yet its specific role remains unclear. Methods This retrospective cohort study analyzed 347 male patients with type 2 diabetes mellitus (T2DM), including 165 with DN and 182 without DN, to explore the relationship between plasma testosterone levels and DN progression. Clinical and biochemical data were collected, and univariate, multivariate regression, and logistic regression analyses were performed. A nomogram predictive model was developed incorporating DN risk factors. Results No significant difference in plasma testosterone levels was observed between DN and DM patients. However, testosterone levels varied significantly across DN stages, peaking in stage G5. Multivariate analysis identified testosterone (OR = 3.13, 95% CI [1.25–8.87]) as an independent risk predictor for poor DN prognosis. The predictive model combining Cyc, testosterone, Age, SBP, DBP, UACR, and demonstrated excellent prediction for the adverse outcomes in DN. (AUC = 0.923, 95% CI: 0.891–1). Conclusion Testosterone plays critical roles in DN progression and prognosis. The developed nomogram offers a practical tool for risk stratification and management of male DN patients. Further research is needed to validate these findings and elucidate the mechanistic pathways linking testosterone to DN progression. Clinical trial number No applicable.

Background Inhibition of inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor signaling proteins associated with endoplasmic reticulum (ER) stress, has been shown to alleviate brain injury and improve neurological behavior in a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. However, there is no information about the role of IRE1α inhibitor as well as its molecular mechanisms in preventing neuronal pyroptosis induced by NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome. In the present study, we hypothesized that IRE1α can degrade microRNA-125-b-2-3p (miR-125-b-2-3p) and activate NLRP1/caspased-1 pathway, and subsequently promote neuronal pyroptosis in HIE rat model. Methods Ten-day old unsexed rat pups were subjected to hypoxia-ischemia (HI) injury, and the inhibitor of IRE1α, STF083010, was administered intranasally at 1 h after HI induction. AntimiR-125 or NLRP1 activation CRISPR was administered by intracerebroventricular (i.c.v) injection at 24 h before HI induction. Immunofluorescence staining, western blot analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), brain infarct volume measurement, neurological function tests, and Fluoro-Jade C staining were performed. Results Endogenous phosphorylated IRE1α (p-IRE1α), NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were increased and miR-125-b-2-3p was decreased in HIE rat model. STF083010 administration significantly upregulated the expression of miR-125-b-2-3p, reduced the infarct volume, improved neurobehavioral outcomes and downregulated the protein expression of NLRP1, cleaved caspase-1, IL-1β and IL-18. The protective effects of STF083010 were reversed by antimiR-125 or NLRP1 activation CRISPR. Conclusions IRE1α inhibitor, STF083010, reduced neuronal pyroptosis at least in part via miR-125/NLRP1/caspase-1 signaling pathway after HI. Graphical Abstract

The majority of circular RNAs (circRNAs) spliced from coding genes contain open reading frames (ORFs) and thus, have protein coding potential. However, it remains unknown what regulates the biogenesis of these ORF-containing circRNAs, whether they are actually translated into proteins and what functions they play in specific physiological contexts. Here, we report that a large number of circRNAs are synthesized with increasing abundance when late pachytene spermatocytes develop into round and then elongating spermatids during murine spermatogenesis. For a subset of circRNAs, the back splicing appears to occur mostly at m 6 A-enriched sites, which are usually located around the start and stop codons in linear mRNAs. Consequently, approximately a half of these male germ cell circRNAs contain large ORFs with m 6 A-modified start codons in their junctions, features that have been recently shown to be associated with protein-coding potential. Hundreds of peptides encoded by the junction sequences of these circRNAs were detected using liquid chromatography coupled with mass spectrometry, suggesting that these circRNAs can indeed be translated into proteins in both developing (spermatocytes and spermatids) and mature (spermatozoa) male germ cells. The present study discovered not only a novel role of m 6 A in the biogenesis of coding circRNAs, but also a potential mechanism to ensure stable and long-lasting protein production in the absence of linear mRNAs, i.e., through production of circRNAs containing large ORFs and m 6 A-modified start codons in junction sequences.

Epigenetic modifications of histones are associated with development and pathogenesis of disease. Existing approaches cannot provide insights into long-range interactions and represent the average chromatin state. Here we describe BIND&MODIFY, a method using long-read sequencing for profiling histone modifications and transcription factors on individual DNA fibers. We use recombinant fused protein A-M.EcoGII to tether methyltransferase M.EcoGII to protein binding sites to label neighboring regions by methylation. Aggregated BIND&MODIFY signal matches bulk ChIP-seq and CUT&TAG. BIND&MODIFY can simultaneously measure histone modification status, transcription factor binding, and CpG 5mC methylation at single-molecule resolution and also quantifies correlation between local and distal elements.

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.

Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in prostate cancer (PCa). Although branched-chain amino acid (BCAA) metabolism is implicated in cancer biology, its specific role in PARPi resistance remains unclear. This study aims to investigate how BCAA metabolism contributes to PARPi resistance in PCa. Methods We compared BCAA and Branched-Chain Amino Acid Aminotransferase 2 (BCAT2) levels between PARPi-resistant and PARPi-sensitive cell lines and assessed their clinical relevance. Functional studies were conducted in vitro and in vivo using cell and mouse models. Mechanistic assays, including RNA sequencing, metabolomics, RNA-binding protein immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and Cleavage Under Targets and Tagmentation (CUT&Tag), were used to delineate BCAT2-mediated PARPi resistance. Results BCAT2 expression correlated with PARPi resistance in PCa, and increased BCAA/BCAT2 levels in PARPi-resistant tissues were associated with reduced patient survival. Mechanistically, the DNA-binding domain (DBD) of PARP1 directly bound BCAT2 mRNA and regulated its stability; PARPi-induced PARP1 trapping weakened this interaction, increased BCAT2 expression, and promoted resistance. Transcriptomic and energy-metabolism analyses indicated that BCAT2 enhanced ABCG1 transcription by augmenting glycolysis and lactate secretion, thereby increasing histone H3K18la lactylation. These findings support a PARP1–BCAT2–ABCG1 axis in PARPi resistance. Combining a BCAT2 inhibitor with PARPi produced synergistic effects in cell line–derived xenografts (CDXs) and patient-derived organoids (PDOs). Conclusion The PARP1–BCAT2/H3K18la–ABCG1 axis drives PARPi resistance in PCa. Targeted BCAT2 inhibition may enhance the therapeutic efficacy of PARPi.

Background Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a germinal matrix hemorrhage (GMH) rat model. Methods One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Results Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Conclusions Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

As the genome is organized into a three-dimensional structure in intracellular space, epigenomic information also has a complex spatial arrangement. However, most epigenetic studies describe locations of methylation marks, chromatin accessibility regions, and histone modifications in the horizontal dimension. Proper spatial epigenomic information has rarely been obtained. In this study, we designed spatial chromatin accessibility sequencing (SCA-seq) to resolve the genome conformation by capturing the epigenetic information in single-molecular resolution while simultaneously resolving the genome conformation. Using SCA-seq, we are able to examine the spatial interaction of chromatin accessibility (e.g. enhancer–promoter contacts), CpG island methylation, and spatial insulating functions of the CCCTC-binding factor. We demonstrate that SCA-seq paves the way to explore the mechanism of epigenetic interactions and extends our knowledge in 3D packaging of DNA in the nucleus.