Objective:To develop and temporally validate an admission-variable model for estimating the risk of persistent inflammation-immunosuppression-catabolism syndrome (PICS) among patients with sepsis who remained in the intensive care unit (ICU) for ≥14 days. Methods:We conducted an ambispective, single-center cohort study. The retrospective development cohort included patients admitted from January 2023 to May 2025, and the prospective temporal validation cohort included patients admitted from June 2025 to February 2026. Candidate predictors measured at ICU admission were selected using least absolute shrinkage and selection operator (LASSO) regression and entered into a multivariable logistic regression model. Discrimination, calibration, and potential clinical utility were evaluated using the area under the receiver operating characteristic curve (AUC), calibration analyses, and decision curve analysis. Results:The development cohort included 242 patients, of whom 93 (38.4%) met the PICS criteria. Compared with respiratory infection, urinary infection (adjusted odds ratio (aOR 0.07, 95% CI 0.01-0.67), gastrointestinal infection (aOR 0.15, 95% CI 0.05-0.45), and skin or soft-tissue infection (aOR 0.29, 95% CI 0.11-0.77) were associated with lower odds of PICS. Higher lactate was associated with higher odds of PICS (aOR 1.20, 95% CI 1.07-1.34), whereas higher lymphocyte count (aOR 0.46, 95% CI 0.28-0.77), albumin (aOR 0.92, 95% CI 0.86-0.99), and vitamin D (aOR 0.88, 95% CI 0.83-0.94) were associated with lower odds. The AUC was 0.803 (95% CI 0.747-0.859) in the development cohort and 0.791 (95% CI 0.718-0.864) in the temporal validation cohort. Conclusion:Among patients with sepsis who remained in the ICU for ≥14 days, an admission-variable model showed acceptable discrimination in the development and temporal validation cohorts. External multicenter validation and prospective impact evaluation are required before clinical use.

OBJECTIVES:Sepsis patients exhibit diverse immune states, making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis. METHODS:We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital, Southern Medical University from June 1, 2020, to February 1, 2022. An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels, with the primary outcome being the 7-day mortality rate post-ICU admission. Cox proportional hazards and Restricted Mean Survival Time (RMST) analyses were utilized to explore survival outcomes. RESULTS:A total of 321 sepsis patients were included. IL-6 (HR 1.69, 95%CI: 1.22, 2.34) and IL-10 (HR 1.81, 95% CI: 1.37, 2.40) emerged as independent predictors of 7-day mortality. Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups: Cluster 1 (n=166, low inflammatory response), Cluster 2 (n=99, moderate inflammatory response with immune suppression), and Cluster 3 (n=56, strong inflammatory and immune suppression). Compared to Cluster 1, Clusters 2 and 3 had higher 7-day mortality risks (14.4% vs 23.2%, HR=4.30, 95% CI: 1.51-12.26; 14.4% vs 35.7%, HR=7.32, 95% CI: 2.57-20.79). CONCLUSIONS:Septic patients in a protective immune response state (Cluster 1) exhibit better short-term prognoses, suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.

Large-scale studies indicate a strong relationship between the gut microbiome, type 2 diabetes mellitus (T2DM), and atherosclerotic cardiovascular disease (ASCVD). Here, a higher abundance of the type III secretion system (T3SS) virulence factors of Enterobacteriaceae/Escherichia-Shigella in patients with T2DM-related-ASCVD, which correlates with their atherosclerotic stenosis is reported. Overexpression of T3SS via Citrobacter rodentium (CR) infection in Apoe-/- T2DM mice exacerbated atherosclerotic lesion formation and increased gut permeability. Non-targeted metabolomic and proteomic analysis of mouse serum showed that T3SS caused abnormal glycerophospholipid metabolism in mice. Proteomics, RNA sequencing, and functional analyses showed that T3SS induced ferroptosis in intestinal epithelial cells, partly due to increased expression of ferritin heavy chains (FTH1). This findings first demonstrated that T3SS increases ferroptosis in intestinal epithelial cells, via disrupting the intestinal barrier and upregulation of phosphatidylcholine, thereby exacerbating T2DM-related ASCVD.

This study aims to evaluate the impact of diabetic ketoacidosis (DKA) on clinical outcomes among intensive care unit (ICU) patients diagnosed with COVID-19 and concurrent diabetes. A retrospective analysis was conducted on ICU patients diagnosed with both COVID-19 and diabetes at a tertiary-level hospital. Patients were stratified into two groups, non-DKA and DKA, based on the presence of DKA. Comparative analyses were performed to assess clinical characteristics, laboratory parameters, treatment modalities, and prognostic outcomes between the two groups. The study included 111 ICU patients with COVID-19 and concurrent diabetes, comprising 88 patients in the non-DKA group and 23 patients in the DKA group. Compared to the non-DKA group, the DKA group exhibited a significantly higher proportion of female patients, younger age, and lower prevalence of hypertension, cardiac, and renal comorbidities (p < 0.05). The overall mortality rate was 43.5

Background Atherosclerosis (AS) is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Leonurine (LEO) is a unique alkaloid compound with protective effects on the cardiovascular system. However, the exact mechanisms underlying its cardiovascular-protecting action are still not fully elucidated. The methyltransferase 3 (METTL3), the catalytic core of the N6-methyladenosine modification (m6A) methyltransferase complex, has been shown to inhibit autophagy and exacerbate the process of AS via regulation of m6A modification of mRNA. Purpose We aimed to determine whether the inhibited effect of LEO on AS is related to METTL3-mediated AKT1S1 stability. Methods The apolipoprotein E (ApoE) knockout mice was subjected to a high-fat diet (HFD), and THP-1 derived macrophages was exposed to oxidized low-density lipoprotein (ox-LDL), to establish the animal and cellular models of AS, respectively. Results We found that LEO effectively improved AS and reduced the plaque area and inflammation via diminishing macrophage lipid accumulation and remodeling the lipid metabolism profile. LEO activated ox-LDL-induced macrophage autophagy, enhancing lipid metabolism decrease, according to the lipidomic and molecular biology analyses. Additionally, LEO caused a marked increase in autophagy marker levels in mouse models with advanced AS. Furthermore, we found that LEO reactivated autophagy and reversed lipid accumulation by suppressing METTL3 expression. The m6A-seq from ox-LDL-induced macrophages showed that a total of five autophagy-related mRNA transcripts (AKT1S1, AKT1, RB1CC1, CFLAR, and MTMR4) were altered, and AKT1S1 was significantly upregulated by LEO. Mechanistically, LEO-mediated regulation of METTL3 decreased AKT1S1 expression by attenuating its mRNA stability. Silencing AKT1S1 inhibited LEO-METTL3 axis-mediated autophagy and enhanced lipid accumulation in ox-LDL-induced macrophages. Conclusion The study first revealed that LEO exerts anti-atherosclerotic effect by activating METTL3-mediated macrophage autophagy in vivo and in vitro. The mechanism of LEO was further found to be the enhancement of METTL3-mediated AKT1S1 stability to activate autophagy thereby reducing lipid accumulation. This study provides a new perspective of natural medicines on the treatment of AS via an epigenetic manner.

Background: Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM). Ferroptosis is an atypical form of iron-dependent, modulated cell death that has been shown to occur in human umbilical vein endothelial cells (HUVECs). Leonurine (LEO) is a single active ingredient extracted from Leonurus japonicus Houtt. It has various biological activities, including anti-inflammatory and anti-cancer effects. However, whether LEO affects ferroptosis in DN has yet to be investigated. Methods: An animal model of DN was established by subjecting C57/BL6 mice to a high-fat diet (HFD) while being induced with Streptozotocin (STZ). A cellular model of DN was established by exposing HUVECs to a high glucose (HG) concentration of 30 mM. Results: LEO was found to improve DN and to attenuate the degree of glomerulosclerosis and tubular atrophy in the mouse model. Additionally, it markedly decreased the levels of ferroptosis markers. Molecular analyses revealed that LEO inhibited HG-induced oxidative stress in HUVECs, thereby decreasing endothelial cell (EC) dysfunction. Furthermore, LEO was found to reduce ferroptosis and reverse EC dysfunction by increasing the expression of glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The suppression of Nrf2 in HG-induced HUVECs inhibited LEO-GPX4 axis-mediated ferroptosis and increased EC dysfunction. Conclusions: LEO exerts anti-DN effects both in vivo and in vitro by suppressing GPX4-mediated EC ferroptosis. Mechanistically, LEO appears to induce Nrf2-mediated GPX4 expression to inhibit ferroptosis, thereby reducing EC dysfunction. This study provides a new perspective on the treatment of diseases using natural medicines. It involves a novel form of cell death that could potentially lead to better treatment of DN.

A growing number of studies have shown that melatonin is a potent agonist of SIRT3 (sirtuin 3) and effectively protects mitochondria, suggesting melatonin as a promising therapeutic drug to treat sepsis-induced acute kidney injury (SAKI). In this study, we first included 48 sepsis patients for cross-sectional analysis and the result revealed that plasma melatonin levels are inversely proportional to the mitochondrial injury of renal tubular epithelial cells and directly proportional to the acute kidney injury recovery in sepsis patients. We further explored the effects of exogenous melatonin on SAKI and its mechanism in animal model of cecal ligation and puncture-treated mice, and cellular model of LPS-challenged HK-2 cells. The results demonstrate that the protective effect of melatonin on the progression of SAKI depends on SIRT3 activation as well as mitophagic flux. Mechanistically, TFAM (transcription factor A, mitochondrial)-K154 site deacetylation via SIRT3 is indispensable for melatonin-enhanced mitophagic flux on SAKI. Together, our study unveils a previously unappreciated mechanism of melatonin as agonists of SIRT3 to hold promise for treatment of patients with SAKI.AbbreviationsAKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H & E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.

BACKGROUND:Studies have found that the plasma content of gut-derived 4-hydroxyphenylacetic acid (4-HPA) was significantly increased in septic patients. However, the mechanism of 4-HPA elevation during sepsis and its relationship with sepsis-induced acute kidney injury (SAKI) remain unclear.METHODS:Cecal ligation and puncture (CLP) was performed in C57BL/6 mice to establish the SAKI animal model. Human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide were used to establish the SAKI cell model. The widely targeted metabolomics was applied to analyze the renal metabolite changes after CLP. Proteomics was used to explore potential target proteins regulated by 4-HPA. The blood sample of clinical sepsis patients was collected to examine the 4-HPA content.RESULTS:We found that renal gut-derived 4-HPA levels were significantly increased after CLP. The high permeability of intestinal barrier after sepsis contributed to the dramatic increase of renal 4-HPA. Intriguingly, we demonstrated that exogenous 4-HPA administration could further significantly reduce CLP-induced increases in serum creatinine, urea nitrogen, and cystatin C, inhibit renal pathological damage and apoptosis, and improve the survival of mice. Mechanistically, 4-HPA inhibited necroptosis in renal tubular epithelial cells by upregulating the protein expression of apoptosis repressor with caspase recruitment domain (ARC) and enhancing the interaction between ARC and receptor-interacting protein kinase 1 (RIPK1).CONCLUSIONS:The increase of gut-derived 4-HPA in the kidney after sepsis could play a protective effect in SAKI by upregulating ARC to inhibit necroptosis.

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.

Background: Many studies demonstrated no improved survival in patients with pulmonary artery catheter placement. However, no consistent conclusions have been drawn regarding the impact of pulmonary artery catheter in critically ill patients with heart disease. This study aimed to investigate the association of early pulmonary artery catheter use with 28-day mortality in that population. Methods: The Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database, a single-center critical care database, was employed to investigate this issue. This study enrolled a total of 11,887 critically ill patients with cardiac disease with or without pulmonary artery catheter insertion. The primary outcome was 28-day mortality. The multivariate regression was modeled to examine the association between pulmonary artery catheter and outcomes. Additionally, we examined the effect modification by cardiac surgeries. Propensity score matching was conducted to validate our findings. Results: No improvement in 28-day mortality was observed among the pulmonary artery catheter group compared to the non-pulmonary artery catheter group (odds ratio 95% confidence interval: 1.18 [1.00-1.38], P =.049). When stratified by cardiac surgeries, the results were consistent. The patients in the pulmonary artery catheter group had fewer ventilation-free days and vasopressor-free days than those in the nonpulmonary artery catheter group after surgery stratification. In the surgical patients, pulmonary artery catheter insertion was not associated with the occurrence of acute kidney injury, and it was associated with a higher daily fluid input (mean difference 95% confidence interval: 0.13 [0.05-0.20], P =.001). In nonsurgical patients, the pulmonary artery catheter group had a higher risk of acute kidney injury occurrence (odds ratio 95% confidence interval: 1.94 [1.32-2.84], P =.001). Conclusion: Early pulmonary artery catheter placement is not associated with survival benefits in critically ill patients with cardiac diseases, either in surgical or nonsurgical patients. (c) 2022 Elsevier Inc. All rights reserved.

In diabetic cardiomyopathy (DCM), a major diabetic complication, the myocardium is structurally and functionally altered without evidence of coronary artery disease, hypertension or valvular disease.Although numerous anti-diabetic drugs have been applied clinically, specific medicines to prevent DCM progression are unavailable, so the prognosis of DCM remains poor.Mitochondrial ATP production maintains the energetic requirements of cardiomyocytes, whereas mitochondrial dysfunction can induce or aggravate DCM by promoting oxidative stress, dysregulated calcium homeostasis, metabolic reprogramming, abnormal intracellular signaling and mitochondrial apoptosis in cardiomyocytes.In response to mitochondrial dysfunction, the mitochondrial quality control (MQC) system (including mitochondrial fission, fusion, and mitophagy) is activated to repair damaged mitochondria.Physiological mitochondrial fission fragments the network to isolate damaged mitochondria.Mitophagy then allows dysfunctional mitochondria to be engulfed by autophagosomes and degraded in lysosomes.However, abnormal MQC results in excessive mitochondrial fission, impaired mitochondrial fusion and delayed mitophagy, causing fragmented mitochondria to accumulate in cardiomyocytes.In this review, we summarize the molecular mechanisms of MQC and discuss how pathological MQC contributes to DCM development.We then present promising therapeutic approaches to improve MQC and prevent DCM progression.

Mitochondria maintain mitochondrial homeostasis through continuous fusion and fission, that is, mitochondrial dynamics, which is precisely mediated by mitochondrial fission and fusion proteins, including dynamin-related protein 1 (Drp1), mitofusin 1 and 2 (Mfn1/2), and optic atrophy 1 (OPA1). When the mitochondrial fission and fusion of cardiomyocytes are out of balance, they will cause their own morphology and function disorders, which damage the structure and function of the heart, are involved in the occurrence and progression of cardiovascular disease such as ischemia-reperfusion injury (IRI), septic cardiomyopathy, and diabetic cardiomyopathy. In this paper, we focus on the latest findings regarding the molecular features and regulatory mechanisms of mitochondrial dynamic disorder in cardiovascular pathologies. Finally, we will address how these findings can be applied to improve the treatment of cardiovascular disease.

糖尿病心肌病是糖尿病患者的一种特殊的心脏并发症,其特征主要表现为早期阶段的左心室肥大和舒张功能障碍,直至发展为心力衰竭.因此,探索糖尿病心肌病的治疗方案具有重要的临床意义.研究表明,生酮饮食具有改善糖尿病心肌病的作用,但具体机制尚未阐明.本文总结了糖尿病引发心力衰竭的途径和机制,阐述了生酮饮食改善糖尿病心肌病的潜在机制,如改善氧化应激、炎症、线粒体功能、心肌代谢等,为糖尿病心肌病的防治提供新的思路.

As a nicotinamide adenine dinucleotide (NAD)(+)-dependent protein deacetylase, SIRT3 is highly expressed in tissues with high metabolic turnover and mitochondrial content. It has been demonstrated that SIRT3 plays a critical role in maintaining normal mitochondrial biological function through reversible protein lysine deacetylation. SIRT3 has a variety of substrates that are involved in mitochondrial biological processes such as energy metabolism, reactive oxygen species production and clearance, electron transport chain flux, mitochondrial membrane potential maintenance, and mitochondrial dynamics. In the suppression of SIRT3, functional deficiencies of mitochondria contribute to the development of various cardiovascular disorders. Activation of SIRT3 may represent a promising therapeutic strategy for the improvement of mitochondrial function and the treatment of relevant cardiovascular disorders. In the current review, we discuss the emerging roles of SIRT3 in mitochondrial derangements and subsequent cardiovascular malfunctions, including cardiac hypertrophy and heart failure, ischemia-reperfusion injury, and endothelial dysfunction in hypertension and atherosclerosis.

Sepsis is a threatening health problem and characterized by microvascular dysfunction. In this study, we verified that LPS caused the downregulation of Sirt1 and the hyperpermeability of endothelial cells. Inhibition of Sirt1 with ex527 or Sirt1 siRNA displayed a higher permeability, while activation of Sirt1 with SRT1720 reversed the LPS-induced hyperpermeability, formation of fiber stress, and disruption of VE-cadherin distribution. In pulmonary microvascular vein endothelial cells isolated from wild-type mice, Sirt1 was attenuated upon LPS, while Sirt1 was preserved in a receptor of advanced glycation end product-knockout mice. The RAGE antibody could also diminish the downregulation and ubiquitination of Sirt1 in LPS-exposed human umbilical vein endothelial cells. An LPS-induced decrease in Sirt1 activity was attenuated by the RAGE antibody and TLR4 inhibitor. In vivo study also demonstrated the attenuating role of Sirt1 and RAGE knockout in LPS-induced increases in dextran leakage of mesenteric venules. Furthermore, activation of Sirt1 prevented LPS-induced decreases in the activity and expression of superoxide dismutase 2, as well as the increases in NADPH oxidase 4 and reactive oxygen species, while inhibition of Sirt1 aggravated the SOD2 decline. It also demonstrated that Sirt1-deacetylated p53 is required for p53 inactivation, which reversed the downregulation of β-catenin caused by LPS.

The vascular endothelium is a layer of cells lining the inner surface of vessels, serving as a barrier that mediates microenvironment homeostasis. Deterioration of either the structure or function of endothelial cells (ECs) results in a variety of cardiovascular diseases. Previous studies have shown that reactive oxygen species (ROS) is a key factor that contributes to the impairment of ECs and the subsequent endothelial dysfunction. The longevity regulator Sirt1 is a NAD+-dependent deacetylase that has a potential antioxidative stress activity in vascular ECs. The mechanisms underlying the protective effects involve Sirt1/FOXOs, Sirt1/NF-κB, Sirt1/NOX, Sirt1/SOD, and Sirt1/eNOs pathways. In this review, we summarize the most recent reports in this field to recapitulate the potent mechanisms involving the protective role of Sirt1 in oxidative stress and to highlight the beneficial effects of Sirt1 on cardiovascular functions.