ObjectiveThis study aimed to evaluate the predictive value of combining visceral fat area (VFA) with blood lipid levels for perioperative risk and long-term prognosis in patients undergoing radical resection for colorectal cancer (CRC).MethodsWe conducted a retrospective analysis of 482 CRC patients who underwent radical surgery between December 2014 and December 2022. Patients were categorized into four groups based on VFA (visceral obesity defined as VFA ≥ 100 cm²) and lipid levels (elevated: TC ≥ 6.2 mmol/L, LDL-C ≥ 4.1 mmol/L, TG ≥ 2.3 mmol/L, or HDL-C < 1.0 mmol/L). Baseline characteristics, surgical outcomes, and survival data were compared. Multivariate logistic and Cox regression models were used to identify independent factors influencing complications and survival.ResultsThe combined VFA/lipid groups showed no significant differences in short-term complications (P > 0.05) but demonstrated significant stratification in long-term survival. Patients with both high VFA and high lipid levels (Group 2) exhibited significantly better overall survival (OS) and recurrence-free survival (RFS) compared to those with low VFA and normal lipids (HR ≈ 0.50, P < 0.01), supporting the “obesity paradox.” Age, TNM stage, and surgical approach were also identified as independent prognostic factors.ConclusionThe combination of VFA and blood lipid levels may serve as a useful preoperative indicator for risk stratification and prognostic assessment in CRC patients, with high VFA and high lipids potentially associated with improved survival outcomes.

Introduction:Pancreatic exocrine insufficiency (PEI), presenting as bloating or diarrhea, affects 26%-100% of patients after gastrectomy, delaying recovery and impairing quality of life. Pancreatic enzyme replacement therapy (PERT) is the standard PEI management, yet its efficacy after gastric cancer surgery remains controversial. This study evaluates PERT's effectiveness in alleviating postoperative gastrointestinal symptoms. Methods and Analysis:In this multicenter randomized controlled trial, 204 patients undergoing radical gastrectomy will be randomized 1:1 to PERT or control. The PERT group will receive Pancreatin Enteric-coated Capsules (containing 450 mg pancrelipase microgranules) three times daily with meals for 1 month post-discharge. The primary outcome is the incidence of gastrointestinal symptoms at 1 month post-surgery, assessed using the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI). Secondary outcomes include nutritional status and treatment compliance. Discussion:This protocol establishes a framework for definitively evaluating PERT in gastric cancer patients. Results will inform evidence-based PEI management, with significant implications for survivorship care. By integrating patient-reported outcomes and nutritional metrics, we aim to validate a patient-centered strategy optimizing functional recovery after curative resection. Clinical Trial Registration:This study was registered with the Chinese Clinical Trial Registry (ChiCTR; registry number: ChiCTR2500102557). Date of registration: 16 May 2025.

BACKGROUND. In patients undergoing cardiac MRI after ST-elevation myocardial infarction (STEMI), microvascular obstruction (MVO) often decreases in size between early gadolinium enhancement (EGE) and late gadolinium enhancement (LGE) images. Persistence of MVO between these images may indicate greater microvascular injury. OBJECTIVE. The purpose of this study was to evaluate the prognostic utility of measures of MVO persistence between EGE and LGE images in patients undergoing cardiac MRI after STEMI. METHODS. This retrospective study included 584 patients (mean age, 60 ± 11 [SD] years; 507 men, 77 women) enrolled in the multicenter Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry from June 2017 to March 2023 who underwent cardiac MRI, including EGE and LGE imaging, within 1 week after percutaneous intervention for STEMI. Using semiautomated software, a radiologist measured MVO volumes (i.e., hypointense cores within hyperenhancing territories) on EGE and LGE images. The MVO persistence index was calculated as the ratio of MVO volume between LGE and EGE images. Patients were assigned to one of four MVO patterns (none [absent on EGE and LGE images]; reversible [present on EGE, absent on LGE images]; partially reversible [present on both images, persistence index < 40%]; persistent [present on both images, persistence index ≥ 40%]). Cox regression models were performed to predict major adverse cardiovascular event (MACE, including all-cause death, heart failure hospitalization, and reinfarction), adjusted for established clinical and MRI risk factors including static EGE and LGE MVO volumes. Propensity-score matching (PSM) analysis was performed between partially reversible and persistent MVO patterns. RESULTS. No MVO, reversible MVO, partially reversible MVO, and persistent MVO patterns were observed in 157, 133, 195, and 99 patients, respectively. In separate models, increased risk of MACE (n = 103) showed independent associations with MVO persistence index (HR per 10% increase: 1.36; p < .001) and persistent MVO pattern (HR vs no MVO pattern: 5.14; p < .001). Heart failure hospitalizations and reinfarctions also showed significant independent associations with MVO persistence index (HR: 1.26-1.45) and persistent MVO pattern (HR: 7.06-11.16). In PSM analysis (99 patients per group), MACE was independently associated with the persistent MVO pattern relative to the partially reversible MVO pattern (HR: 3.33; p = .004). CONCLUSION. MVO persistence between EGE and LGE images was a significant independent predictor of MACE. CLINICAL IMPACT. Measures of MVO dynamics provide prognostic information beyond standard static MVO measures.

OBJECTIVE:Functional complete revascularisation (FCR) has been proven to be associated with superior prognosis following percutaneous coronary intervention. Whether guideline-directed medical therapy (GDMT) still impacts clinical outcomes in patients who have achieved FCR requires further evaluation. METHODS:The study population was drawn from patients who achieved FCR in the FAVOR III China trial, defined as a quantitative flow ratio (QFR)-based residual functional Synergy between percutaneous coronary intervention with taxus and cardiac Surgery score of 0, measured only in vessels with QFR≤0.80. GDMT was defined as the combination of single or dual antiplatelet therapy, a beta-blocker and a statin, with or without an ACE inhibitor or angiotensin receptor blocker, according to contemporary guideline recommendations. Patients were categorised into the GDMT group (compliance with all 4 agents) or non-GDMT group (compliance with 0-3 agents). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE) at 3 years, a composite of death, myocardial infarction, stroke and ischaemia-driven revascularisation. RESULTS:Among 3221 (85.2%) patients who achieved FCR, a total of 1964 (61.2%), 1919 (59.9%), 1545 (48.4%), 1483 (46.6%) and 1084 (35.3%) patients adhered to GDMT at 1 month, 6 months, 1 year, 2 years and 3 years, respectively. The MACCE occurred in 313 (10.2%) patients through 3 years. The rate of MACCE was similar between GDMT and non-GDMT groups within the first year, but significantly lower in the GDMT group from the second year (adjusted HR: 0.66, 95% CI: 0.51 to 0.85; p<0.01) and sustained until the third year (adjusted HR: 0.65, 95% CI: 0.50 to 0.85; p<0.01), compared with the non-GDMT group. CONCLUSIONS:In patients who achieved FCR, the benefit of good adherence to GDMT remained significant, starting from the second year and continuing up to 3 years. TRIAL REGISTRATION NUMBER:NCT03656848.

Inguinal hernia, a common surgical condition, is preferably managed via transabdominal preperitoneal laparoscopic hernia repair (TAPP) ; however, indirect hernia sac management remains challenging. This randomized controlled trial aimed to assess the efficacy of hydrodissection in reducing seroma incidence and improving perioperative outcomes during TAPP repair for indirect inguinal hernia. A prospective, single-blinded randomized controlled trial enrolled 128 male patients, randomized 1:1 to hydrodissection or conventional dissection. The hydrodissection technique involved injecting 10 mL of normal saline into the preperitoneal space on the medial and lateral sides of the internal inguinal ring under laparoscopic guidance, creating a circular fluid distribution to facilitate dissection while avoiding critical structures. Primary outcome was seroma incidence at follow-up; secondary outcomes included operation time and chronic pain. Analyses followed intention-to-treat principles. The median follow-up duration was 14 months. Hydrodissection demonstrated significant reductions in seroma formation (4.69

Background:The benefits of physiology-guided management in acute coronary syndrome (ACS) remain inconclusive due to limited evidence. In our FAVOR III China trial, a quantitative flow ratio (QFR)-based physiology-guided strategy versus standard angiography guidance improved the 1-year primary outcome among participants with coronary artery disease (CAD). We aimed to investigate, in a prespecified analysis, the outcomes of QFR-based physiological guidance in the FAVOR III China participants with low-risk ACS. Methods:This pre-specified secondary analysis included patients diagnosed with low-risk ACS who were enrolled in the FAVOR III China trial. The trial was a prospective, randomised study that assigned 3825 CAD patients to receive QFR-guided or angiography-guided percutaneous coronary intervention (PCI) at 26 hospitals in China between December, 2018 and January, 2020. The primary outcome of interest for this study was major adverse cardiac events (MACE), defined as a composite of all-cause death, myocardial infarction, and ischaemia-driven revascularisation, at 1-year (primary outcome of FAVOR III China) and 2-year follow-up. Secondary outcomes included PCI strategy change and the procedural characteristics. FAVOR III China is registered with ClinicalTrials.gov, NCT03656848. Findings:Of the 2371 participants with low-risk ACS (93.7% unstable angina and 6.3% non-ST elevation myocardial infarction [NSTEMI]) in the FAVOR III China trial, the QFR-guided strategy changed the original intended treatment plan in 23.6% of the low-risk ACS patients, resulting in more PCI deferrals (19.0% vs 3.8%; P < 0.001), less stenting (1.5 ± 1.1 vs 1.6 ± 1.0 per participant; P = 0.034), and shorter fluoroscopy time (13.7 ± 7.7 min vs 14.6 ± 7.1 min; P = 0.01) compared with the angiography-guided strategy. During follow-up, there was some evidence that the QFR guided strategy is superior to the angiography-guided approach at reducing the risk of MACE at 1-year follow-up (6.1% vs 8.2%; HR, 0.74; 95% CI, 0.54-1.01, P = 0.055), with a significant risk reduction at 2-year follow-up (8.3% vs 11.7%; HR, 0.70; 95% CI, 0.54-0.91, P = 0.009). The landmark analysis indicated consistent patterns both before and after 1 year (P interaction = 0.35). Interpretation:Our findings favoured the superiority of QFR-guided lesion selection strategy over standard angiography guidance in reducing long-term MACE for the low-risk ACS population. The benefits associated with QFR need to be confirmed by future studies with extended follow-up. Funding:The National High Level Hospital Clinical Research Funding, the Capital's Funds for Health Improvement and Research, the Chinese Academy of Medical Sciences, the Noncommunicable Chronic Diseases National Science and Technology Major Project, Shanghai Municipal Health Commission "Top Priority Research Centre", and Shanghai Shenkang Hospital Development Centre.

CD27, as a member of the immune checkpoints (IC), is physiologically expressed on various immune cells, with CD70 being its only known ligand. Together, they play a significant role in the co-stimulation and activation of T and B cells, regulating the body's immune response. Currently, the CD27/CD70 pathway shows great potential in the clinical treatment of tumors. Previous studies have found that immune checkpoint inhibitors (ICIs) provide significant benefits to cancer patients while also causing various adverse reactions, including cardiovascular diseases. The critical role of inflammation and adaptive immunity in coronary atherosclerotic heart disease (CAD) is widely recognized. Studies have found that the absence of CD27 or the blockade of the CD27/CD70 pathway exacerbates the occurrence of CAD. This review mainly summarizes the impact and mechanisms of CD27 and the CD27/CD70 pathway on CAD through immune regulatory pathways, providing important theoretical support for clinical treatment and prevention of adverse events in coronary heart disease, as well as new therapeutic strategies.

Growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs) arise from the anterior pituitary gland and constitute 20-30% of all PitNETs, representing a significant subset of functional pituitary tumors. Despite their prevalence, the precise mechanisms underlying the development of these tumors remain elusive due to the complex pathophysiology of pituitary neoplasia. To investigate the potential role of the gut microbiome in GH-PitNETs, we conducted a comprehensive study involving 16S rRNA gene sequencing and metabolomics analysis of fecal and serum samples from 20 GH-PitNET patients and 30 healthy controls at Peking Union Medical College Hospital. Our findings revealed a distinct gut microbiota profile in GH-PitNET patients compared to healthy individuals, characterized by dysbiosis with increased abundance of Bacteroides and decreased abundance of Blautia and Bifidobacterium. Notably, alterations in specific bacterial taxa, including Intestinibacter bartlettii, Fusicatenibacter faecihominis, and Massilioclostridium, were observed in GH-PitNET patients. Concomitantly, serum metabolomics analysis identified 154 differentially abundant metabolites in GH-PitNET patients, with significant enrichment in pathways related to tryptophan metabolism. Among these metabolites, 3-indoleacetic acid (IAA) exhibited a obvious change, suggesting its potential research value for disease processing of GH-PitNETs. To further elucidate the mechanistic link between the gut microbiome and GH-PitNETs, we conducted in vitro and in vivo experiments, our results demonstrated that IAA could promote the proliferation of GH3 cells and significantly enhance growth hormone secretion by activating the cAMP pathway. These findings collectively suggest that gut microbiota dysbiosis may contribute to in the development and progression of GH-PitNETs by contributing to metabolic disturbances.

BACKGROUND:Coronary microvascular dysfunction (CMD) leads to inadequate myocardial perfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). The index of microcirculatory resistance (IMR) is an intraoperative diagnostic tool for CMD. However, its widespread application is hindered by the requirement for pressure wires and hyperaemic agents. The angiographic microcirculatory resistance (AMR) index is concise, convenient, accurate, and serves as a pressure wire-free alternative to the IMR. AIMS:This study aimed to demonstrate the ability of AMR to detect CMD in patients with STEMI undergoing PPCI therapy and to assess its predictive value for long-term prognosis. METHODS:The EARLY-MYO-AMR trial comprised two cohorts. The derivation cohort included 495 patients with STEMI who underwent PPCI within 12 h and cardiac magnetic resonance (CMR) within 14 days of symptom onset. The optimal AMR cutoff value for diagnosing CMD using CMR was determined by analysing the receiver operating characteristic curves. The validation cohort enrolled 2,663 patients with STEMI who underwent PPCI within 12 h of symptom onset from January 2012 to April 2022 across 5 medical centres. All patients were followed up for at least 1 year. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE), including cardiac death, hospitalisation for heart failure, repeat myocardial infarction, and target lesion revascularisation. RESULTS:The derivation cohort identified an AMR cutoff >26.6 mmHg*s/dm for predicting CMD post-PPCI (area under the curve 0.721, 95% confidence interval [CI]: 0.677-0.763). Multivariable logistic regression analysis indicated that AMR >26.6 mmHg*s/dm was a CMD risk factor (odds ratio 4.10, 95% CI: 2.56-6.56; p<0.001). The MACE incidence was significantly higher among patients in the validation cohort with AMR >26.6 mmHg*s/dm than among those with AMR ≤26.6 mmHg*s/dm (30.9% vs 21.5%, adjusted hazard ratio [HR] 1.47, 95% CI: 1.20-1.80; p<0.001). MACE incidence increased with AMR, with an adjusted HR of 1.30 (95% CI: 1.17-1.46; p<0.001) per 10 mmHg*s/dm increase. The Bland-Altman and Kappa analyses showed good intra- and interobserver agreement for AMR (intraobserver: bias=-0.104, k=0.914; interobserver: bias=-0.032, k=0.958). CONCLUSIONS:AMR >26.6 mmHg*s/dm predicts CMD during PPCI and increased MACE incidence in patients with STEMI. This convenient tool helps in risk stratification and treatment guidance for STEMI prognosis.

The progression of atherosclerosis (AS) is marked by escalating chronic inflammation and oxidative stress within the arterial wall, which heightens the risk of plaque rupture and subsequent acute ischemic cardiovascular and cerebrovascular events. Conventional anti-inflammatory and antioxidant therapies, however, are often limited by modest efficacy and potential side effects. Here, we synthesized iron-curcumin coordination polymers (Fe-Cur CPs) coordinated by trivalent iron ions and the natural product curcumin (Cur). These Fe-Cur CPs effectively scavenged excessive reactive oxygen species (ROS) in endothelial cells and macrophages, significantly reduced monocyte adhesion to activated endothelial cells, and attenuated the production of inflammatory factors by macrophages, thereby demonstrating potent antioxidant and anti-inflammatory properties. Additionally, they inhibited foam cell formation. In atherosclerotic ApoE -/- mice, intravenous administration of Fe-Cur CPs significantly reduced plaque burden. Furthermore, these nanoparticles mitigated macrophage aggregation within plaques, effectively inhibited ROS levels and inflammatory cytokine production, enhanced collagen deposition and α-smooth muscle actin (α-SMA) levels, and downregulated matrix metalloproteinase 9 (MMP9) levels, thereby collectively contributing to plaque stabilization. This study proposed a safe and efficient self-assembly strategy for constructing multifunctional coordination polymers that possessed drug-delivery capabilities. These nanoparticles can synergistically modulate multiple risk factors in the atherosclerotic plaque microenvironment, thereby offering a promising therapeutic approach for the treatment of AS.

BACKGROUND:Doxorubicin (DOX), a classical chemotherapeutic agent, remains indispensable in cancer treatment but is limited by dose-dependent cardiotoxicity. Investigating strategies to mitigate DOX-induced cardiac damage is critical. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, exhibits anti-inflammatory and antioxidant effects in cardiovascular disease. This study investigated empagliflozin's protective effects against DOX-induced cardiotoxicity and underlying mechanisms. METHODS:DOX-induced cardiotoxicity models were established in male C57BL/6 J mice, with cardiac-specific RIPK1 overexpression achieved via adeno-associated virus (AAV9) technology. Cardiac function was assessed using echocardiography, and heart tissue was analyzed for injury, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and autophagy through various biochemical and molecular assays. RESULTS:Empagliflozin alleviated DOX-induced cardiac dysfunction, reduced fibrosis, and suppressed systemic inflammation and oxidative stress in mice. Mechanistic studies revealed that empagliflozin mitigated DOX-induced cardiotoxicity by inhibiting ER stress and autophagy, as evidenced by the downregulation of BIP, p-IRE1, and ATF6 expression, alongside elevated p62 and reduced LC3BII/LC3BI levels. RIPK1 was identified as a crucial mediator of empagliflozin's cardioprotective effects, with similar protection observed using the RIPK1 inhibitor Nec-1. RIPK1 knockdown in cardiomyocytes mimicked empagliflozin's antioxidant effects, while its protective effects were abolished in RIPK1-deficient cells. Importantly, RIPK1 overexpression reduced empagliflozin's benefits in DOX-treated mice. In addition, empagliflozin enhanced DOX-induced cytotoxicity in 4 T1 breast cancer cells. CONCLUSION:Empagliflozin protects against DOX-induced cardiotoxicity by attenuating inflammation, oxidative stress, ER stress and autophagy, primarily through RIPK1 inhibition, providing insights into its cardioprotective mechanisms. Additionally, empagliflozin enhances DOX-induced cytotoxicity in vitro, providing support for its combination with DOX in cancer therapy.

Background:Quantitative flow ratio (QFR) based lesion selection for percutaneous coronary intervention (PCI) treatment has shown clinical benefits in terms of reduced risk for myocardial infarction and repeat revascularization. Whether this benefit is consistent across different age groups still needs further investigation. Methods:In this prespecified subgroup study of FAVOR III China trial, we compared long-term clinical outcomes between QFR-guided and angiography-guided PCI among different age groups among 3825 enrolled subjects. The primary endpoint was major adverse cardiac events (MACEs), a composite of all-cause death, myocardial infarction, and ischemia-driven revascularization. Results:Of the 3825 patients, 1717 (44.9%) were aged ≥ 65 years. At baseline, patients ≥ 65 had higher rates of hypertension, hyperlipidaemia, stroke history (P < 0.0001), and peripheral vascular disease (P = 0.024) and had higher SYNTAX scores (P = 0.0095). Compared with standard angiography guidance, the QFR-guided strategy consistently reduced the 1-year (≥ 65 years, 6.04% vs. 9.19%, HR = 0.65, 95% CI: 0.46-0.92; < 65 years, 5.53% vs. 8.43%, HR = 0.65, 95% CI: 0.47-0.91) and 3-year MACE rates in both age groups (≥ 65 years, 11.8% vs. 15.2%, HR: 0.75, 95% CI: 0.58-0.98; < 65 years, 9.5% vs. 14.6%, HR = 0.63; 95% CI: 0.49-0.81), without a significant interaction (P interaction = 0.99). Within the QFR-guided group, the 3-year MACE rate in patients with deferred vessels was numerically greater in patients aged ≥ 65 years than in those aged < 65 years (8.3% vs. 3.0%, P = 0.10). Conclusions:Although with higher rate of comorbidities and more complex coronary anatomy, the long-term benefit of the QFR-guided PCI strategy remained consistent in patients ≥ 65 years, compared with those < 65 years.

Atherosclerosis (AS) is a key pathological process leading to cardiovascular diseases, with its occurrence closely associated with the immune microenvironment, yet there remains a gap in detailed studies that explore these effects across different artery beds. With panvascular perspective, this study goes beyond traditional single‐site analysis to investigate AS plaques in five key arterial regions: the abdominal aorta, infrapopliteal artery, femoral artery, carotid artery, and coronary artery. We performed immune infiltration analysis and differential gene analysis, and obtained key genes for AS diagnosis through multiple feature selection, and performed drug screening targeting these genes. Among these diagnostic genes identified were genes such as CCR1, LPL, which has been shown to play an important role in AS, and genes such as BDNF, whose role in AS is not yet clear. Our findings highlight unique patterns of immune gene expression and immune cell infiltration at each site, providing new insights into the complex nature of AS. By identifying distinct molecular signatures, we uncover potential diagnostic markers and therapeutic targets. We validated these results in single‐cell datasets and noted different patterns of macrophage activation in carotid and coronary arteries. We also investigated the expression patterns of these diagnostic genes in venous sclerosis disease, revealing possible similarities between AS and venous sclerosis in the immune microenvironment. This study highlights the variability of the immune microenvironment of AS at different sites and explores the differences in interactions between immune cells, providing new ideas for the mechanisms of AS from a panvascular perspective.

Objective: We aimed to identify molecular candidates to serve as diagnostic biomarkers and therapeutic targets for abdominal aortic aneurysm (AAA). Method: We conducted integrative bioinformatics analysis and used machine learning for key genetic screening. Gene expression profiles at the single-cell level were validated through in vitro experiments. Results: We identified Betacellulin (BTC) and Kruppel-like transcription factor 15 (KLF15) as biomarkers and potential therapeutic targets for AAA. Notably, BTC is expressed predominantly in vascular smooth muscle cells (VSMCs) in AAA, whereas KLF15 is expressed in VSMCs, fibroblasts, and other cell types. RT-qPCR validated a significant decrease in mRNA levels of BTC and KLF15 in VSMCs after angiotensin II administration. All-trans retinal, which interacts with BTC, was identified as a potential drug for AAA treatment. RAD21 might be a common TF driving both BTC and KLF15 expression. Conclusions: We identified two biomarkers and a potential therapeutic agent for AAA, thus enhancing understanding of the molecular mechanisms underlying the disease and offering novel strategies for its clinical management.

Protein markers secreted by various human cells provide crucial insights for the early diagnosis and prognostic assessment of clinical diseases. However, restricted by efficient protein marker signal amplification in real clinical samples with complex compositions, accurate, sensitive, and rapid detection of protein markers remains largely challenging. Herein, a DNA nanoflower (DNF)-powered CRISPR/Cas12a biosensing platform (DNF-CRISPR) is presented that employs the DNF in upstream to amplify input signals for protein markers, while utilizing the CRISPR system in downstream to amplify output signals by trans cleavage. This upstream and downstream cascade amplification sensing platform exhibits high sensitivity (500 fg mL-1), rapid (≤2 h), and a broad dynamic range (2.5 pg mL-1 to 25 ng mL-1). As a proof of concept, DNF-CRISPR biosensing platform enables the quantitative detection of neutrophil gelatinase-associated lipocalin (NGAL) biomarkers in blood and urine samples from kidney injury patients with 91% accuracy. This study provides a powerful and versatile approach for the accurate diagnosis of protein markers in clinical settings, facilitating the application of CRISPR/Cas12a-based sensing platforms for non-nucleic acid markers.

Intermittent fasting (IF) is increasingly recognized as an effective dietary intervention for slowing aging process and alleviating metabolic disturbances in multiple chronic diseases, especially in cardiovascular diseases (CVDs). Despite recent progress, the mechanisms behind its effects on cardiovascular health from the perspective of circadian rhythms are not yet fully understood. This review aims to explore the interaction between IF and circadian rhythms, focusing on their combined effects on cardiometabolic risks and cardiovascular outcomes. Evidence from animal models and clinical trials suggests that IF provides protective effects against cardiac damage and dysfunction. It is also indicated that IF influences key cardiometabolic risk factors, such as insulin sensitivity, inflammation, and lipid metabolism, by aligning with the intrinsic biological rhythms. Additionally, we discuss the therapeutic potential of IF in cardiovascular outcomes, particularly in individuals with circadian disruptions. This review also highlights future research directions to identify the most effective fasting protocols and assess the long-term cardiovascular benefits of IF in disease prevention and treatment.

BACKGROUND:The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload-induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential. METHODS:Protein synthesis and degradation inhibitors were used to verify the reasons for the decrease in GSNOR. Mass spectrometry and database filtering were used to uncover NEDD4, the E3 Ub (ubiquitin) ligase, involved in GSNOR decrease. NEDD4 cardiomyocyte-specific deficiency mice were used to evaluate the role of NEDD4 and NEDD4-induced ubiquitination of GSNOR in cardiac hypertrophy in vivo. Both IBM (indolebutenate methyl ester derivatives), a highly specific NEDD4 inhibitor, and indole-3-carbinol, a NEDD4 inhibitor currently undergoing phase 2 clinical trial, were used to effectively suppress the NEDD4/GSNOR axis. RESULTS:GSNOR protein levels were reduced, while mRNA levels remained unchanged in myocardium samples from hypertrophic patients and transverse aortic constriction-induced mice, indicating GSNOR is regulated by ubiquitination. NEDD4, an E3 Ub ligase, was associated with GSNOR ubiquitination, which exhibited significantly higher expression levels in hypertrophic myocardial samples. Moreover, either the NEDD4 enzyme-dead mutant or GSNOR nonubiquitylated mutant decreased GSNOR ubiquitination and inhibited cardiac hypertrophic growth. Cardiomyocyte-specific NEDD4 deficiency inhibited cardiac hypertrophy in vitro and in vivo. NEDD4 inhibitor IBM effectively suppressed GSNOR ubiquitination and cardiac hypertrophy. Clinically, indole-3-carbinol, a NEDD4 inhibitor in phase II clinical trials used as an antitumor drug, demonstrated comparable efficacy. CONCLUSIONS:Our findings showed that upregulated NEDD4 leads to GSNOR ubiquitination and subsequent degradation, thereby facilitating the progression of cardiac hypertrophy. NEDD4 inhibitors may serve as a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.

Hypoxia severely limits the antitumor immunotherapy for breast cancer. Although efforts to alleviate tumor hypoxia and drug delivery using diverse nanostructures achieve promising results, the creation of a versatile controllable oxygen-releasing nano-platform for co-delivery with immunostimulatory molecules remains a persistent challenge. To address this problem, a versatile oxygen controllable releasing vehicle PFOB@F127@PDA (PFPNPs) is developed, which effectively co-delivered either protein drug lactate oxidase (LOX) or nucleic acids drug unmethylated cytosine-phosphate-guanine oligonucleotide (CpG ODNs). Upon photothermal heating, this platform triggered oxygen release, thereby augmenting LOX-mediated lactate detection rates, and improving T cells infiltrating and cytokine expression. Moreover, under an oxygenated tumor microenvironment (TME), PFPNPs co-delivered with CpG ODNs effectively reprogrammed the immunosuppressive TME by repolarizing macrophages to an M1-like phenotype, promoting dendritic cells maturation, and increasing tumor-infiltrating T cells while decreasing the ratio of regulatory T cells (Tregs). Our study demonstrated that this controlled oxygen-releasing platform possessed adaptive drug-loading capabilities to meet varied immunotherapeutic demands in clinical settings.

Background:Systemic immune-inflammation index (SII), calculated as platelet count × neutrophil count/lymphocyte count, is a novel and easily accessible inflammatory marker. Its prognostic value in predicting infarct size and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) remains to be fully explored. Methods:We analyzed 421 patients who underwent primary percutaneous coronary intervention (PCI) within 12 h of symptom onset, enrolled in a prospective multicenter registry (NCT03768453).All patients received immediate admission blood tests for SII calculation (platelet × neutrophil/lymphocyte counts) and completed standardized CMR imaging within 10 days post-PCI.Receiver operating characteristic (ROC) analysis identified the optimal SII cut-off value (914) to predict large infarct size (≥20 % of left ventricular mass). Patients were stratified into high (≥914) and low (<914) SII groups. The relationships between SII, infarct size, and MACE were analyzed using multivariate logistic and Cox regression models. Results:Patients with high SII had significantly larger infarct size (median 29.0 % vs. 22.3 %, p < 0.001). SII ≥ 914 was independently associated with large infarct size (OR 1.889, 95 %CI: 1.100-3.242, p = 0.021) and higher incidence of MACE (HR 1.874, 95 % CI: 1.255-2.796, p = 0.002). Conclusions:Elevated SII (≥914) independently associates with larger infarct size and increased MACE risk post-PCI, suggesting potential utility in risk stratification.

Background: Doxorubicin (DOX), a classical chemotherapeutic agent, faces significant limitations because of its well-documented risk of inducing cardiotoxicity. Effective prevention of DOX-induced cardiotoxicity is urgently needed. Given that alterations in metabolic pathways have been observed in both cardiovascular diseases and cancer, targeting specific metabolic pathways may offer dual benefits by mitigating DOX-induced cardiotoxicity while simultaneously enhancing its antitumor efficacy. Objectives: This study sought to explore the characteristic metabolic alterations associated with early DOX-induced cardiotoxicity and identify a therapeutic target that simultaneously inhibits cancer and protects the myocardium. Methods: Metabolomic and transcriptomic analyses were performed on heart tissues from murine models of DOX-induced cardiotoxicity to identify the most significantly altered metabolic pathway. The most altered metabolite involved in the candidate pathway was chosen and verified in both mice and humans. The protective effects of the chosen metabolite against DOX-induced cardiotoxicity and its antitumor effects were evaluated. Potential mechanisms were explored using C57BL/6J mice, OPLAH global knockout mice, BALB/c nude mice and NSG mice. Results: The glutathione metabolic pathway was identified as the most altered pathway in heart tissues with DOX-induced cardiotoxicity. The 5-oxoproline/OPLAH (5-oxoprolinase) axis was the most critical node. Downregulation of 5-oxoproline was observed in serum samples from both humans and mice. Exogenous 5-oxoproline supplementation effectively restored myocardial 5-oxoproline levels, subsequently mitigating DOX-induced cardiac dysfunction. Interestingly, we observed an additional inhibitory effect of 5-oxoproline on tumor proliferation in tumor-bearing mice treated with DOX. Mechanistically, 5-oxoproline exerts its cardioprotective effects by restoring glutathione metabolic homeostasis through the modulation of its downstream enzyme OPLAH while simultaneously suppressing tumor proliferation by inhibiting its upstream enzyme, gamma-glutamyl cyclotransferase (GGCT). Conclusions: This study reveals a previously unrecognized dual role of 5-oxoproline, which functions both as an early biomarker for DOX-induced cardiotoxicity detection and as a therapeutic target that simultaneously inhibits cancer growth and protects the myocardium.