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.

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.

The journal retracts the article, “Mipu1 protects H9c2 myogenic cells from hydrogen peroxide-induced apoptosis through inhibition of the expression of the death receptor Fas” [...]

Background: Multiple cell death modalities are implicated in sepsis pathobiology. However, the clinical relevance of NINJ1, a key mediator of plasma membrane rupture during lytic cell death, in sepsis progression and outcomes has remained poorly explored. Methods: Circulating NINJ1 levels were measured in 116 septic intensive care unit (ICU) patients, 16 nonseptic ICU controls, and 16 healthy controls. Comparative analysis of serum NINJ1 across these groups was performed. Correlations between NINJ1 and clinical disease severity scores (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation [APACHE II]) as well as laboratory parameters were examined in the sepsis cohort. Furthermore, we assessed the prognostic performance of NINJ1 for predicting 28-day mortality in septic patients using receiver operating characteristic (ROC) analyses. Results: Circulating NINJ1 levels were elevated in septic patients and positively correlated with sepsis severity scores. NINJ1 also showed positive correlations with liver injury markers (aspartate transaminase/alanine aminotransferase) and coagulation parameters (D-dimer, activated partial thromboplastin time, prothrombin time, thrombin time) in sepsis. Further analysis using the International Society on Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring system revealed an association between NINJ1 and sepsis-induced coagulopathy. ROC analysis demonstrated that NINJ1 outperformed traditional inflammatory biomarkers procalcitonin and C-reactive protein in predicting 28-day sepsis mortality, although its prognostic accuracy was lower than SOFA and APACHE II scores. Combining NINJ1 with SOFA improved mortality prediction from an area under the curve of 0.6843 to 0.773. Conclusions: Circulating NINJ1 serves as a novel sepsis biomarker indicative of disease severity, coagulopathy and mortality risk, and its integration with SOFA and APACHE II scores substantially enhances prognostic risk stratification. These findings highlight the prospective clinical utility of NINJ1 for sepsis prognostication and monitoring, warranting further validation studies to facilitate implementation.

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.

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.

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.

Zinc finger protein 667 (ZNF667, also referred as Mipu1), a widely expressed KRAB/C2H2-type zinc finger transcription factor, can protect against hypoxic-ischemic myocardial injury. Pro-angiogenesis is regarded as a promising strategy for the treatment of acute myocardial infarction (AMI). However, whether ZNF667 is involved in the angiogenesis following AMI remains to be elucidated. The present study reported that the expression of ZNF667 in CD31-positive endothelial cells (ECs) was upregulated in the heart of AMI mice. Hypoxic challenge (1% oxygen) promoted the mRNA and protein expression of ZNF667 in the human umbilical vein endothelial cells (HUVECs) in a time-dependent manner. Moreover, ZNF667 promoted hypoxia-induced invasion and tube formation of HUVECs. Mechanically, ZNF667 could directly bind to the promoter of anti-angiogenic gene VASH1 and inhibit its expression. Consequently, VASH1 overexpression abolished hypoxic challenge or ZNF667 overexpression-induced invasion and tube formation of HUVECs. Further bioinformatic analyses suggested that overexpression of ZNF667 or knockdown of VASH1-induced differentially expressed genes in HUVECs were greatly enriched in the Wnt signaling pathway (DAAM1, LEF1, RAC2, FRAT1, NFATc2 and WNT5A). Together, these data suggested that ZNF667 facilitates myocardial ischemia-driven angiogenesis through transcriptional repression of VASH1 and regulation of Wnt signaling pathway.

教师授课的好坏是决定教学质量高低的关键性指标."金教鞭"工程就是基于授课质量评估,将好的教学方法、教学艺术进行示范性传授,以培养年轻教师的手段.文章旨在探索一种以学生受益效果为主要指标的授课质量监管评价体系,以促进教学质量提高.

Objective: The present study aimed to investigate whether the drug nicorandil can improve cardiac remodeling after myocardial infarction (MI) and the underlying mechanisms. Methods: Mouse MI was established by the ligation of the left anterior descending coronary artery and H9C2 cells were cultured to investigate the underlying molecular mechanisms. The degree of myocardial collagen (Col) deposition was evaluated by Masson's staining. The expressions of nucleolin, autophagy and myocardial remodeling-associated genes were measured by Western blotting, qPCR, and immunofluorescence. The apoptosis of myocardial tissue cells and H9C2 cells were detected by TUNEL staining and flow cytometry, respectively. Autophagosomes were observed by transmission electron microscopy. Results: Treatment with nicorandil mitigated left ventricular enlargement, improved the capacity of myocardial diastolic-contractility, decreased cardiomyocyte apoptosis, and inhibited myocardial fibrosis development post-MI. Nicorandil up-regulated the expression of nucleolin, promoted autophagic flux, and decreased the expres-sions of TGF-beta 1 and phosphorylated Smad2/3, while enhanced the expression of BMP-7 and phosphorylated Smad1 in myocardium. Nicorandil decreased apoptosis and promoted autophagic flux in H2O2-treated H9C2 cells. Autophagy inhibitors 3-methyladenine (3MA) and chloroquine diphosphate salt (CDS) alleviated the effects of nicorandil on apoptosis. Knockdown of nucleolin decreased the effects of nicorandil on apoptosis and nicorandil-promoted autophagic flux of cardiomyocytes treated with H2O2. Conclusions: Treatment with nicorandil alleviated myocardial remodeling post-MI through up-regulating the expression of nucleolin, and subsequently promoting autophagy, followed by regulating TGF-beta/Smad signaling pathway.

目的:探讨热休克因子1(HSF1)是否通过抑制中性粒细胞浸润减轻LPS诱导的小鼠急性肺损伤(ALI)及其分子机制.方法:采用气管滴注脂多糖(LPS)的方法制备小鼠ALI模型,采用流式细胞术检测HSF1野生型(HSF1+/+)小鼠和HSF1敲除(HSF1-/-)小鼠LPS处理后12、24和36 h支气管肺泡灌洗液(BALF)中性粒细胞比例和表达趋化因子受体XCR-1的中性粒细胞比例;采用免疫荧光法检测HSF1+/+和HSF1-/-小鼠上述时点肺组织中性粒细胞含量;运用ELISA方法检测不同时点血清、肺组织及BALF中趋化因子配体XCL-1的浓度.结果:流式细胞术结果显示,HSF1-/-+LPS组BALF中的中性粒细胞百分率和中性粒细胞表面XCR-1表达水平均高于HSF1+/++LPS组,LPS处理后24 h达到高峰(P<0.05);肺组织免疫荧光观察结果显示,HSF1-/-+LPS组的中性粒细胞数目均多于HSF1+/++LPS组,以LPS处理后24 h最多;HSF1-/-+LPS组血清、BALF和肺组织中XCL-1浓度均显著高于HSF1+/++LPS组(P<0.05).结论:HSF1可能通过抑制XCL-1/XCR-1这对趋化因子配体/受体的表达,抑制了中性粒细胞的浸润,从而减轻LPS所致的小鼠ALI.

As an important transcription factor, heat shock factor 1 (HSF1) plays an endogenous anti-inflammation role in the body and can alleviate multiple organ dysfunction caused by sepsis, which contributes to an uncontrolled inflammatory response. The NLRP3 inflammasome is a supramolecular complex that plays key roles in immune surveillance. Inflammation is accomplished by NLRP3 inflammasome activation, which leads to the proteolytic maturation of IL-1β and pyroptosis. However, whether HSF1 is involved in the activation of the NLRP3 inflammasome in septic acute lung injury (ALI) has not been reported. Here, we show that HSF1 suppresses NLRP3 inflammasome activation in transcriptional and post-translational modification levels. HSF1 can repress NLRP3 expression via inhibiting NF-κB phosphorylation. HSF1 can inhibit caspase-1 activation and IL-1β maturation via promoting NLRP3 ubiquitination. Our finding not only elucidates a novel mechanism for HSF1-mediated protection of septic ALI but also identifies new therapeutic targets for septic ALI and related diseases.

BACKGROUND:MicroRNAs (miRNAs) are widely distributed in cells and participate in the regulation of the pathophysiological process of many diseases. As an important part of non-coding RNA, miRNAs regulate a variety of molecules and signal pathways in tumour cells. However, the evidence for regulatory mechanisms of specific miRNAs in tumour cells is still lacking. METHODS:In this study, we used transcriptomics analysis and integrated a variety of public databases to screen miRNAs that have key regulatory effects on breast cancer (BC). In addition, we used in vitro and in vivo studies and combined clinical samples to verify its regulatory mechanism. RESULTS:We found that among the specific miRNAs, miR-215-5p is a key regulator in BC. Compared with normal adjacent tissues, miR-215-5p has a lower expression level in BC tissues. Patients with high expression levels of miR-215-5p have a longer survival time. miR-215-5p can specifically target the 3'UTR region of RAD54B mRNA and down-regulate the expression of RAD54B, thereby inhibiting the proliferation of BC cells and promoting the apoptosis of BC cells. CONCLUSIONS:Finally, we found that miR-215-5p can be used as an important biomarker for BC. We have clarified its function and revealed its mechanism of targeting RAD54B mRNA for the first time. This may provide important clues to reveal the deeper molecular regulation mechanism of BC.

以临床常见的急性心肌梗塞为主导方向,从临床病例中采集可用于多途径分析的有价值的信息,进行数字化处理与3D建模,利用虚拟现实(VR)技术构建虚拟场景,建立心梗及相关的发生机制学习系统,设立分析反馈评价模块,研发出一个医学机理分析与临床诊治相融合的虚拟仿真实验项目.

Palmitic acid (PA)-induced myocardial injury is considered a critical contributor to the development of obesity and type 2 diabetes mellitus (T2DM)-related cardiomyopathy. However, the underlying mechanism has not been fully understood. Here, we demonstrated that PA induced the cell death of H9c2 cardiomyoblasts in a dose- and time-dependent manner, while different ferroptosis inhibitors significantly abrogated the cell death of H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes exposed to PA. Mechanistically, PA decreased the protein expression levels of both heat shock factor 1 (HSF1) and glutathione peroxidase 4 (GPX4) in a dose- and time-dependent manner, which were restored by different ferroptosis inhibitors. Overexpression of HSF1 not only alleviated PA-induced cell death and lipid peroxidation but also improved disturbed iron homeostasis by regulating the transcription of iron metabolism-related genes (e.g., Fth1, Tfrc, Slc40a1). Additionally, PA-blocked GPX4 protein expression was evidently restored by HSF1 overexpression. Inhibition of endoplasmic reticulum (ER) stress rather than autophagy contributed to HSF1-mediated GPX4 expression. Moreover, GPX4 overexpression protected against PA-induced ferroptosis, whereas knockdown of GPX4 reversed the anti-ferroptotic effect of HSF1. Consistent with the in vitro findings, PA-challenged Hsf1−/− mice exhibited more serious ferroptosis, increased Slc40a1 and Fth1 mRNA expression, decreased GPX4 and TFRC expression and enhanced ER stress in the heart compared with Hsf1+/+ mice. Altogether, HSF1 may function as a key defender against PA-induced ferroptosis in cardiomyocytes by maintaining cellular iron homeostasis and GPX4 expression.

目的:探讨miR-412-3p及乳运铁蛋白(lactotransferrin,LTF)在鼻咽癌组织及癌旁组织中的表达差异并观察干预miR-412-3p能否改善鼻咽癌细胞株CNE1的顺铂敏感性.方法:分别采用实时反转录聚合酶链反应(RT-qPCR)及蛋白质印迹法检测收集的20例配对的鼻咽癌组织及癌旁组织中miR-412-3p及LTF的表达水平;MTT法及克隆形成实验检测miR-412-3p抑制剂、顺铂处理对CNE1细胞活性及克隆形成能力的影响;蛋白质印迹法检测不同处理对CNE1细胞ERK1/2,STAT3,AKT信号通路的影响.结果:与配对的癌旁组织相比,鼻咽癌组织中miR-412-3p的表达明显升高,伴随LTF表达的显著降低(均P<0.01);在体外培养的CNE1细胞中,不同浓度的miR-412-3p抑制剂可显著抑制miR-412-3p及磷酸化AKT蛋白的表达,同时促进LTF蛋白的表达(P<0.05);预先使用200 nmol/L miR-412-3p抑制剂处理CNE1细胞24 h后,可明显增加20μg/mL顺铂对CNE1细胞活性及克隆形成能力的抑制(P<0.01).结论:鼻咽癌组织中miR-412-3p的高表达及LTF的低表达可能与鼻咽癌的发病有关;利用miR-412-3p抑制剂降低CNE1细胞中miR-412-3p的水平可增加CNE1细胞对顺铂的敏感性.

In this study, we investigated the effects of nucleolin on lipopolysaccharide (LPS)-induced activation of MAPK and NF-KappaB (NF-κB) signaling pathways and secretion of TNF-α, IL-1β and HMGB1 in THP-1 monocytes. Immunofluorescence assay and Western blotting were used to identify the nucleolin expression in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Inactivation of nucleolin was induced by neutralizing antibody against nucleolin. THP-1 monocytes were pretreated with anti-nucleolin antibody for 1 h prior to LPS challenge. The irrelevant IgG group was used as control. Secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1) and activation of MAPK and NF-κB/I-κB signaling pathways were examined to assess the effects of nucleolin on LPS-mediated inflammatory response. Nucleolin existed in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Pretreatment of anti-nucleolin antibody significantly inhibited the LPS-induced secretion of TNF-α, IL-1β and HMGB1. P38, JNK, ERK and NF-κB subunit p65 inhibitors could significantly inhibit the secretion of IL-1β, TNF-α and HMGB1 induced by LPS. Moreover, the phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65) was significantly increased after LPS challenge. In contrast, pretreatment of anti-nucleolin antibody could significantly inhibit the LPS-induced phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). However, the irrelevant IgG, as a negative control, had no effect on LPS-induced secretion of TNF-α and IL-1β and phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). We demonstrated that nucleolin mediated the LPS-induced activation of MAPK and NF-κB signaling pathways, and regulated the secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1).