Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection, often progressing to multiple organ dysfunction syndrome (MODS). Recent evidence highlights macrophage metabolic reprogramming as a critical driver of immune responses, yet macrophages operate within a broader immunometabolic network involving dendritic cells, neutrophils, and lymphocytes that collectively shape sepsis outcomes. The coordination of these metabolic changes across multicellular interactions and their contribution to organ-specific vulnerability remain poorly understood. Here we present a holistic framework linking macrophage metabolism to multicellular communication and organ vulnerability. We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation. These signals reshape cellular networks through cytokines, extracellular vesicles, and damage-associated molecule patterns (DAMPs), differentially impacting organs with diverse metabolic demands, including the heart, lung, liver, kidney, brain, and intestine, resulting in distinct injury patterns. Our framework enhances understanding of sepsis-induced organ heterogeneity and advocates for stage-specific, organ-targeted therapies that consider integrated multicellular immunometabolic contributions.

Sepsis is a life-threatening clinical syndrome characterized by dysregulated host response, metabolic disturbance, and multiple organ dysfunction. Mitochondrial damage and bioenergetic failure are core pathological events driving sepsis progression. As a critical intercellular communication mechanism, mitochondrial transfer (MT) participates in mitochondrial quality control, energy homeostasis, and inflammatory regulation under septic stress. This review systematically summarizes the structural and functional mitochondrial injury in sepsis and endogenous quality control pathways. We focus on the four major MT routes, their crosstalk, and regulatory networks. The dual role of MT in sepsis is highlighted: functional MT supports tissue repair and organ protection, while damaged MT amplifies inflammation and exacerbates organ injury. We further outline current strategies to optimize MT-based therapy, including donor cell preconditioning, carrier engineering, and direct mitochondrial modification, as well as biosafety and translational challenges. This review provides an integrated theoretical framework and practical strategies for mitochondria-targeted interventions in sepsis.

Hyperuricemia (HUA) is implicated in various metabolic and inflammatory diseases. Its role in the pathogenesis of acute pancreatitis (AP), particularly in gut-pancreas crosstalk and the underlying molecular mechanisms, remains poorly understood. This study integrates clinical epidemiology (UK Biobank cohort and the Third Xiangya Hospital cohort), (L-arginine-induced AP mouse models), and multi-omics analyses (RNA sequencing, fecal metabolomics, and gut microbiome profiling) to elucidate the role and mechanistic pathways of uric acid in the onset and severity of AP. Key molecular targets and regulatory relationships identified were further validated via in vitro cellular experiments using pancreatic acinar cells and bone marrow-derived macrophages. In the UK Biobank cohort, over a median follow-up period of 13.69 years, participants in the highest uric acid quartile exhibited a significantly increased risk of developing AP compared to the lowest quartile (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.10-1.43). In the Third Xiangya Hospital cohort, AP patients with elevated serum uric acid levels exhibited more severe symptoms. The combination of uric acid and calcium demonstrated superior predictive capability for AP severity (AUC 0.9504). In the preclinical models, HUA aggravated AP progression, as demonstrated by increased pancreatic histopathological damage, elevated serum amylase levels, multi-organ dysfunction, and higher mortality. Mechanistically, HUA exacerbated AP in mice via cannabinoid receptor 1 (CNR1)-mediated retrograde endocannabinoid signaling, which enhanced macrophage-derived IL-1β and IL-6 production. Metabolomics revealed that the gut-derived flavonoid maesopsin exerted a protective anti-inflammatory effect in the context of HUA-augmented AP. Additionally, Limosilactobacillus genus, particularly Limosilactobacillus reuteri D, was enriched in the HUA + AP group and strongly associated with maesopsin levels. Uric acid exacerbates AP progression via CNR1 driven inflammatory signaling and modulates gut microbiota composition and metabolism. Serum uric acid, especially when combined with calcium, may be integrated into routine clinical assessment for AP risk stratification and severity prediction, while CNR1 and gut microbiota-related targets provided potential directions for the developing adjunctive therapies for HUA-associated AP.

Sarcopenia and ulcerative colitis (UC) may share potential biological links through mechanisms involving immune dysregulation, gut microbiota imbalance, and inflammatory pathway activation. This study aimed to identify fatty acid metabolism-related shared genes between UC and sarcopenia. A total of 277 shared differentially expressed genes (sDEGs) were identified, which were mainly enriched in immune-, inflammation-, and metabolism-related pathways. By intersecting the sDEGs with fatty acid metabolism-related gene sets, 13 fatty acid metabolism-related shared differentially expressed genes (FAM-sDEGs) were obtained, and unsupervised clustering based on these genes stratified UC patients into distinct molecular subtypes. Using machine learning and feature-ranking methods, PHYH and HSD17B3 were ultimately identified as key hub genes. ROC analysis showed that these two genes exhibited diagnostic value for both sarcopenia and UC across multiple datasets. In addition, the expression of the hub genes was significantly associated with immune cell infiltration profiles and was further validated in independent datasets. Preliminary validation in a UC cell model confirmed the downregulation of PHYH, while immunohistochemical analysis of colonic tissues further supported the downregulated expression of PHYH in patients with UC, consistent with the bioinformatics results. Collectively, these findings suggest that fatty acid metabolism may play an important role in the shared molecular features between UC and sarcopenia, and that PHYH may serve as potential diagnostic biomarkers.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.

BACKGROUND:Acute pancreatitis (AP) is a severe inflammatory disorder characterized by pancreatic self-digestion, often progressing to systemic inflammation. Despite advances in understanding its pathogenesis, effective therapeutic strategies remain limited. Heat shock factor 1 (HSF1), a critical transcription factor that maintains cellular homeostasis and regulates the stress response, is downregulated in the pancreas of L-arginine-induced AP mice. However, its role and regulatory mechanisms in the pathogenesis of AP remain unclear. This study aims to elucidate the molecular function and mechanisms of HSF1 in AP, focusing on its regulation by E1A binding protein p300 (EP300) and the downstream effects on mitophagy and inflammation. METHODS:Two distinct mouse models of AP were established using L-arginine and cerulein. Pancreatic acinar cells (AR42J) were used to study the effects of HSF1 and parkin RBR E3 ubiquitin protein ligase (PRKN) on mitophagy and inflammation. The expression and regulation between HSF1, PRKN, and EP300 were assessed using genetic and pharmacological approaches. RESULTS:HSF1 deficiency exacerbates AP severity in two distinct mouse models, with increased mortality, pancreatic necrosis, and systemic inflammation. Mechanistically, HSF1 directly binds to the promoter of PRKN, enhancing its transcriptional activity. Thus, HSF1 alleviates the inflammatory response in pancreatic acinar cells during AP by promoting PRKN-mediated mitophagy, reducing ROS production, and inhibiting NLRP3 inflammasome activation. HSF1 expression is downregulated in pancreatic acinar cells due to decreased acetylation by EP300, leading to proteasomal degradation and impaired mitophagy. Pharmacological activation of EP300 (e.g., CTB) restores HSF1 expression, enhances mitophagy, and attenuates inflammation in both in vivo and in vitro settings. CONCLUSION:These findings highlight the critical role of EP300 in regulating HSF1 acetylation and stability, which in turn modulates mitophagy and pyroptosis in AP. Targeting EP300 and its downstream pathways, such as HSF1-PRKN axis, may offer novel therapeutic strategies for AP.

Sepsis is a life-threatening condition characterized by a dysregulated host innate immune response to pathogen infection. Here, we identify a pathological role for bromodomain-containing 3 (BRD3) in driving septic shock by upregulating aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages via a non-canonical pathway. Mechanistically, lipopolysaccharide triggers an interaction between BRD3 and tripartite motif containing 21 (TRIM21), which activates CREB binding lysine acetyltransferase (CREBBP) via its E3 ligase activity, facilitating CREBBP's binding to and acetylation of cyclic adenosine monophophate (cAMP)-response-element-binding protein 1 (CREB1). BRD3 then recognizes and phosphorylates acetylated CREB1 at the transcription-activating site, thereby upregulating ACOD1 transcription. In four murine models of infection, myeloid-specific Brd3 deletion (Brd3Mye-/-) or pharmacological intervention using small-molecule inhibitor OTX015 confers significant protection, reducing systemic inflammation and organ injury, similar to the effects observed in Acod1Mye-/- mice. In patients with sepsis, elevated BRD3 levels correlate with accelerated inflammation, increased disease severity, and a greater risk of in-hospital death. These findings establish BRD3 as a potential therapeutic target for managing infection-associated immune dysregulation.

Innate immunity, the first line of host defense against viral infections, recognizes viral components through different pattern-recognition receptors. Nucleic acids derived from viruses are mainly recognized by Toll-like receptors, nucleotide-binding domain leucine-rich repeat-containing receptors, absent in melanoma 2-like receptors, and cytosolic DNA sensors (e.g., Z-DNA-binding protein 1 and cyclic GMP-AMP synthase). Different types of nucleic acid sensors can recognize specific viruses due to their unique structures. PANoptosis is a unique form of inflammatory cell death pathway that is triggered by innate immune sensors and driven by caspases and receptor-interacting serine/threonine kinases through PANoptosome complexes. Nucleic acid sensors (e.g., Z-DNA-binding protein 1 and absent in melanoma 2) not only detect viruses, but also mediate PANoptosis through providing scaffold for the assembly of PANoptosomes. This review summarizes the structures of different nucleic acid sensors, discusses their roles in viral infections by driving PANoptosis, and highlights the crosstalk between different nucleic acid sensors. It also underscores the promising prospect of manipulating nucleic acid sensors as a therapeutic approach for viral infections.

Acute myocardial infarction (AMI), primarily caused by coronary atherosclerosis, initiates a series of events that culminate in the obstruction of coronary arteries, resulting in severe myocardial ischemia and hypoxia. The subsequent myocardial ischemia/reperfusion (I/R) injury further aggravates cardiac damage, leading to a decline in heart function and the risk of life-threatening complications. The complex interplay of multiple regulated cell death (RCD) pathways plays a pivotal role in the pathogenesis of AMI. Each RCD pathway is orchestrated by a symphony of molecular regulatory mechanisms, highlighting the dynamic changes and critical roles of key effector molecules. Strategic disruption or inhibition of these molecular targets offers a tantalizing prospect for mitigating or even averting the onset of RCD, thereby limiting the extensive loss of cardiomyocytes and the progression of detrimental myocardial fibrosis. This review systematically summarizes the mechanisms underlying various forms of RCD, provides an in-depth exploration of the pathogenesis of AMI through the lens of RCD, and highlights a range of promising therapeutic targets that hold the potential to revolutionize the management of AMI.

Z-DNA binding protein 1 (ZBP1), a cytosolic nucleic acid sensor for Z-form nucleic acids (Z-NA), can detect both exogenous and endogenous nucleic acids. Upon sensing of self Z-NA or exposure to diverse noxious stimuli, ZBP1 regulates inflammation by activating nuclear factor kappa B and interferon regulating factor 3 signaling pathways. In addition, ZBP1 promotes the assembly of ZBP1 PANoptosome, which initiates caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis (PANoptosis), leading to the release of various damage-associated molecular patterns. Thereby, ZBP1 is implicated in the development and progression of diverse sterile inflammatory diseases. This review outlines the expression, structure, and function of ZBP1, along with its dual roles in controlling inflammation and cell death to orchestrate innate immunity in sterile inflammation, especially autoimmune diseases, and cancers. ZBP1 has emerged as an attractive therapeutic target for various sterile inflammatory diseases.

Innate immunity is not only the first line of host defense against microbial infections but is also crucial for the host responses against a variety of noxious stimuli. Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that can induce inflammatory cell death in both immune and nonimmune cells upon sensing of incursive virus-derived Z-form nucleic acids and self-nucleic acids via its Zα domain. Mechanistically, aberrantly expressed or activated ZBP1 induced by pathogens or noxious stimuli enables recruitment of TANK binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 to drive type I interferon (IFN-I) responses and activation of nuclear factor kappa B (NF-κB) signaling. Meanwhile, ZBP1 promotes the assembly of ZBP1- and absent in melanoma 2 (AIM2)-PANoptosome, which ultimately triggers PANoptosis through caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis. In response to damaged mitochondrial DNA, ZBP1 can interact with cyclic GMP-AMP synthase to augment IFN-I responses but inhibits toll like receptor 9-mediated inflammatory responses. This review summarizes the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases.

Objective: Bone marrow stromal stem cells（BMSCs） of SD rats were cultured and identified by the method of whole bone marrow culture in vitro. Methods: Mouse bone marrow stromal stem cells were isolated and enlarged by the whole bone marrow adherent method, and the expressions of CD29, CD34 and CD45 on the cell surface were detected by flow cytometry. Results: The whole bone marrow culture method can rapidly and effectively culture and obtain a large number of bone marrow stromal stem cells. The positive rate of CD29, CD34 and CD45 were 99.0%, 1.5% and 0.8%respectively. Conclusion: The whole bone marrow adherent culture is a simple, efficient and economical way to obtain bone marrow stromal stem cells, and can obtain relatively pure BMSCs.

本团队遵循"循环系统"课程的特点,按照课程设置泰勒模型的要求,有机结合《中国本科医学教育标准》和社会主义核心价值观,深入提炼"循环系统"课程中所蕴含的职业素养、道德等德育元素,以具体案例为教学载体,在教学的各个环节中融入课程思政,旨在为器官系统整合课程及其他医学课程教学提供参考.

Several heat shock proteins are implicated in the endogenous cardioprotective mechanisms, but little is known about the role of heat shock protein beta-1 (HSPB1). This study aims to investigate the oxidation state and role of HSPB1 in cardiomyocytes undergoing oxidative stress and underlying mechanisms. Here, we demonstrate that hydrogen peroxide (H2O2) promotes the homo-oxidation of HSPB1. Cys137 residue of HSPB1 is not only required for it to protect cardiomyocytes against oxidative injury but also modulates its oxidation, phosphorylation at Ser15, and distribution to insoluble cell components after H2O2 treatment. Moreover, Cys137 residue is indispensable for HSPB1 to interact with KEAP1, thus regulating its oxidation and intracellular distribution, subsequently promoting the nuclear translocation of NRF2, and increasing the transcription of GLCM, HMOX1, and TXNRD1. Altogether, these findings provide evidence that Cys137 residue is indispensable for HSPB1 to maintain its redox state and antioxidant activity via activating KEAP1/NRF2 signaling cascade in cardiomyocytes.

Objectives: To investigate the role of protein tyrosine phosphatase non-receptor type 1 (PTPN1) in mitophagy during sepsis and its underlying mechanisms and determine the therapeutic potential of PTPN1 inhibitors in endotoxemia-induced cardiac dysfunction. Methods: A mouse model of endotoxemia was established by administering an intraperitoneal injection of lipopolysaccharide (LPS). The therapeutic effect of targeting PTPN1 was evaluated using its inhibitor Claramine (CLA). Mitochondrial structure and function as well as the expression of mitophagy-related proteins were evaluated. Rat H9c2 cardiomyocytes were exposed to mouse RAW264.7 macrophage-derived conditioned medium. Cryptotanshinone, a specific p-STAT3 (Y705) inhibitor, was used to confirm the role of STAT3 in PTPN1mediated mitophagy following LPS exposure. Electrophoretic mobility shift and dual luciferase reporter assays were performed to discern the mechanisms by which STAT3 regulated the expression of PINK1 and PRKN. Results: CLA alleviated LPS-induced myocardial damage, cardiac dysfunction, and mitochondrial injury and dysfunction in the mouse heart. PTPN1 upregulation exacerbated LPS-induced mitochondrial injury and dysfunction in H9c2 cardiomyocytes, but inhibited LPS-induced mitophagy. LPS promoted the interaction between PTPN1 and STAT3 and reduced STAT3 phosphorylation at Tyr705 (Y705), which was required to inhibit mitophagy by PTPN1. Upon LPS stimulation, PTPN1 negatively regulated the transcription of PINK1 and PRKN through dephosphorylation of STAT3 at Y705. STAT3 regulated the transcription of PINK1 and PRKN by binding to STAT3-responsive elements in their promoters. Conclusion: PTPN1 upregulation aggravates endotoxemia-induced cardiac dysfunction by impeding mitophagy through dephosphorylation of STAT3 at Y705 and negative regulation of PINK1 and PRKN transcription.

PANoptosis, a unique new form of programmed cell death (PCD), is characterized by pyroptosis, apoptosis, and necroptosis, but it cannot be explained by pyroptosis, apoptosis or necroptosis alone. Assembly of the PANoptosome complex is a key feature of PANoptosis. To date, four kinds of PANoptosomes with distinct sensors and regulators have been defined, namely Z-DNA binding protein 1 (ZBP1) PANoptosome, absent in melanoma 2 (AIM2) PANoptosome, receptor-interacting protein kinase 1 (RIPK1) PANoptosome, and nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12). Each PANoptosome contains three components: sensors for pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), adaptors as connected bridges, and catalytic effectors or executioners. Mechanistically, different PAMPs or DAMPs are recognized by the sensors in a context-dependent manner, which initiates PANoptosome assembly through adaptors, and ultimately engages synchronous activation of pyroptosis, apoptosis, and necroptosis via different catalytic effectors. Resultantly, PANoptosis is emerged as a prospective and promising therapeutic target for various diseases. This review covers the accumulating evidence about the roles and mechanisms of PANoptosis in innate immunity and discusses the attractive prospect of manipulating PANoptosis as a new treatment for diseases.

目的:研究和探讨整合素β1在转化生长因子(TGF)诱导BMSCs分化为软骨细胞过程中的作用.方法:全骨髓法体外培养大鼠骨髓基质干细胞(BMSCs),TGF-β3促进和诱导BMSCs的软骨分化、抗整合素β1单克隆抗体抑制整合素的表达.实验分为对照组、诱导组和抑制组,BMSCs培养7d和14d后,分别采用免疫细胞化学(SABC法)检测Ⅱ型胶原(col-Ⅱ),甲苯胺蓝染色检测蛋白多糖的表达情况,Western Blot检测型胶原蛋白和相应整合素β1蛋白含量的表达.结果:培养7d和14d后,诱导组col-Ⅱ和蛋白多糖的表达均呈阳性,细胞形态由原来的长形或长梭形变短变圆,而对照组和抑制组均为阴性.诱导组col-Ⅱ和相应整合素β1蛋白的表达量均增多,而抑制组则较对照组减少,但两组的col-Ⅱ表达均为阴性.结论:TGF-β3能上调整合素受体的表达,促进BMSCs的软骨分化;抗整合素β1的单克隆抗体可以下调整合素β1的表达,抑制BMSCs的软骨分化.

Myocardial infarction (MI) is a cardiovascular disease with high morbidity and mortality. Clinically, rehabilitation after massive MI often has a poor prognosis. Therefore, it is necessary to explore the therapeutic methods of myocardial protection after MI. As a first-line treatment for type 2 diabetes, metformin has been found to have a certain protective effect on myocardial tissue. However, its pharmacological mechanism remains unclear. In this study, we investigated key factors that reduced MI with metformin. Through in vivo, in vitro, and in silico analyses, we identified HSF1 as a key target for metformin. HSF1 could up-regulate the transcriptional level of AMPKα2 through transcriptional activation and stimulate the activity of the downstream AMPK/mTOR signaling pathway. Metformin stimulated cardiomyocytes to form stress granules (SGs), and knockdown of HSF1 reversed this process. Furthermore, HSF1 exhibited better in vitro affinity for metformin than AMPK, suggesting that HSF1 may be a more sensitive target for metformin.

分析紧急医疗服务前自动体外除颤器使用的影响因素,并对提高我国自动体外除颤器的使用率提出相关建议.通过描述国内外紧急医疗服务到达前自动体外除颤器使用现状,从人力资源因素(专业第一反应者和公民第一反应者)、自动体外除颤器可用性(数量、位置、时间因素)及可及性(距离、运送设备、紧急医疗服务因素)3个方面总结归纳了紧急医疗服务前自动体外除颤器使用的影响因素,并在此基础上探讨加强自动体外除颤器培训、建立全国自动体外除颤器登记处及减少自动体外除颤器使用时间的干预策略,以期为进一步提高自动体外除颤器的使用率提供参考依据.