INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning–based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179–1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058–1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132–1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192–7.234), pancreatic cancer (HR 1.976, 95% CI 1.054–3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122–1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

Background: Notch signaling is critical for regulating the function of vascular endothelial cells (ECs). However, the effect of the intracellular domain of Notch1 (NICD) on EC injury in sepsis remains unclear.Methods: We established a cell model of vascular endothelial dysfunction and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Endothelial barrier function and expression of endothelial-related proteins were determined using CCK-8, permeability, flow cytometry, immunoblot, and immunoprecipitation assays. The effect of NICD inhibition or activation on endothelial barrier function was evaluated in vitro. Melatonin was used for NICD activation in sepsis mice. The survival rate, Evans blue dye of organs, vessel relaxation assay, immunohistochemistry, ELISA, immunoblot were used to explore the specific role of melatonin for sepsis induced vascular dysfunction in vivo.Results: We found that LPS, interleukin 6, and serum collected from septic children could inhibit the expression of NICD and its downstream regulator Hes1, which impaired endothelial barrier function and led to EC apoptosis through the AKT pathway. Mechanistically, LPS decreased the stability of NICD by inhibiting the expression of a deubiquitylating enzyme, ubiquitin-specific proteases 8 (USP8). Melatonin, however, upregulated USP8 expression, thus maintaining the stability of NICD and Notch signaling, which ultimately reduced EC injury in our sepsis model and elevated the survival rate of septic mice.Conclusions: We found a previously uncharacterized role of Notch1 in mediating vascular permeability during sepsis, and we showed that inhibition of NICD resulted in vascular EC dysfunction in sepsis, which was reversed by melatonin. Thus, the Notch1 signaling pathway is a potential target for the treatment of sepsis.

Objective. HMGCS2 is the rate-limiting enzyme of ketogenesis, which is vital for tumor initiation or metastasis. The aim of this study is to determine the relationship between HMGCS2 and tumor angiogenesis.Materials and Methods. The study consisted of 100 cases with colorectal cancer and healthy control, the expression of HMGCS2 and the microvessel density (MVD) (marker: CD31) were analyzed by immunohistochemistry and tube formation, and the centration ofβ-hydroxybutyrate in serum was assessed by biochemical analysis.Results. The results showed that HMGCS2 expression is significantly reduced in colorectal cancer compared with healthy control, which is inversely correlated with MVD in colorectal cancer by IHC analysis. What is more, knockdown HMGCS2 expression in HT-29 cells significantly contributed endothelial cell tube formation.Conclusion. These findings implying HMGCS2 may have a negative regulation of tumor angiogenesis and provide an approach to inhibit tumor angiogenesis.

Background: The tetraspanin CD53 transmembrane protein is vital in immune cells like B cells and T cells, playing a crucial role in various inflammatory conditions. However, its involvement in neutrophils regarding inflammation remains uncertain. This study aims to examine the impact of CD53 on neutrophil extracellular traps (NETs) formation. Methods: Phorbol 12-myristate 13-acetate (PMA) was utilized to establish an in vitro classical NETs model to investigate the influence of CD53 on NETs formation and its regulatory mechanisms. Subsequently, the link between CD53 and acute pancreatitis (AP), a model of aseptic inflammatory responses connected to NETs, was verified. Peripheral blood neutrophils from clinical AP patients were collected to explore the role of CD53 in AP, while an AP mouse model induced by caerulein was employed to confirm the impact of CD53 inhibition on AP mice pancreatic tissue. Results: Our study has shown that CD53 is significantly elevated in in vitro NETs models and neutrophils from AP patients. The expression of CD53 is closely related to the clinical prognosis of AP patients. At the same time, CD53 neutralizing antibody (Anti-CD53) can significantly inhibit the formation of NETs in vitro, inflammatory injury in AP mice and the formation of NETs in damaged tissues. Mechanistically, CD53 can modulate the PI3K/AKT pathway and promote the formation of NETs. Finally, targeted regulation of CD53 can effectively reduce inflammatory injury and NETs formation in damaged tissues of AP mice. Conclusion: The results of this study mark the first confirmation that CD53 plays a crucial role in NETs formation. Targeting CD53 inhibition could potentially serve as a novel therapeutic approach for the treatment of AP.

Introduction: Macrophage activation is closely associated with Acute pancreatitis (AP). We screened and found that Growth factor receptor bound protein 2 (Grb2) is highly expressed in macrophages during AP. However, the relationship between Grb2 and AP is still poorly understood. In this study, we explored the role of Grb2 in AP.Methods: We screened for gene affecting macrophage activation in AP by combining transcriptomics with Single-cell RNA-sequence analysis. Next, the expression of Grb2 in M1/M2 macrophage activation was detected by Single-cell RNA-sequence analysis and western blot. Furthermore, the effect of Grb2 on M1/M2 macrophage activation was detected by flow cytometry. The severity of AP was assessed by histological analysis, serum amylase, serum lipase and serum inflammatory factors in vivo. NOD-like receptor thermal protein domain associated protein 3 (Nlrp3) and Nuclear factor kappa-B (NF-kB) signaling pathways were also evaluated.Results: Grb2 is mainly expressed in macrophages of pancreas in AP and up-regulated in M1 macrophage activation. Inhibiting Grb2 could alleviate AP by preventing M1 macrophage activation through down-regulating Nlrp3 and NF-κB.Discussion: Inhibition of Grb2 can effectively prevent M1 macrophage activation and alleviate AP. Grb2 may potentially be an effective target of macrophage activation for the treatment of AP.

Radiation-induced intestinal injury (RIII) remains a major clinical challenge, partly due to the lack of local delivery systems capable of concurrently coordinating oxidative stress and immune responses at the lesion site. In this study, we identify the transmembrane mucin MUC13 as a key regulator of intestinal epithelial homeostasis. MUC13 deficiency aggravates oxidative stress, epithelial apoptosis, and inflammatory responses, whereas supplementation with recombinant human MUC13 (rhMUC13) markedly attenuates epithelial injury. To achieve site-specific and durable delivery to inflamed tissue, we developed an inflammation-responsive polydopamine–gelatin methacryloyl (PDA–GelMA) hydrogel microsphere system that integrates targeted local delivery with intrinsic microenvironment modulation. The therapeutic efficacy arises from complementary, component-specific functions. The PDA shell mediates inflammation-associated adhesion and prolonged mucosal retention, rapidly scavenges reactive oxygen species (ROS), suppresses early inflammatory amplification, and promotes macrophage polarization toward a reparative M2 phenotype. Within this favorable redox–immune milieu, the GelMA core enables sustained rhMUC13 release, enhancing epithelial survival and barrier reconstruction by inhibiting NF-κB–associated pro-apoptotic signaling (the Bax/Bcl-2 axis) and restoring tight-junction proteins (ZO-1, Occludin, and Claudin-1). This cooperative mechanism likely accounts for the superior efficacy of the composite microspheres compared with single-component controls. Moreover, 16S rRNA gene sequencing revealed that irradiation induces pronounced gut microbiota dysbiosis, characterized by disrupted microbial diversity and community structure, increased inflammation-associated opportunistic taxa, and reduced beneficial commensal/metabolism-related bacteria; notably, PDA–GelMA@rhMUC13 partially ameliorated irradiation-induced dysbiosis, showing an overall remodeling trend toward reduced inflammation-associated taxa and increased putatively beneficial and metabolism-related bacteria. Collectively, these findings establish MUC13 as a critical mediator of epithelial–immune crosstalk and introduce a multifunctional hydrogel microsphere platform that combines targeted protein delivery with endogenous antioxidative and immunomodulatory capacities. This strategy may additionally promote restoration of intestinal homeostasis through microbiota remodeling, offering translational potential for RIII and other inflammatory intestinal disorders.