In many data-driven online decision systems, actions determine not only operational costs but also the data availability for future learning – a phenomenon termed Prediction-Induced Censoring (PIC). This challenge is particularly acute in large-scale resource allocation for generative AI (GenAI) serving: insufficient capacity triggers shortages but hides the true demand, leaving the system with only a "greater-than" constraint. Standard decision-making approaches that rely on uncensored data suffer from selection bias, often locking the system into a self-reinforcing low-provisioning trap. To break this loop, this paper proposes an adaptive approach named PIC-Reinforcement Learning (PIC-RL), a closed-loop framework that transforms censoring from a data quality problem into a decision signal. PIC-RL integrates (1) Uncertainty-Aware Demand Prediction to manage the information-cost trade-off, (2) Pessimistic Surrogate Inference to construct decision-aligned conservative feedback from shortage events, and (3) Dual-Timescale Adaptation to stabilize online learning against distribution drift. The analysis provides theoretical guarantees that the feedback design corrects the selection bias inherent in naive learning. Experiments on production Alibaba GenAI traces demonstrate that PIC-RL consistently outperforms state-of-the-art baselines, reducing service degradation by up to 50

Background: Sirtuin 3 (SIRT3) is a key mitochondrial regulator that functions as an oncogene in breast cancer, where its overexpression drives chemoresistance. Targeting SIRT3 offers a strategy to overcome resistance mechanisms and improve chemotherapy efficacy. Methods: We utilized molecular docking-based virtual screening to identify SIRT3 inhibitors from a natural product library. Candidates were validated via molecular dynamics simulations and binding assays. Efficacy was tested in breast cancer cells and an orthotopic mouse model by assessing cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment. Results: Jionoside B1 was identified as a potent SIRT3 inhibitor that suppresses enzymatic activity, leading to increased SOD2 acetylation. In breast cancer cells, Jionoside B1 significantly enhanced cisplatin sensitivity by promoting ROS accumulation, disrupting mitochondrial potential, and triggering apoptosis. In vivo, the combination of Jionoside B1 and cisplatin inhibited tumor growth more effectively than cisplatin alone. Conclusions: Jionoside B1 sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense. These findings highlight Jionoside B1 as a promising therapeutic candidate for combination chemotherapy to enhance cisplatin responsiveness in breast cancer.

Cisplatin is an effective chemotherapeutic agent, but its clinical use is limited by nephrotoxicity characterized by renal tubular epithelial injury. In this study, we found that carnosic acid (CA), a natural phenolic diterpene derived from rosemary and sage, significantly alleviated cisplatin-induced renal dysfunction and tubular epithelial damage. Mechanistically, CA suppressed mitochondria-dependent apoptosis and reduced mitochondrial damage by activating mitophagy. Further analysis revealed that CA upregulated prohibitin 2 (PHB2), a key mitophagy receptor involved in mitochondrial quality control. Importantly, inhibition or silencing of PHB2 abolished CA-induced mitophagy and cytoprotective effects. These findings indicate that CA protects against cisplatin-induced acute kidney injury by maintaining mitochondrial homeostasis through PHB2-dependent mitophagy, suggesting its potential as a therapeutic strategy for preventing cisplatin-associated nephrotoxicity.

OBJECTIVE:Cholesterol, High-density lipoprotein, and Glucose (CHG) index has recently been proposed as a marker of metabolic dysfunction. However, the association of CHG and CHG modified indices with the risk of stroke remains unclear. METHODS:We analyzed 8908 participants aged 45 years or older from the CHARLS. Baseline CHG and its modified forms (CHG-WC, CHG-BMI, CHG-BRI, CHG-WWI, CHG-WHtR, CHG-ABSI, and CHG-CVAI) were collected. Kaplan-Meier curves, Cox proportional hazards models, and restricted cubic spline (RCS) analyses were applied to assess associations with incident stroke. RESULTS:During a 9-year follow-up period, 828 (9.3%) participants had occurred strokes. Our analysis found a significant positive association between CHG, CHG-WC, CHG-BMI, CHG-BRI, CHG-WWI, CHG-WHtR, CHG-ABSI, CHG-CVAI, with stroke risk. The adjusted HR for the highest quartile compared to the lowest were: CHG 1.57 (95% CI:1.18-2.10), CHG-WC 1.72 (95% CI:1.34-2.20), CHG-BMI 1.62 (95% CI:1.26-2.08), CHG-BRI 1.65 (95% CI:1.29-2.10), CHG-WWI 1.71 (95% CI:1.32-2.23), CHG-WHtR 1.67 (95% CI:1.29-2.16), CHG-ABSI 1.41 (95% CI:1.10-1.80), and CHG-CVAI 1.99 (95% CI:1.54-2.57), with CHG-CVAI showing strongest associations. The RCS revealed a significant linear association between CHG, CHG-WC, CHG-BMI, and CHG-CVAI with the risk of stroke, whereas CHG-BRI, CHG-WWI, CHG-WHtR, and CHG-ABSI showed significant nonlinear associations with stroke risk. According to ROC analysis, CHG-CVAI had the highest predictive power for stroke risk (C-index:0.618). CONCLUSIONS:Elevated CHG and its modified indices were strongly associated with stroke risk in middle-aged and older Chinese populations. CHG-related indices combined with obesity measures may help enhance the identification of individuals at higher risk of stroke.

Purpose:Cardiac fibrosis, a key contributor to ventricular pathologic remodeling and heart failure, currently lacks effective therapeutic approaches. Patients and Methods:Small extracellular vesicles from young healthy human plasma (Young-sEVs) were characterized via protein marker, transmission electron microscopy, and nanoparticle tracking analysis, then applied in cellular models and mouse models of cardiac fibrosis. Western blotting and qRT-PCR were used to identify protective signaling pathways in cardiac fibroblasts (CFs). Results:Young-sEVs significantly inhibited cardiac fibrosis and subsequent cardiac dysfunction post-myocardial infarction (MI) in mice. The main findings included that echocardiographic assessments four weeks post-MI indicated that Young-sEVs improved left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), and reduced left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs). Treatment with Young-sEVs also decreased Masson-positive fibroblast areas and collagen synthesis in cardiac tissue. However, sEVs from the old control group did not achieve the above effect. Consistent with in vivo results, Young-sEVs could also inhibit the proliferation, migration, and collagen synthesis of CFs in the TGF-β1-induced cellular fibrosis model. High-throughput microRNA (miRNA) sequencing and qRT-PCR analysis revealed that miR-664a-3p was abundant in Young-sEVs. The high expression of miR-664a-3p significantly inhibited the proliferation, migration, and collagen synthesis of TGF-β1-induced CFs. However, suppressing the expression of miR-664a-3p in Young-sEVs eliminated their therapeutic effect on cardiac fibrosis in mice. Further studies confirmed SMAD4 as a direct downstream target of miR-664a-3p, whose overexpression could reverse the anti-fibrotic effects of miR-664a-3p. Conclusion:In summary, these findings firstly revealed that Young-sEVs could directly bind to the 3'-untranslated region of SMAD4 mRNA through miR-664a-3p, thereby inhibiting the TGF-β/SMAD4 signaling pathway to protect heart from fibrosis and improve cardiac function. Considering the ease of obtaining plasma-derived sEVs, our study offers a promising therapeutic strategy for heart failure, with the potential for rapid clinical translation in the near future.

Sepsis is a severe organ dysfunction syndrome caused by a dysregulated host response to infection, closely associated with poor prognosis. It disrupts the balance between oxidative and antioxidative systems, which may ultimately result in cellular dysfunction and death. However, the key regulatory genes involved in this process remain unclear and require further investigation. In this study, we analyzed a single-cell RNA sequencing dataset from the Single Cell Portal and an oxidative stress (OS) gene set from GeneCards. We employed multiple algorithms and correlation analysis to identify OS-related gene sets that were upregulated in sepsis. Subsequently, RNA expression datasets from the Gene Expression Omnibus were used to filter for overlapping genes that were upregulated in the sepsis group. Furthermore, we used three machine learning algorithms to identify the optimal characteristic genes and verified them with animal models. Analysis of both scRNA-seq and bulk RNA-seq datasets using various algorithms revealed a significant increase in OS activity scores following sepsis, with heterogeneity observed across different cell layers. TXN, NUDT1, MAPK14, and CYP1B1 were found to be closely associated with the elevated OS levels in sepsis. Furthermore, our animal experiments confirmed a significant increase in OS activity in septic mice, along with elevated expression of TXN, MAPK14, and CYP1B1. This study is the first to elucidate the heterogeneity of oxidative stress at the single-cell level in sepsis. The identification of TXN, MAPK14, and CYP1B1 as pivotal regulators of oxidative stress in sepsis highlights their potential as biomarkers and therapeutic targets.

AIMS:Circulating tumor cells (CTCs) are a critical biomarker for cancer evaluation. The more excellent detection system for CTCs is in demand. PATIENTS & METHODS:One hundred and thirty-seven breast cancer patients, 97 patients with benign breast diseases, and 42 healthy volunteers were enrolled. Four milliliters of peripheral blood was used for CTCs detection. The performance was assessed by the receiver operator characteristic curve. A short-term follow-up with 23 patients was presented for real-time monitoring. RESULTS:In clinical, CTCs were found in 96.35% of patients with malignant breast cancer and 25.77% of patients with benign breast diseases but not in healthy group, by CytoBot® 2000. The sensitivity and specificity of 89.8% and 98.6%, respectively, when the cutoff value of 1.5 CTCs per 4 ml whole blood. Significant differences of CTC count were found between malignant and nonmalignant group (p < 0.0001), tumor progression (p < 0.0001), and tumor size (p < 0.0001). In follow-up, 82.61% of patients exhibited a reduction in CTC count, which corresponds with medical observation that benefits from treatment. Additionally, CD45+ positive CTC showed with anomalous pattern during treatment. CONCLUSION:CTCs and this platform both have practical implications in clinical breast cancer diagnosis and monitoring.

Leaves typically harbor a community of pre-existing beneficial and commensal bacteria that contribute to plant health. When pathogens invade, plants employ a series of strategies to response to the invasion, including the modulation of the microbial community structure. However, it remains unclear how commensal bacteria respond to pathogen at the early stage, and whether this response is specifically regulated. Here, we show that infection of Arabidopsis thaliana leaves by the pathogen Pseudomonas syringae pv. tomato DC3000 leads to a significant increase in the population of commensal bacteria, characterized by enrichment of Gammaproteobacteria and Alphaproteobacteria, alongside a reduction in Firmicutes and Betaproteobacteria. This cascade of events specifically occurs because AvrPto, an effector secreted by Pst DC3000, targets and inhibits the host receptor kinase FER, resulting in suppression of FER-mediated pattern-triggered immunity via the previously identified RIPK-RBOHD module. This specific suppression via FER pathway creates a condition that facilitates rapid proliferation of pre-existing commensal bacteria during early pathogen invasion. Our work provides a paradigm for the study of the interaction and ecological generality between commensal bacteria and pathogens with spatiotemporal patterns.

Patients with chronic kidney disease (CKD) are recognized as a higher risk group for cardiovascular disease (CVD) due to various traditional risk factors, kidney-specific factors, and comorbidities, which have recently attracted significant attention. However, the long-term risk of acute CVD events such as sudden cardiac death (SCD) in CKD patients is unclear. Using the UK Biobank and Changsha cohorts, we find that CKD is associated with an increased risk of SCD. Patients with early-stage CKD, especially those with advanced CKD, faced an elevated risk of SCD. Furthermore, through proteomic analyses of the UK Biobank and Framingham Offspring Cohort, we identify five candidate proteins (NTproBNP, ANGPT2, FGF23, DTNB, and SEPTIN8) linked to SCD risk in CKD patients. Here, we show that patients with CKD have an increased risk of SCD in the long term, underscoring the imperative for strategies that address both cardiovascular risk and renal function in this population.

Sulfatase, traditionally known for its role in sulfate ester hydrolysis, has recently emerged as a potential player in tumor biology through its involvement in oxidative stress pathways. Here, we demonstrate for the first time that sulfatase exhibits peroxidase-like activity, catalyzing the generation of singlet oxygen (1O2) in the presence of oxygen. Based on the sulfatase-dependent 1O2 generation, the developed adamantly-enolether chemiluminescence probe QM-CF for imaging tumors of high sulfatase expression further verified the theory that sulfatase can be involved in tumor development. High-throughput screening (HTS) of natural compounds and clinical drugs identified scutellarin and sinomenine as potent sulfatase inhibitors that suppress tumor growth in mice. Mechanistic investigations revealed that these inhibitors modulate oxidative stress by downregulating MAPK and NF-κB pathways. Our findings unveil a previously unappreciated role of sulfatase in tumor-related oxidative stress and provide a promising platform for the discovery of novel sulfatase inhibitors, and advancing cancer therapeutics.

To the Editor: Coronary artery disease (CAD) is the leading cause of mortality worldwide. Effective treatments, such as percutaneous coronary intervention (PCI), have reduced the mortality of patients with CAD and have transitioned most of them to the chronic phase of cardiovascular disease (CVD). Consequently, there is a high demand for secondary prevention strategies to reduce adverse outcomes of CAD. Risk assessment can quantify the residual risk, identify patients at high secondary risk, and facilitate informed preventive treatment decisions.[1] However, the existing scoring systems for secondary risk, such as the Global Registry of Acute Coronary Events (GRACE) and Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) scores, usually involve certain clinical indicators that are unfamiliar to the public and demonstrate poor performance when applied to Chinese patients, thus, it limited their utility, especially as self-assessment tools. The Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) score is a guideline-recommended pragmatic tool for primary prevention using several conventional risk factors.[2] The risk factors related to primary CVD risk are likely implicated in the recurrent events because of the same underlying pathophysiology of atherosclerosis. Furthermore, primary and secondary CVDs prevention shares similar risk prevention strategies.[3] Hence, the risk score for primary prevention may be speculated to be extended to secondary prevention. Nevertheless, the effectiveness of the China-PAR score in risk assessment for secondary events among patients with CAD is unclear. This study aimed to evaluate the utility of the China-PAR score in predicting long-term secondary events in 10,724 Chinese patients with CAD undergoing PCI at Fuwai Hospital in Beijing, China in 2013. All patients were followed up according to the standard protocol until 2019, and 9843 patients (91.8%) completed the 5-year follow-up survey. After excluding 482 patients with incomplete data for the China-PAR score assessment, 9361 patients were included in the final analysis. This study was approved by the Institutional Review Board at Fuwai Hospital (No. 2013‑449), and written informed consent was obtained from each patient. Data on admission were acquired from inpatient medical records, including demographic characteristics, lifestyle information, medical history, and anthropometric measurements. The follow-up surveys were conducted using standard protocols. Endpoints were obtained from medical records and telephone interviews and adjudicated by two independent cardiologists, with discrepancies resolved by an additional cardiologist. The endpoints included all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs). MACCEs were defined as the occurrence of myocardial infarction, stroke, stent thrombosis, or cardiac death. The China-PAR score is a sex-specific tool for assessing the 10-year risk of first CVD events in the Chinese population using age, residence, waist circumference, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, current smoking, antihypertensive treatment, diabetes mellitus, and family history of CVD.[4] Considering the unavailability of data on waist circumference and family history of CVD in our study, the score was revised using the derivation cohort in the China-PAR study that included body mass index and family history of CAD instead. When the revised China-PAR score was applied to the derivation cohort, C-indices of 0.792 (95% confidence interval [CI]: 0.772–0.812) and 0.807 (95% CI: 0.783–0.832) for male and female participants, respectively, were similar to those of the original score (0.794 and 0.811).[4] Moreover, the difference between the original and revised scores among the derivation cohort was 0, with a median (5th and 95th percentile) of 0.03% (−1.02%, 1.03%). The revised China-PAR score was calculated for each patient with CAD and divided into four categories, including low (<5.0%), moderate (5.0–<10.0%), high (10.0–<20.0%), and very high (≥20.0%) according to the guideline.[2] Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CIs for secondary events associated with the revised China-PAR score. Dose–response relationships were assessed using the restricted cubic spline analyses with five knots at scores of 5%, 10%, 15%, 20%, and 25%, with 5% as the reference. C-indices were computed to estimate the discrimination capacity of the revised China-PAR score on the endpoints. Subgroup analysis was conducted to assess the association between the endpoints and the revised China-PAR score stratified by previous CAD, including myocardial infarction, PCI, and coronary artery bypass grafting. Differences across subgroups were evaluated using P values for the interactions of previous CAD and the score categories. Sensitivity analysis was performed by excluding patients who experienced the endpoints within the first month or 3 months after PCI. All analyses were conducted using the SAS statistical package (version 9.4; SAS Institute, Inc., Cary, NC, USA). Among the 9361 patients with CAD undergoing PCI, the average age was 58.4 years, and 77.4% were males. According to the revised China-PAR score, there were 2259 (24.1%), 2929 (31.3%), 3143 (33.6%), and 1030 (11.0%) patients with low, moderate, high, and very high scores, respectively. During an average follow-up of 4.9 years, 365 all-cause deaths and 1048 MACCEs were identified, with event rates of 7.9 and 23.7 per 1000 person-years, respectively. Supplementary Table 1, https://links.lww.com/CM9/C296 presents the HRs and 95% CIs for the associations between the endpoints and the revised China-PAR score. The risk of all-cause death and MACCE gradually increased with elevated score. Compared with patients who underwent PCI and had a low score, the HRs of all-cause death were 1.39 (95% CI: 0.96–2.01), 2.44 (95% CI: 1.74–3.41), and 4.95 (95% CI: 3.46–7.07) for patients with moderate, high, and very high score, respectively. The corresponding HRs of MACCE were 1.25 (95% CI: 1.03–1.50), 1.78 (95% CI: 1.49–2.12), and 2.28 (95% CI: 1.85–2.82), respectively. The associations between MACCE subtypes and revised China-PAR score were further estimated. The score was significantly and positively related to stroke, stent thrombosis, and cardiac death, but not to myocardial infarction [Supplementary Table 2, https://links.lww.com/CM9/C296]. Similar findings were observed among male and female patients [Supplementary Table 3, https://links.lww.com/CM9/C296]. However, most HRs for males were higher than those for females across the score categories. The dose–response curves showed that the HRs for all-cause death and MACCE increased dramatically with the revised China-PAR score, indicating monotonic and linear dose–response relationships [Supplementary Figure 1, https://links.lww.com/CM9/C296]. Furthermore, linear dose–response relationships were observed for myocardial infarction, stent thrombosis, and cardiac death, whereas a non-linear relationship was observed for stroke [Supplementary Figure 2, https://links.lww.com/CM9/C296]. Male patients had similar dose–response relationships with all the patients. Notably, there was no dose–response relationship for myocardial infarction and a linear relationship for stroke in female patients. The revised China-PAR score had potential discrimination ability for all-cause death with a C-index of 0.661 (95% CI: 0.632–0.689), which was comparable to that of the GRACE score (0.671, 95% CI: 0.641–0.700) and better than that of the PARIS score (0.598, 95% CI: 0.569–0.627). To some extent, it could also predict MACCEs with a C-index of 0.588 (95% CI: 0.571–0.606), which was slightly higher than those of the GRACE (0.572, 95% CI: 0.553–0.590) and PARIS scores (0.570, 95% CI: 0.552–0.587). Moreover, it could potentially discriminate all MACCE subtypes except myocardial infarction [Supplementary Table 4, https://links.lww.com/CM9/C296]. Interestingly, the performance among males was slightly better than that among females. Subgroup analysis indicated that the HRs and C-indices of the revised China-PAR score related to the endpoints in patients without previous CAD were slightly higher than those in patients with previous CAD, although the difference was not statistically significant [Supplementary Tables 5 and 6, https://links.lww.com/CM9/C296]. Sensitivity analysis revealed the robustness of the associations after excluding incident endpoints within the first month or 3 months after PCI [Supplementary Table 7, https://links.lww.com/CM9/C296]. A previous study demonstrated the poor performance of the Framingham risk score for first CAD in predicting long-term recurrent events among patients who underwent PCI.[5] By contrast, our study revealed the potential discrimination ability of the revised China-PAR score for secondary events, which might be explained by its derivation from contemporary cohorts involving more comprehensive CVD events.[4] Moreover, its performance was equal to or better than the existing scores for secondary prevention, which emphasized more on short-term risk within one year. Nevertheless, short- and long-term secondary outcomes exhibit different underlying pathophysiology and lesion sites. Additionally, the free risk assessment platform (www.cvdrisk.com.cn) and smartphone-based tools using more easily obtainable risk factors further improved accessibility of the China-PAR score to clinicians, health staff, and the general population. As it is known, intensive pharmacotherapy for CAD, such as dual antiplatelet and lipid-lowering therapies, has a dramatic impact on coronary events. However, these factors are not considered in the China-PAR score. The C-indices of revised China-PAR for secondary events might not have exceeded 0.7 for this reason. Consequently, an updated China-PAR score is required for more precise secondary prevention by including intensive pharmacotherapy. The clinical implications of the China-PAR score are highlighted by the lack of a published decision support tool to guide self-assessment in patients with CAD. The China-PAR score eliminates major obstacles in the implementation of risk-based secondary prevention between clinicians and patients. Thus, it could be used to direct secondary preventative measures by clinicians, understand their risk, and enhance the adherence to the therapeutic decisions of physicians, especially in resource-constrained settings. Our study extended the utility of the China-PAR score from primary to secondary prevention, provided novel ideas for the risk assessment of secondary prevention of CAD, and further bridged the gap between clinicians and patients using this pragmatic tool. It also provides examples of other primary prevention scores. The major strength of this study is the large sample size and a 5-year follow-up. This study had several potential limitations. First, the China-PAR score had to be revised before evaluating its utility because waist circumference and family history of CVD were unavailable in this study. This might have caused misclassification bias, but the effect should be small because the difference between the original and revised China-PAR scores approached zero. Second, this was a tertiary-hospital single-center study on patients who underwent PCI, and more studies from multiple centers and diverse regions with longer follow-up periods are needed to validate our findings and enhance their generalizability. Finally, the applicability of the China-PAR score in patients with CAD in other countries or for secondary prevention of stroke and other CVDs remains unclear. However, further studies are required to confirm this hypothesis. In conclusion, the China-PAR score has the potential to discriminate long-term secondary events in patients who underwent PCI. It can be used as a pragmatic tool for the secondary prevention of CAD by both clinicians and patients. It can identify patients with the greatest potential benefit, enhance risk-based secondary prevention, and further decrease the CVD burden in China. Acknowledgements We acknowledge the patients and staffs for their important participation and contribution. Funding This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (Nos. 2023ZD0504000 and 2023ZD0503500), the National Key Research and Development Program of China (Nos. 2016YFC1301300, 2016YFC1301301, 2017YFC0211706, 2018YFE0115300, and 2023YFC2506703), the National Natural Science Foundation of China (Nos. 82473720 and 81770365), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. 2021-I2M-1-010), and the National High Level Hospital Clinical Research Funding (No. 2022-GSP-GG-2). Conflicts of interest None.

Unspecific peroxygenases (UPOs) have been proven to be promiscuous catalysts in various challenging oxidative reactions. Today, thousands of putative UPO sequences have been stored in the Genbank, however, only seven crystal structures of the model enzymes have been elucidated. Herein, we aim to use the fast-evolving artificial intelligence tool, AlphaFold2, to predict the protein structure and reactivity of UPOs. The prediction accuracy of AlphaFold2 was first evaluated by comparing the alignment of key amino acids of seven UPO proteins established by X-ray crystallography. It showed that AlphaFold2 demonstrates high accuracy and stability in its predictions of the overall structure, albeit deviations of certain crucial amino acids exist. This discrepancy can be attributed to the impact of ligands and covalent modifications on the protein structure. Subsequently, based on the guidance of AlphaFold2 we explored the catalytic function of unspecific peroxygenase from Coprinopsis cinerea (CciUPO) to catalyze benzylic C-H bond oxyfunctionalization and asymmetric sulfoxidation reactions. Using the predicted structure of CciUPO, protein engineering was carried out to further enhance the stereoselectivity in sulfoxidation reactions.

Cardiovascular diseases (CVDs) threaten the human health. Lots of researches suggest that ROS accumulates in cardiomyocytes in CVDs. Excessive mitochondrial autophagy caused by reactive oxygen species (ROS) impairs the function of cardiomyocytes. Here, we found that extracellular vesicles derived human umbilical cord blood plasma (UCB-EV) inhibited oxidative stress-induced mitophagy to promote cell survival. The viability of UCB-EV pre-protected H9C2 cardiomyocytes was maintained after H2O2 exposure. In addition, UCB-EV partially restored mitochondrial membrane potential and promoted mitochondrial biogenesis. Furthermore, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine protein kinase, was inhibited by UCB-EV during oxidative stress. We further demonstrate the role of UCB-EV in inhibiting mitophagy to make H9C2 cells survival by PINK1/Parkin pathway. Our findings elucidate the protective mechanism of UCB-EV against oxidative stress in H9C2 cells. These findings reveal the potential role of UCB-EV in alleviate oxidative stress in cardiomyocytes.

Fifteen new isocoumarin derivatives 1-3, (±)-4, (±)-5, 6-10, (+)-11, (+)-12, and 13, together with eleven known analogues (-)-11, (-)-12, and 14-22 were isolated from the mangrove endophytic fungus Alternaria sp. HN-17. Their structures were unambiguously established by 1D/2D NMR and HRESIMS spectra, and electronic circular dichroism (ECD) calculations. Alterisocoumarin A (1) possesses a rare 6/6/6/5 tetracyclic skeleton featuring a γ-butyrolactone-fused dibenzo-α-pyrone core, while 2 and 3 have an unusual chlorinated furan ring system. In bioassay, compounds 1, (-)-4, 10, and 18 displayed good anti-inflammatory activity with IC50 values ranging from 10.68 to 28.05 μM than positive control (L-NMMA: 32.83 μM). Moreover, 1 exerts anti-inflammatory effects by down-regulated expression the NF-κB and MAPK pathways. In addition, compounds 21 and 22 showed notable anti-tuberculosis activities by inhibiting MptpA, MptpB and PTP1B. The molecular docking results showed that compound 22 binds deeply in the active cavity of PTP1B.

BACKGROUND:Paranitrophenol, a metabolite of organophosphate insecticides, was associated with various adverse health outcomes. However, the association of Paranitrophenol with all-cause and cancer mortality in adults remains unclear. METHODS:A total of 3,362 participants (1680 male) were included from the National Health and Nutrition Examination Surveys (NHANES). Urinary Paranitrophenol was measured using ultra-high-performance LC-MS/MS. Mortality status and causes were obtained from National Death Index. Cox proportional hazards regression analysis was performed to explore the associations between Paranitrophenol and all-cause and cancer mortality, respectively. RESULTS:After a follow-up of 22.75 thousand person-years, there were 297 deaths from all causes and 69 deaths from cancer. Comparing with the lowest quartile, the highest quartile was not associated with all-cause mortality in the neither univariate model nor adjusted model. In terms of cancer mortality, the hazard ratios and 95% confidence interval of the highest quartile is 0.44 (0.21-0.93) in the univariate model, 0.40 (0.18-0.86) in the partly-adjusted model, and 0.40 (0.18-0.88) in the fully-adjusted model. CONCLUSION:Higher urinary Paranitrophenol levels were associated with a decreased risk of cancer mortality. This association remained independent of demographics, lifestyle factors, and comorbidities.

A conceptual innovative electrochemical sensing platform was constructed for microRNA (miRNA) detection based on terminal deoxynucleotidyl transferase (TdT)-mediated synthesis of copper nanoclusters. In principle, the substrate strand immobilized on working electrode acted as the template for the TdT-mediated DNA extension reaction, while the DNAzyme probe would be activated in the absence of miRNA 21, which led to the cleavage of the substrate strand to produce the 5’ phosphate terminus and inhibited the TdT-mediated DNA extension reaction. On the other hand, the presence of miRNA 21 initiated the toehold-mediated strand displacement reaction, causing the disassembly of the DNAzyme structure and preventing the substrate strand from being cleaved. This enabled the recycle amplification of target miRNA 21, and TdT catalyzed the DNA extension reaction on the 3’ hydroxyl terminus of the substrate strand, producing a large number of poly thymine (polyT) sequences. These sequences bound with copper ions for in-situ synthesis of copper nanoclusters on the sensing electrode, and the increased electrochemical signal of copper was recorded by differential pulse stripping voltammetry (DPSV), which paved the way for sensitive determination of miRNA 21 extracted from cancer cells with a detection limit of 36 aM. Due to its high sensitivity, user-friendly operation, and cost-effectiveness, this method is helpful for the fundamental research of sensing mechanism as well as the diagnosis of related diseases.

Talaromeroterpenoids A-G (1-7), seven new 3,5-dimethylorsellinic-acid-derived meroterpenoids, and two known analogues (8 and 9) were isolated from the mangrove endophytic fungus Talaromyces sp. JNQQJ-4 by genome analysis and a molecular networking strategy. Their structures and absolute configurations were established by nuclear magnetic resonance data, high-resolution electrospray ionization mass spectrometry, and X-ray diffraction. Compound 1 possesses an unprecedented rearrangement 7/6/6/6/5/5 hexacyclic skeleton based on a 2,8,18,21-tetraoxa-hexacyclo-[12.5.2.13,12.01,16.04,10.016,22]docosane core. In bioassays, compound 2 exhibited promising anti-inflammatory activity by suppressing the expression of pro-inflammatory factors and inactivating the NF-κB signaling pathway.

BACKGROUND:Deficiencies in fat-soluble vitamins (FSVs) have been linked to various systemic disorders. In this study, we introduce a novel and straightforward assay for the analysis of FSVs, suitable for large-scale sample screening while reducing laboratory testing costs. METHODS:The method, termed sodium-acetonitrile extraction (SoAce), was developed and validated for the quantification of selected FSVs, including Vitamin A (retinol), Vitamin D2 (25-hydroxyvitamin D2), Vitamin D3 (25-hydroxyvitamin D3), Vitamin E (α-tocopherol), and Vitamin K1 (phylloquinone). A saturated sodium chloride solution combined with acetonitrile was employed as the extraction reagent. Mass spectrometric detection was carried out using a triple quadrupole mass spectrometer in positive ion mode via an APCI source. Method validation was conducted in accordance with Chinese regulatory guidelines and the C62-A standard. RESULTS:Using the SoAce-liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, FSVs were successfully separated and quantified within 30 min. The assay demonstrated excellent linearity, with all regression coefficients exceeding 0.996. The lower limit of quantification (LLOQ) was determined as 12.5 ng/mL for Vitamin A, 0.31 ng/mL for Vitamin D2, 1.56 ng/mL for Vitamin D3, 625 ng/mL for Vitamin E, and 0.08 ng/mL for Vitamin K1. Specificity, stability, accuracy, and precision were all evaluated and met the required validation criteria. A comparative analysis against an existing commercial FSV kit using the same instrumentation revealed strong correlation, with coefficients ranging from 0.928 to 0.962. CONCLUSIONS:The developed SoAce-LC-MS/MS method fulfills the requirements for rapid and reliable assessment of FSV status in human serum. Further studies are warranted to fully explore the potential applications and clinical utility of this assay.

OBJECTIVE:This study evaluated the benefits of immune checkpoint inhibitors (ICIs) and/or targeted therapies in mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) patients with advanced or recurrent endometrial cancer (EC) via network meta-analysis. METHODS:English databases were searched from inception through January 2025. Randomized controlled trials (RCTs) assessing the efficacy and safety of related therapies for patients with EC stratified by MMR status were included. The main evaluation indicators included progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and severe adverse events (SAEs). RESULTS:Ten studies were included in the analysis. The results indicated that in the dMMR population, ICIs provide superior survival benefits. Among these, Dostarlimab combined with carboplatin and paclitaxel (CP) had the highest PFS and OS rates. For the pMMR population, Selinexor + CP offers significant benefits over CP alone, although OS outcome data are limited. In pMMR patients with prior chemotherapy, the lenvatinib + pembrolizumab strategy may provide additional PFS benefits relative to chemotherapy treatment. CONCLUSIONS:ICIs offered advantages for the dMMR population, whereas selinexor could provide survival benefits for the pMMR population. For pMMR patients who have received prior chemotherapy, the lenvatinib plus pembrolizumab strategy shows promise.

Correction for 'Melatonin as an inducer of arecoline and their coordinated roles in anti-oxidative activity and immune responses' by Xiaojian Yin et al., Food Funct., 2020, 11, 8788-8799, https://doi.org/10.1039/D0FO01841D.