Zi-Gang Zhao

Endomucin (EMCN), a highly glycosylated type I transmembrane sialomucin, is predominantly expressed on the luminal surface of venous and capillary endothelial cells and serves as a critical guardian of vascular homeostasis and immunological silencing. Its highly extended, O‐glycosylated extracellular domain provides significant steric hindrance and electrostatic repulsion, functioning as a dual physical barrier that prevents nonspecific leukocyte tethering and adhesion. Beyond its anti‐adhesive role, EMCN is a pivotal orchestrator of angiogenesis, modulating the vascular endothelial growth factor signaling cascade by facilitating vascular endothelial growth factor receptor 2 autophosphorylation at the Y1175 residue and subsequent receptor internalization. Furthermore, EMCN has emerged as a specialized marker for type H vessels and human hematopoietic stem cells, playing indispensable roles in vessel‐bone coupling and hematopoietic development. Clinical evidence indicates that the dysregulation of EMCN expression or post‐translational modifications contributes to the pathogenesis of diabetic complications, atherosclerosis, bone metabolic disorders, and tumor metastasis. This review systematically summarizes structural characteristics, expression patterns, and multifaceted biological functions of EMCN, providing a theoretical foundation for the development of novel therapeutic strategies for microvascular and metabolic diseases.

Background: Although a high-salt diet (HSD) impairs cardiovascular function, its impact on the prognosis of hemorrhagic shock (HS) has not been elucidated. Impaired mesenteric lymphatic contractility post-HS contributes to an unfavorable prognosis. Since mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate calcium-dependent contraction, we hypothesized that HSD exacerbates HS-induced lymphatic dysfunction by damaging MAM integrity in lymphatic smooth muscle cells (LSMCs). Methods: Male Wistar rats were fed either a normal diet (ND) or HSD containing 8% NaCl for 8 weeks. A conscious rat model of fixed-pressure HS (40 mmHg for 90 minutes) with resuscitation was established. The rats were divided into four groups: ND + sham shock, ND + HS, HSD + sham shock, and HSD + HS. Additional HS groups were treated with either the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) inhibitor 2-aminoethyl diphenylborinate (2-APB) (HSD + HS + 2-APB) or the IP3R1 activator cadmium chloride (CdCl ₂ ) (ND + HS + CdCl ₂ ). Survival time and in vivo and ex vivo mesenteric lymphatic contractility were assessed. The ultrastructure and protein expression of MAM were analyzed. Results: HSD significantly increased blood pressure but not body weight and markedly reduced survival time after HS. HSD alone impaired mesenteric lymphatic contractility and exacerbated HS-induced contractile and reactive dysfunction. HS and HSD independently shortened the contact distance and increased the contact coefficient of MAM in LSMCs, with combined exposure producing the most severe disruption. These structural alterations were accompanied by increased protein expression of IP3R1 and voltage‑dependent anion channel 1. Importantly, therapeutic inhibition of MAM with 2-APB in HSD + HS rats improved survival, restored lymphatic contractility, and normalized MAM structure and protein expression. Conversely, pharmacological aggravation of MAM with CdCl ₂ in ND + HS rats worsened survival and lymphatic function, paralleling MAM disruption. Conclusion: Chronic HSD is a risk factor for poor outcomes after HS, worsening both survival and mesenteric lymphatic function by disrupting MAM integrity in LSMCs. Targeting MAM, exemplified by IP3R1 inhibition, represents a novel therapeutic strategy for mitigating shock-induced lymphatic dysfunction, particularly in salt-sensitive populations.

The pathogenesis of neurological disorders involves complex interactions among genetic, environmental, immunological, and metabolic factors. Characterized by high disability rates and prolonged disease courses, these conditions impose a significant burden on patients and society. As a dynamic and modifiable component of the internal environment, gut microbiota plays a central role in the onset and progression of neurological disorders through the “gut-brain axis.” Bidirectional communication occurs between gut microbiota and the central nervous system via neural, immune, and endocrine pathways. This interplay regulates blood-brain barrier integrity, modulates neuroinflammatory responses, and maintains neurotransmitter balance, thereby influencing disease progression. This review systematically summarizes current evidence on the role of gut microbiota in representative neurological disorders, such as traumatic brain injury, stroke, and epilepsy, and critically evaluates the therapeutic potential of microbiota-targeted interventions, including fecal microbiota transplantation, ketogenic diets, and probiotics. Collectively, this review provides novel insights into disease pathogenesis and highlights innovative microbiome-based therapeutic strategies for the prevention and management of neurological diseases. Graphical Abstract The alternative text for this image may have been generated using AI.

Acute lung injury (ALI) is a life-threatening condition characterized by dysregulated pulmonary inflammation and high mortality rates. Alveolar macrophages and neutrophils are central innate immune cells that orchestrate the inflammatory response in injured lungs. Accumulating evidence indicates that dynamic interactions between these two cell types play a pivotal role in ALI progression; however, the underlying regulatory mechanisms remain insufficiently understood. This review aims to comprehensively analyze themolecular and cellular processes governing the communication between alveolar macrophages and neutrophils in ALI and to discuss emerging therapeutic strategies targeting this cell-cell interaction, with the goal of providing insights into novel biomarkers and therapeutic targets for ALI. A comprehensive review of the relevant literature was conducted to summarize the molecular and cellular mechanisms underlyingalveolar macrophage-neutrophil crosstalk in ALI, including cytokine/chemokine signaling, pattern recognition receptor activation, inflammasome pathways, reactive oxygen species-mediated regulation, and neutrophil extracellular trap formation. In addition, therapeutic strategies targeting these interactions were collated and analyzed. Alveolar macrophage-neutrophil communication in ALI is mediatedby multiple pathways, including cytokine and chemokine signaling, pattern recognition receptor activation, inflammasome activation, reactive oxygen species regulation, and neutrophil extracellular trap (NET) formation. Bidirectional feedback loops exist between the two cell types,where they either amplify or limit each other's activities depending on the pathological state, thereby regulating the balance between host defense and tissue damage. Emerging therapeutic strategies targeting this crosstalk, such as the modulation of macrophage inflammatory phenotypes, inhibition of neutrophil recruitment, and prevention of neutrophil extracellular trap formation, show promising translational potential for restoring immune homeostasis in ALI. Alveolar macrophage-neutrophil crosstalk constitutes a critical regulatory axisin ALI pathogenesis. Elucidating the mechanisms and feedback networks of this interaction is essential for identifying novel biomarkers and therapeutic targets, which will facilitate the development of more precise and effective immunomodulatory treatments for ALI.

The mitochondrial-associated endoplasmic reticulum membrane (MAM) is a dynamic contact site formed through protein-mediated connections between the endoplasmic reticulum (ER) and outer mitochondrial membrane. As a pivotal signaling and metabolic hub, MAM regulates core cellular physiological processes, including calcium homeostasis, lipid biosynthesis and trafficking, mitochondrial dynamics, autophagy, apoptosis, and inflammasome formation and activation. Growing evidence indicates that the disruption of MAM integrity and function is closely associated with various disorders induced by excessive salt consumption. High salt intake perturbs ER-mitochondrial calcium ion exchange, partly through elevated intracellular sodium concentrations, leading to the structural and functional impairment of MAM. This disruption of calcium homeostasis subsequently triggers the ER and oxidative stress responses, exacerbating cellular damage. Concurrently, high-salt diets interfere with MAM-mediated lipid synthesis and transport, contributing to mitochondrial dysfunction and accelerating disease development. This review summarizes the involvement and underlying molecular mechanisms of MAM in high-salt diet-related disorders including hypertension, cardiovascular disease, obesity, and metabolic dysfunction-associated fatty liver disease. Furthermore, this review explores the translational potential of targeting MAM as a therapeutic intervention, providing novel insights for developing interventions that target inter-organelle communication to combat salt-related systemic disorders.

Sepsis, a life-threatening systemic inflammatory response induced by infection, remains a major therapeutic challenge with high mortality rates, especially when progressing to multiple organ dysfunction syndrome. Ulinastatin (UTI), a serine protease inhibitor with anti-inflammatory and antioxidative properties, has emerged as a promising therapeutic candidate for sepsis-induced organ injury. This article systematically reviews recent advances in the multiorgan protective effects of UTI against sepsis, focusing on its mechanisms through modulating key signaling pathways, reducing inflammatory cytokine release, inhibiting oxidative stress, and regulating cellular apoptosis/autophagy. Clinical and preclinical evidence demonstrates UTI’s efficacy in alleviating injury in critical organs, including lungs, heart, liver, spleen, intestines, and kidneys. The current review clarifies the mechanism by which UTI mitigates sepsis-related multiple organ dysfunction syndrome and provides a theoretical basis for identifying potential therapeutic targets of UTI to mitigate sepsis injury.

Purpose: Acute lung injury is the most severe complication of hemorrhagic shock and closely correlates with the mortality rate of hemorrhagic shock. TIPE2 is a critical regulator of inflammation and is implicated in the pathogenesis of various inflammatory diseases. However, its role in hemorrhagic shock-induced acute lung injury is unclear, and the underlying mechanisms remain to be elucidated. Therefore, the purpose of this study was to investigate the role of TIPE2 in hemorrhagic shock-induced acute lung injury and its underlying mechanisms. Methods: C57BL/6J and TIPE2 knockout mice were used to establish hemorrhagic shock model, with a sham surgery as the control. The pulmonary ventilation function was evaluated using in-vivo testing system. Blood gas analysis was conducted to evaluate changes in blood oxygen level, reflecting the body’s acid-base balance. Hematoxylin and eosin staining facilitated the observation of lesion progression in pulmonary tissue. The expression levels of TIPE2, myeloperoxidase, and citrullinated histone in lung tissues were determined by Western blotting, whereas the levels of tumor necrosis factor-α and IFN-γ in bronchoalveolar lavage fluid were quantified by enzyme-linked immunosorbent assay to evaluate the levels of key inflammatory mediators. VE-cadherin and E-cadherin expression in lung tissues were assessed by Western blotting to indicate changes of lung microvascular and alveolar permeability. Results: Following hemorrhagic shock, mice developed severe acute lung injury, characterized by impaired lung function, respiratory acidosis, structural damage, and pulmonary edema. This was accompanied by a heightened inflammatory response, evidenced by elevated neutrophil activity and pro-inflammatory cytokines, alongside impaired endothelial and epithelial barrier integrity. Notably, TIPE2 knockout conferred protection against hemorrhagic shock-induced lung injury in mice. Conclusion: TIPE2 knockout attenuates hemorrhagic shock-induced acute lung injury through mechanisms involving downregulation of inflammatory-associated protein expression, suppression of proinflammatory cytokine release, and restoration of pulmonary barrier permeability.

Post-hemorrhagic shock mesenteric lymph (PHSML) return plays a critical role in the development of acute kidney injury (AKI). However, the molecular mechanism underlying PHSML-mediated AKI remains unclear. In this study, bioinformatics analysis identified key common targets of hemorrhagic shock and AKI, revealing significant enrichment in the renin-angiotensin system (RAS). To further investigate the role of RAS in PHSML-mediated AKI, we established mesenteric lymph duct ligation (MLDL) technology in mice and confirmed that MLDL alleviated hemorrhagic shock-induced AKI. Subsequently, male C57BL/6 mice subjected to hemorrhagic shock were treated with the angiotensin converting enzyme (ACE) inhibitor enalapril, angiotensin (1-7) (Ang (1-7)), and angiotensin II (Ang II) type 1 receptor (AT1R) inhibitor losartan. Additionally, mice with hemorrhage and MLDL were treated with Ang II, the Mas receptor (MasR) inhibitor A-779, or subjected to Ace2 knockout. Renal histomorphology, expression of ACE, ACE2, AT1R, and MasR, and levels of Ang II and Ang (1-7) were assessed 4 h after resuscitation. The results demonstrated that hemorrhagic shock upregulated ACE and AT1R, while downregulating ACE2 and MasR, accompanied by elevated Ang II and reduced Ang (1-7). These adverse effects were partially reversed by MLDL, enalapril, Ang-(1-7), or losartan. Conversely, the beneficial role of MLDL was abolished by Ace2 deficiency and the administration of Ang II and A-779. Collectively, these findings indicate that disequilibrium between the ACE-AngII-AT1R and ACE2-Ang (1-7)-MasR axes is implicated in PHSML-mediated AKI.