The role of immunoresponsive gene 1 (IRG1)-itaconate (ITA) in hypertension remains poorly understood. This study aimed to investigate this role and the underlying mechanisms. IRG1 expression and ITA levels were assessed by Western blotting, targeted metabolomics, and ELISA. We employed global Irg1 (mouse gene coding IRG1)-knockout mice, smooth muscle cell (SMC)-specific Irg1 overexpression mice, and mice receiving intraperitoneal ITA injection. Hypertension was induced by angiotensin II (Ang II) infusion. Blood pressure was measured by tail-cuff method and radiotelemetry, while vascular structure and function were evaluated by histology, vascular ring assays, and Western blotting. The target proteins of ITA were identified through thermal proteomic profiling, cellular thermal shift assay, surface plasmon resonance, and molecular docking. IRG1 expression and ITA levels were significantly upregulated in mouse aortas and vascular smooth muscle cells (VSMCs) under hypertensive conditions. Irg1 knockout markedly attenuated Ang II-induced hypertension and vascular remodeling, whereas SMC-specific Irg1 overexpression or exogenous ITA exacerbated these pathological phenotypes. Mechanistically, ITA directly bound to cystathionine gamma-lyase (CTH) at cysteine 229, inhibiting its enzymatic activity and hydrogen sulfide (H2S) production. These findings demonstrate that IRG1-ITA promotes hypertension and vascular remodeling by directly targeting CTH and suppressing H2S production, suggesting a novel therapeutic target.

Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H2S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H2S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary vascular structural remodeling is unknown. In this study, we aimed to test whether H2S donor therapy can reverse the existing PAH in a chronic-hypoxia rat model. Methods: After 3 weeks of hypoxia exposure, rats with established hypoxia-induced pulmonary hypertension (HPH) were randomized to receive either continued hypoxia alone or hypoxia plus the H2S donor NaHS (56 μmol/kg·d, ip) for an additional 6 weeks. Pulmonary artery pressure, pulmonary artery muscularization, and right ventricular hypertrophy were assessed. Furthermore, the cell proliferation (Ki-67 and PCNA), ERK1/2 phosphorylation, and persulfidation of the endothelin type A receptor (ETAR) were examined and detected in rat lung tissues and pulmonary artery smooth muscle cells (PASMCs). Results: H2S therapy effectively reversed established HPH and pulmonary artery structural remodeling, reducing RVSP, mPAP, and the proportion of fully muscularized small pulmonary arteries by 13.8%, 12.0%, and 62.7%, respectively. Moreover, the PAT/PET ratio was normalized to normoxic levels. The right ventricular hypertrophy index decreased by 29.2%. Mechanistically, H2S therapy suppressed PASMC proliferation, reduced ERK1/2 phosphorylation, and enhanced ETAR persulfidation. Furthermore, dithiothreitol-mediated reduction of ETAR persulfidation abrogated these antiproliferative effects of H2S therapy, establishing persulfidation as an obligatory mechanism. Conclusions: H2S donor therapy effectively reverses established HPH and pulmonary vascular structural remodeling by inhibiting PASMC proliferation, which is linked to enhanced ETAR persulfidation. These data provide preclinical proof-of-concept for H2S-based interventions in patients with manifest PAH.

The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H2S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H2S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.

Objective: Vasovagal syncope (VVS) complicated by convulsions or incontinence (atypical VVS) has distinct manifestations prone to misdiagnosis. This study sought to investigate the clinical manifestations and contributing risk factors of atypical VVS in pediatric patients, with the goals of providing a scientific basis for early identification and improving diagnostic accuracy. Methods: We carried out a case-control study focusing on children with a diagnosis of VVS who received inpatient care in the Pediatric Department of Peking University First Hospital from January 2021 to June 2025. Patients who experienced convulsions or incontinence during syncopal episodes were assigned to the atypical VVS group, while those without these symptoms formed the control group. The clinical data of the two groups were compared, and logistic regression analysis was utilized to detect factors associated with atypical VVS. Results: A total of 393 qualified patients were recruited; there were 68 cases in the atypical VVS group and 325 cases in the control group. The age of the first syncopal episode in children with atypical VVS was significantly lower than that in the control group [9.5 (7.0, 12.0) vs. 11.0 (8.0, 13.0) years, p < 0.05]. Additionally, the atypical VVS group showed higher rates of syncope-related trauma (22.1% vs. 9.2%, χ2 = 7.905, p < 0.01), positive syncope-related family history (35.3% vs. 22.8%, χ2 = -4.067, p < 0.05), and syncope triggered by central factors (33.8% vs. 19.7%, χ2 = 5.721, p < 0.05). The Holter monitoring results revealed that the minimum heart rate was significantly reduced in the atypical VVS group [48.0 (44.8, 52.0) vs. 50.0 (47.0, 54.0) beats/min, p < 0.01]. The analysis of heart rate variability (HRV) showed that the index of the percentage of adjacent normal-to-normal interval differences greater than 50 ms [pNN50; 23.4 (16.6, 34.2) vs. 20.1 (13.1, 28.4), p < 0.05)] and the root mean square of successive differences between adjacent normal cycles [rMSSD; 47.5 (41.0, 64.0) vs. 45.0 (36.0, 56.0), p < 0.05)] was significantly higher in the atypical VVS group than in the control group. Two independent factors associated with atypical VVS were detected with multivariate logistic regression: age at the first episode (OR = 0.874, 95% CI 0.802-0.952, p < 0.01) and minimum heart rate (OR = 0.921, 95% CI 0.879-0.965, p < 0.01). Conclusions: Pediatric patients with atypical VVS present with lower minimum heart rate and a higher incidence of syncope induced by central triggers. Compared with children with typical VVS, those with atypical VVS exhibit more pronounced autonomic nervous system imbalance, characterized by enhanced vagal tone. For children with VVS showing these clinical features, careful differential diagnosis, close follow-up, and vigilance against prolonged asystole during syncopal episodes are recommended.

Objective: To investigate long-term prognosis and impact factors in children with vasovagal syncope (VVS) receiving metoprolol therapy. Methods: This retrospective study included children with VVS who underwent metoprolol therapy at the Pediatric Syncope Unit of Peking University First Hospital between January 2012 and November 2023. Baseline demographic data, pre-treatment indices, including head-up tilt test (HUTT) and 24 h Holter monitoring, were collected. All participants received standardized metoprolol therapy for a minimum duration of one month. Follow-up was conducted between June and July 2025, with syncope recurrence as the primary endpoint. Multivariable Cox proportional hazards regression analysis was performed to identify independent impact factors of prognosis and to construct a Prognostic Risk Score (PRS) model. The model's performance was rigorously validated through receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA), and Bootstrap resampling (1000 iterations). Furthermore, children were stratified into high- and low-risk groups based on median PRS values. Kaplan-Meier survival analysis was then performed to assess the model's discriminative efficacy. Results: This study included 97 children diagnosed with VVS. The median duration of metoprolol therapy was 2.5 months (interquartile range [IQR]: 2.0-3.0 months), with a median follow-up period of 59 months (IQR: 25.5-72 months). During follow-up, syncope recurrence was observed in 37 patients, while 60 patients remained symptom-free. COX regression analysis showed that time-domain indices of heart rate variability (HRV), including the standard deviation of all NN intervals (SDNN) and the triangular index (TR), as well as the frequency-domain index of HRV very low frequency (VLF), were relative factors of the long-term prognosis in children with VVS treated with metoprolol. Based on the above three identified factors, the PRS model was calculated as: PRS = 0.03 × SDNN - 0.02 × VLF - 0.1 × TR. ROC showed that the area under the curve (AUC) for discriminative power related to long-term prognosis was 0.808 (p < 0.01). The cumulative recurrence rate of symptoms in the high-risk score group was significantly higher than that in the low-risk score group (p < 0.01). The DCA curve demonstrated the clinical applicability of the model. Bootstrap internal verification indicated high stability, with the bias-corrected and accelerated (Bca) confidence interval (CI) of the C index ranging from 0.71 to 0.89. Conclusions: After metoprolol treatment, 38.1% of children with VVS experienced syncope recurrence during a median follow-up period of 59 months. Baseline HRV index, SDNN, TR, and VLF were identified as factors associated with the long-term prognosis of children with VVS treated with metoprolol. The PRS model based on the above indices demonstrated good value in linking to the individual long-term prognosis.

Background Oral rehydration solution(ORS)is predominantly utilized in the management of hypovolemic postural orthos-tatic tachycardia syndrome(POTS).This study aimed to identify effective indicators and develop models to assess the impact of ORS on pediatric patients diagnosed with POTS. Methods We utilized a retrospective analysis of totally 158 pediatric patients with POTS receiving a 3-month course of ORS treatment.All patients were classified into training set(n=98)and validation set(n=60).Within the training set,univari-ate analysis and binary logistic regression were employed to select candidate predictors.To predict the efficacy of ORS in pediatric patients with POTS,a nomogram model and a scoring model were constructed and demonstrated.Additionally,the predictive ability and calibration performance were evaluated using receiver operating characteristic(ROC)curves,Hosmer-Lemeshow(H-L)goodness of fit test,and calibration plots.Decision curve analysis(DCA)was employed to assess the clinical applicability of the predictive models. Results Body mass index(BMI)z-score,serum chlorine,and urine specific gravity(USG)before treatment were identified as significant and independent predictors of efficacy of ORS in pediatric patients with POTS.Consequently,these indicators were included in the predictive models.A nomogram model was constructed in the training set(AUC=0.87,which yields a sensitivity of 84.5％ and a specificity of 85.0％)and validated in the validation set(the sensitivity,specificity,and accuracy were 87.5％,85％,and 86.7％,respectively).A scoring model was advanced in the training set(AUC=0.88,which yields a sensitivity of 79.3％ and a specificity of 82.5％)and validated in the validation set(the sensitivity,specificity,and accuracy were 77.5％,80.0％,and 78.3％,respectively).The H-L test results indicated a good model fit.The calibration plots and DCA for both models exhibited excellent calibration and satisfactory net benefit. Conclusions Based on pre-treatment BMI z-score,serum chlorine,and USG,a nomogram model and a scoring model were developed and validated.The models can effectively assess the efficacy of ORS in pediatric patients with POTS,offering an accurate and individualized therapeutic strategy.

Background:Endogenous hydrogen sulfide (H2S) and its key generating enzyme, cystathionine β-synthase (CBS), prevent vascular remodeling and damage to target organs during the advancement of hypertension induced by a high-salt diet. Objective:The contribution of the H2S/CBS pathway to high-salt-induced myocardial fibrosis (MF) was explored, with a focus on the mechanistic involvement of hypoxia-inducible factor-1α (HIF-1α). Methods:We used primary rat cardiac fibroblasts stimulated with high-salt medium and an MF model induced by a high-salt diet in Dahl salt-sensitive rats. Sodium hydrosulfide (NaHS), a commonly used H2S donor, was administered in vitro at 100 μmol/L and in vivo at 90 μmol/kg to maintain adequate H2S levels. An HIF-1α stabilizer, dimethyloxalylglycine (DMOG), was used to maintain the HIF-1α protein level. The H2S/CBS pathway was followed using Western blotting and a sulfide-sensitive probe. The extent of MF was examined using histological and immunofluorescence staining techniques, including Sirius red and Masson trichrome. We performed Western blot analysis to measure fibrosis-related protein and HIF-1α protein levels. Results:High-salt exposure reduced H2S production and downregulated CBS protein expression in cardiac fibroblasts both in vitro and in vivo. In vitro, the H2S donor inhibited the activation of cardiac fibroblasts triggered by high-salt conditions, while in vivo, it alleviated MF in salt-sensitive rats. From a mechanistic standpoint, high-salt exposure markedly upregulated HIF-1α expression. However, this increase was reversed by pretreatment with H2S. Furthermore, the HIF-1α stabilizer DMOG blocked the H2S-induced reduction in HIF-1α protein levels and consequently abolished the antifibrotic effect of H2S on cardiac fibroblasts exposed to high-salt conditions. Conclusion:In conclusion, H2S attenuates high-salt-induced MF by suppressing fibroblast activity and collagen synthesis, potentially via downregulation of HIF-1α.

Background: Metabolic dysfunction is a key driver of heart failure (HF) progression. Identifying metabolic hub genes in HF may reveal novel therapeutic targets. Methods: Transcriptomic datasets from HF patients (GEO database) and metabolism-related genes (PathCards) were analyzed. Differentially expressed genes (DEGs) were intersected with metabolism-related genes, followed by the application of the LASSO, Random Forest, and XGBoost algorithms to prioritize hub genes. Candidate genes were validated via WGCNA, an HF mouse model, and plasma metabolomics. Diagnostic performance and metabolic associations were assessed using ROC analysis and ssGSEA. Results: We identified 1115 HF-associated DEGs (701 upregulated, 414 downregulated), with 119 linked to metabolism. The machine learning algorithms prioritized five genes, including SDC2, which was also validated using WGCNA and the mouse HF model. SDC2 mRNA and protein expression levels were markedly elevated in HF and demonstrated strong diagnostic accuracy. ssGSEA revealed the expression of SDC2 was correlated with dysregulated metabolic pathways, including fatty acid biosynthesis and glycerolipid metabolism, which are potentially associated with metabolic alterations in HF. Conclusions: SDC2 emerges as a central regulator bridging metabolic dysfunction and HF pathogenesis, showing potential as a diagnostic biomarker and therapeutic target.

Vascular smooth muscle cell (VSMC) senescence is a critical driver of vascular aging and various age-related cardiovascular diseases. Endogenous sulfur dioxide (SO2), a newly identified key cardiovascular gaseous signaling mediator, accelerates collagen deposition and vascular remodeling in VSMCs when downregulated. However, its effects on VSMC senescence remain unclear. This study focused on exploring the role of endogenous SO2 in VSMC senescence and its associated molecular pathways. Aged mice (24 months old), VSMC-specific aspartate aminotransferase 1 (AAT1) knockout (VSMC-AAT1-KO) mice, D-galactose (D-gal)-treated aorta rings and rat VSMC line A7r5 were used in the experiments. AAT1 expression was detected by Western blot and single-cell RNA sequencing. Senescence markers Tp53, p21Cip/Waf, interleukin 1β (IL-1β) and IL6 expression were detected by Western blot and real-time quantitative PCR. Senescence-associated β-galactosidase (SA-β-gal) activity was detected using SA-β-gal staining kit. Sulphenylation of interferon regulatory factor 1 (IRF1) was detected using a biotin switch assay. The plasmid for mutant IRF1 (mutation of cysteine 83 to serine, C83S) were constructed by site-directed mutagenesis. The expression of AAT1, a key enzyme for SO2 production, was reduced in the aortic tissue of aged mice in comparison to young mice. VSMC-AAT1-KO mice exhibited elevated protein expression of senescence markers Tp53, p21Cip/Waf and γ-H2AX in the aortic tissue. AAT1 knockdown in VSMCs elevated expression of Tp53, p21Cip/Waf, IL-1β and IL-6, and enhanced SA-β-gal activity. While SO2 donor supplementation rescued VSMC senescence caused by AAT1 knockdown and blocked aortic ring aging induced by D-gal. Mechanistically, SO2 promoted IRF1 sulphenylation, inhibited IRF1 nuclear translocation, which in turn downregulated the expression of senescence markers and the activity of SA-β-gal. Furthermore, mutation of C83 in IRF1 abolished SO2-mediated IRF1 sulphenylation and blocked the inhibitory effect of SO2 on VSMC senescence. Reduction of the endogenous SO2/AAT1 pathway played a crucial role in driving VSMC senescence. Endogenous SO2 counteracted VSMC senescence and vascular aging via the sulphenylation of IRF1 at C83.

Background The binding of endothelin-1 (ET-1) to endothelin type A receptor (ETAR) performs a critical action in pulmonary arterial smooth muscle cell (PASMC) proliferation leading to pulmonary vascular structural remodeling. More evidence showed that cystathionine γ-lyase (CSE)-catalyzed endogenous hydrogen sulfide (H2S) was involved in the pathogenesis of cardiovascular diseases. In this study, we aimed to explore the effect of endogenous H2S/CSE pathway on the ET-1/ETAR binding and its underlying mechanisms in the cellular and animal models of PASMC proliferation. Methods and Results Both live cell imaging and ligand-receptor assays revealed that H2S donor, NaHS, inhibited the binding of ET-1/ETAR in human PASMCs (HPASMCs) and HEK-293A cells, along with an inhibition of ET-1-activated HPASMC proliferation. While, an upregulated Ki-67 expression by the pulmonary arteries, a marked pulmonary artery structural remodeling, and an increased pulmonary artery pressure were observed in CSE knockout (CSE-KO) mice with a deficient H2S/CSE pathway compared with those in the wild type (WT) mice. Meanwhile, NaHS rescued the enhanced binding of ET-1 with ETAR and cell proliferation in the CSE-knockdowned HPASMCs. Moreover, the ETAR antagonist BQ123 blocked the enhanced proliferation of CSE-knockdowned HPASMCs. Mechanistically, ETAR persulfidation was reduced in the lung tissues of CSE-KO mice compared to that in WT mice, which could be reversed by NaHS treatment. Similarly, NaHS persulfidated ETAR in HPASMCs and HEK-293A cells. Whereas a thiol reductant dithiothreitol (DTT) reversed the H2S-induced ETAR persulfidation and further blocked the H2S-inhibited binding of ET-1/ETAR and HPASMC proliferation. Furthermore, the mutation of ETAR at cysteine (Cys) 69 abolished the persulfidation of ETAR by H2S, and subsequently blocked the H2S-suppressed ET-1/ETAR binding and HPASMC proliferation. Conclusion Endogenous H2S persulfidated ETAR at Cys69 to inhibit the binding of ET-1 to ETAR, subsequently suppressed PASMC proliferation, and antagonized pulmonary vascular structural remodeling.

Background: This study aimed to develop a predictive model to assess risk factors and prognoses in pediatric patients with dilated cardiomyopathy (DCM). Methods: A total of 233 pediatric patients with DCM who were hospitalized between January 2019 and June 2024 were enrolled. The children were followed up and categorized into two groups: the death/heart transplantation (D/HT) group and the non-D/HT group. Univariate and multivariate analyses identified risk factors. A nomogram model and a scoring system were developed. The performance of these models was evaluated using the H-L test, ROC analysis, and internal validation. Results: The results demonstrated that the age of onset, cardiac functional classification III–IV, moderate-to-severe mitral regurgitation, low voltage in limb leads on an ECG, and the need for vasoactive drugs are independent predictors of D/HT risk in children with DCM. A nomogram model was developed, achieving an AUC of 0.804 (95% CI: 0.734–0.874), a sensitivity of 80.3%, and a specificity of 66.7%. A scoring system was established: 1 point for age of onset, 10 points for cardiac functional classification III–IV, 2.5 points for moderate-to-severe mitral regurgitation, 4 points for low voltage in limb leads on an ECG, 3 points for the need for vasoactive drugs, or 0 points if none of these criteria were met. When the cumulative score was ≥ 13.25, the sensitivity and specificity increased to 68.9% and 73.9%, respectively. Conclusions: We developed both a nomogram and a scoring system model, which are capable of rapidly and accurately predicting the risk of D/HT in children with DCM.

Objectives: The current study aims to investigate the factors associated with the severity of conditions for pediatric cases with postural orthostatic tachycardia syndrome (POTS). Methods: Patients hospitalized and first diagnosed with POTS were retrospectively included and reviewed. The severity of symptoms was evaluated by symptom scores (SSs). Multiple Spearman correlation analyses and multiple linear regression analyses were used to determine factors independently associated with SS. Patients were divided into the mild (SS ≤ P25) and severe (SS ≥ P75) groups to test the distinguishing efficiency of the candidate factors. The efficiency of each independently correlated factor in indicating the condition of children with POTS was assessed by the receiver operating characteristic (ROC) curve. Results: A series of 296 pediatric patients aged 5–17 years suffering from POTS were included. Multiple Spearman correlation analyses and multiple linear regression analyses showed that corrected QT interval dispersion (QTcd) was independently correlated with SS (p < 0.05). QTcd can be used to suggest the severity of POTS symptoms, and the area under the curve (AUC) was 0.986 (95% CI 0.976–0.997). At a threshold of QTcd = 45 ms, the sensitivity and specificity were, respectively, 94.0% and 91.8% for symptom severity indication. Conclusions: In pediatric cases with POTS, QTcd was positively correlated with their symptom severity and exhibited a strong indicative value. A QTcd of 45 ms was a valid cut-off value for indicating symptom severity.

Protein S-persulfidation, a post-translational modification mediated by hydrogen sulfide (H2S), plays an essential role in regulating protein function. However, current profiling methods, mainly based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), tend to detect abundant proteins and often miss low-abundance but important regulators like transcription factors (TFs). To better understand the S-persulfidation landscape, we integrated datasets from three species—Homo sapiens, Mus musculus, and Arabidopsis thaliana—and found that TFs are strikingly underrepresented. To address this gap, we applied oxidative proteomics data from the Oximouse database, which reflects age-related redox changes, and identified hepatocyte nuclear factor 1α (HNF1α) as a candidate S-persulfidated TF. We confirmed that H2S induces S-persulfidation at Cys241 of HNF1α, disrupting its DNA binding through structural remodeling. This modification reduced PCSK9 expression, improved lipid profiles, and alleviated atherosclerosis in mice. Our study presents a cross-species strategy to uncover functional S-persulfidation targets and reveals a redox-based transcriptional mechanism involved in lipid metabolism and cardiovascular protection.

M1 macrophage polarization plays a pivotal role in inflammation-related diseases. However, the endogenous regulatory factors and mechanisms underlying M1 macrophage polarization have not been entirely clarified. This study aimed to explore whether endogenous sulfur dioxide (SO2) is involved in M1 macrophage polarization and its mechanism. In the study, we found that the endogenous SO2/aspartate aminotransferase1 (AAT1) pathway was downregulated during M1 polarization of macrophages induced by lipopolysaccharide (LPS) stimulation, and supplementation with SO2 donors or AAT1 overexpression restored SO2 content, suppressed protein expression of inducible nitric oxide synthase, restrained mRNA level of M1 phenotype-related genes tumor necrosis factor α, interleukin-1β and interleukin-12β and decreased the CD86 expression. In addition, AAT1-knockdowned macrophages exhibited reduced level of hypoxia-inducible factor-1α (HIF-1α) hydroxylation, elevated HIF-1α protein level, and polarization into M1-type, while supplementation with SO2 reversed the above effects. Mechanistically, SO2 maintained prolyl hydroxylase (PHD) activity in a thiol-dependent manner. SO2 maintained PHD2 activity by sulphenylating PHD2 at Cys260, thereby reducing HIF-1α protein levels and subsequently inhibiting M1 macrophage polarization. Besides, SO2 enhanced PHD2 sulphenylation, inhibited M1 macrophage polarization, and alleviated lung damage in a mouse model of LPS-induced acute lung injury. These results suggested that downregulation of the endogenous SO2/AAT1 pathway was a pivotal mechanism for M1 macrophage polarization. SO2 maintained PHD2 activity via sulphenylation of Cys260, and promoted HIF-1α hydroxylation and degradation, thereby impeding M1 macrophage polarization.

Background Metoprolol therapy for paediatric vasovagal syncope (VVS) has yielded inconsistent results, necessitating predictive markers. We aimed to develop and validate models to identify paediatric VVS patients likely to benefit from metoprolol. Methods 478 metoprolol-treated paediatric patients with VVS were enrolled from three syncope units and divided into retrospective training (March 2017-March 2023, n = 323) and prospective validation cohorts (April 2023-March 2024, n =155). Fourteen patients (2.9%) were excluded for lacking follow-up data. Patients were classified as responders or non-responders based on symptom improvement after 1-3 months of metoprolol therapy. Univariate analysis and logistic regression were used to select the candidate predictors. A nomogram and a scoring model were established to predict treatment efficacy. The model values were analysed using a receiver operating characteristic (ROC) curve. Consistency was evaluated using the Hosmer-Lemeshow (H-L) test, calibration curve, and concordance index (C-index). The clinical utility of model was assessed through the decision curve analysis (DCA). Internal validation was performed using the bootstrap approach. The predictive model derived from the training cohort was validated in the validation cohort to assess its accuracy and feasibility. Findings Increased heart rate during positive response in head-up tilt test (Delta HR), corrected QT interval dispersion (QTcd), and standard deviation of all normal-to-normal intervals (SDNN) were selected as independent predictors to develop a predictive model. A nomogram model was built (AUC: 0.900, 95% CI: 0.867-0.932); the H-L test and calibration curves showed a strong alignment between predicted and actual results. The scoring model was established in the training cohort (AUC: 0.941, 95% CI: 0.897-0.985), yielding a sensitivity of 82.8% and a specificity of 96.5%, with a cut-off value of 2.5 points. In the external validation cohort, the scoring model achieved a sensitivity, specificity, and accuracy of 93.6%, 80.9%, and 87.7%, respectively. Interpretation The nomogram and scoring model were constructed to predict the efficacy of metoprolol for children with VVS, which will greatly assist paediatricians in the individual management of VVS in children and adolescents. Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: This study aimed to identify the risk factors associated with malignant vasovagal syncope (VVS), a rare yet clinically significant subtype of VVS. Methods: This single-center case-control study enrolled children diagnosed with malignant VVS, and the malignant VVS patients were matched in a 1:4 ratio with non-asystolic VVS children as a control group through age and sex stratification. Clinical characteristics and heart rate variability (HRV) parameters were analyzed. Binary logistic regression analyses were used to identify the risk factors significantly associated with malignant VVS. Results: A total of 10 patients in the malignant group and 40 children in the control group were included. The malignant group exhibited earlier symptom onset (7.0 ± 2.7 vs. 9.7 ± 2.7 years, p < 0.05) than the control group, and children in the malignant group had a higher prevalence of central triggers (60.0% vs. 17.5%, p < 0.05) and convulsive/incontinence episodes (80.0% vs. 17.5%, p < 0.05) than the control group. Additionally, the malignant group demonstrated significantly elevated HRV parameters, including very low frequency (VLF), low frequency (LF), and high frequency (HF), indicating substantial autonomic dysregulation characterized by parasympathetic predominance. Central triggers (OR = 7.16, 95%CI 1.10-46.73) and convulsive/incontinence manifestations (OR = 19.02, 95%CI 2.81-128.64) were independent risk factors of malignant VVS. Conclusions: The age at syncope onset was significantly earlier in children with malignant VVS, and children with malignant VVS exhibited profound autonomic dysregulation characterized by significant parasympathetic predominance. Finally, children with episodes induced by central triggers and accompanied by incontinence or convulsions were at a higher risk of asystole.

Gasotransmitter-mediated cysteine post-translational modifications, including S-nitrosylation (SNO) and S-persulfidation (SSH), play crucial roles and interact in various biological processes. However, there has been a delay in appreciating the interactional rules between SNO and SSH. Here, all human S-nitrosylated and S-persulfidated proteomic data were curated, and comprehensive analyses from multiple perspectives, including sequence, structure, function, and exact protein impacts (e.g., up-/down-regulation), were performed. Although these two modifications collectively regulated a wide array of proteins to jointly maintain redox homeostasis, they also exhibited intriguing differences. First, SNO tended to be more accessible and functionally clustered in pathways associated with cell damage repair and other protein modifications, such as phosphorylation and ubiquitination. Second, SSH preferentially targeted cysteines in disulfide bonds and modulated tissue development and immune-related pathways. Finally, regardless of whether SNO and SSH occupied the same position of a given protein, their combined effect tended to be suppressive when acting synergistically; otherwise, SNO likely inhibited while SSH activated the target protein. Indeed, a side-by-side comparison of SNO and SSH shed light on their globally reciprocal effects and provided a reference for further research on gasotransmitter-mediated biological effects.

The objective of this study was to examine the utility of the acceleration index observed in an electrocardiogram (ECG) for the prediction of the effectiveness of orthostatic training in pediatric patients diagnosed with postural orthostatic tachycardia syndrome (POTS). This investigation focused on children diagnosed with POTS and undergoing orthostatic training at the Department of Pediatrics of Peking University First Hospital from January 2012 to October 2022. Specifically, patients hospitalized from January 2012 to December 2019 were included in the training set (54 cases), while those hospitalized from January 2020 to October 2022 were included in the external validation set (37 cases). All children received a 3-month orthostatic training, and the baseline symptom score (SS) was calculated in agreement with the pretreatment orthostatic intolerance symptom frequency. Additionally, we determined post-treatment SS during follow-up via telephone after the 3-month treatment. Children with a decrease in post-treatment SS by ≥ 50

ObjectivesMast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation.MethodsHMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation.ResultsDegranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions.ConclusionThese findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.

Background: This study intended to find out whether the parameters of heart rate variability (HRV) can predict the treatment efficacy of orthostatic training among pediatric cases of vasovagal syncope (VVS). Methods: Patients with VVS who underwent orthostatic training were retrospectively enrolled. Lasso and logistic regression were used to sift through variables and build the model, which is visualized using a nomogram. The model's performance was evaluated through calibration plots, a receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) for both datasets. Results: In total, 119 participants were included in the analysis, and 73 and 46 were assigned to the training and validation datasets, respectively. Five factors with nonzero coefficients were chosen based on lasso regression: age, the root means square of successive differences between normal sinus beats (rMSSD), standard deviation of the averages normal-to-normal intervals in all 5-min segments, minimum heart rate, and high frequency. Drawing from the logistic regression analysis results, the visual predictive model incorporated two variables, namely age and rMSSD. For the training dataset, the sensitivity was 0.686 and the specificity was 0.868 with an area under the curve (AUC) of 0.81 (95% CI, 0.71-0.91) for the ROC curve. For the validation dataset, the AUC of the ROC was 0.80 (95% CI, 0.66-0.93), while sensitivity and specificity were recorded at 0.625 and 0.909, respectively. In the calibration plots for both datasets, the predicted probabilities correlated well with the actual probabilities. According to the DCA, the visual predictive model gained a significant net benefit across a wide threshold range. Conclusions: Pediatric patients with VVS can benefit from orthostatic training using a visual predictive model comprising age and rMSSD.