Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2^-/-) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.

Wilm's tumour‐1 (WT1) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and enhances metastasis. Deubiquitination stabilizes target proteins, and inhibiting deubiquitination facilitates the degradation of target proteins. However, whether inhibiting deubiquitination of WT1 facilitates its degradation and presents anti‐cancer ability in PDAC is unknown. Here, we found that deubiquitinase inhibitor degrasyn rapidly induced the degradation of endogenous and exogenous WT1 through enhancing ubiquitination of WT1 followed by the up‐regulation of E‐cadherin. Knockdown of WT1 by short hairpin RNAs (shRNAs) inhibited metastasis and overexpression of WT1 partially prevented degrasyn‐induced anti‐metastasis activity, suggesting that degrasyn presents anti‐metastasis activity partially through degrading WT1 protein. We further identified that USP5 deubiquitinated WT1 and stabilized its expression. The higher expressions of USP5 and WT1 are associated with tumour metastasis. More importantly, degrasyn inhibited the activity of USP5 and overexpression of USP5 partially prevented degrasyn‐induced degradation of WT1 protein, suggesting that degrasyn degraded WT1 protein through inhibiting the activity of USP5. Finally, degrasyn reduced the tumorigenicity in a xenograft mouse model and reduced the metastasis in vivo. Our results indicate that degrasyn presents strong anti‐cancer activity through USP5‐WT1‐E‐cadherin signalling in PDAC. Therefore, degrasyn holds promise as cancer therapeutic agent in PDAC with high expressions of USP5 and WT1.

Objective. Our aim was to investigate the protective effects of a Lipoxin A₄ analogue (LXA4) in the early phase of acute pancreatitis in rats. Materials and methods. Severe acute pancreatitis (SAP) was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with LXA4 (0.1 mg/kg), 10 min after the 5% sodium taurocholate injection, after which LXA4 was administrated every 8 hours, three times (LXA4 group). The sham group was only given the vehicle after operation. Plasma amylase activity, serum levels of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were measured at 4, 12, and 24 h after induction of SAP. The pancreatic index and histopathologic observations were evaluated and the expression of intercellular adhesion molecule-1 (ICAM-1) and NF-κB p65 in the pancreas, and the expression of ICAM-1 in the lungs were detected by immunohistochemistry. Results. LXA4 treated rats had lower serum levels of TNF-α, IL-1, and IL-6 at all time points measured (p < 0.05), but significantly differed in plasma amylase activity only at 24 h as compared with the SAP group. The pancreatic index and the scores of pancreatitic histopathologic evaluations were lower in the LXA4 group as compared to the SAP group. Immunohistochemistry showed that LXA4 attenuated the expression of ICAM-1 and NF-κB p65 in the pancreas, as well as the expression of ICAM-1 in the lungs in animals with pancreatitis (p < 0.05). Conclusions. We demonstrate that LXA4 has protective effects in experimental SAP, which may be achieved by inhibiting the NF-κB signalling pathway, thereby reducing the production of proinflammatory cytokines.

The onset, development, diagnosis, and treatment of cancer involve intricate interactions among various factors, spanning the realms of mechanics, physics, chemistry, and biology. Within our bodies, cells are subject to a variety of forces such as gravity, magnetism, tension, compression, shear stress, and biological static force/hydrostatic pressure. These forces are perceived by mechanoreceptors as mechanical signals, which are then transmitted to cells through a process known as mechanical transduction. During tumor development, invasion and metastasis, there are significant biomechanical influences on various aspects such as tumor angiogenesis, interactions between tumor cells and the extracellular matrix (ECM), interactions between tumor cells and other cells, and interactions between tumor cells and the circulatory system and vasculature. The tumor microenvironment comprises a complex interplay of cells, ECM and vasculature, with the ECM, comprising collagen, fibronectins, integrins, laminins and matrix metalloproteinases, acting as a critical mediator of mechanical properties and a key component within the mechanical signaling pathway. The vasculature exerts appropriate shear forces on tumor cells, enabling their escape from immune surveillance, facilitating their dissemination in the bloodstream, dictating the trajectory of circulating tumor cells (CTCs) and playing a pivotal role in regulating adhesion to the vessel wall. Tumor biomechanics plays a critical role in tumor progression and metastasis, as alterations in biomechanical properties throughout the malignant transformation process trigger a cascade of changes in cellular behavior and the tumor microenvironment, ultimately culminating in the malignant biological behavior of the tumor.

Regenerative medicine and tissue engineering are promising approaches for organ transplantation. Extracellular matrix (ECM) based scaffolds obtained through the decellularization of natural organs have become the preferred platform for organ bioengineering. In the field of pancreas bioengineering, acellular scaffolds from different animals approximate the biochemical, spatial and vascular relationships of the native extracellular matrix and have been proven to be a good platform for recellularization and in vitro culture. However, artificial endocrine pancreases based on these whole pancreatic scaffolds have a critical flaw, specifically their difficult in vivo transplantation, and connecting their vessels to the recipient is a major limitation in the development of pancreatic tissue engineering. In this study, we focus on preparing a novel acellular extracellular matrix scaffold derived from the rat pancreatic body tail (pan-body-tail ECM scaffold). Several analyses confirmed that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. DNA quantification demonstrated an obvious reduction of DNA compared with that of the natural organ (from 931.9 ± 267.8 to 11.7 ± 3.6 ng/mg, P < 0.001); the retention of the sGAG in the decellularized pancreas (0.878 ± 0.37) showed no significant difference from the natural pancreas (0.819 ± 0.1) (P > 0.05). After transplanted with the recellularized pancreas, fasting glucose levels declined to 9.08 ± 2.4 mmol/l within 2 h of the operation, and 8 h later, they had decreased to 4.7 ± 1.8 mmol/l (P < 0.05). The current study describes a novel pancreatic ECM scaffold prepared from the rat pancreatic body tail via perfusion through the left gastric artery. We further showed the pioneering possibility of in vivo circulation-connected transplantation of a recellularized pancreas based on this novel scaffold. By providing such a promising pancreatic ECM scaffold, the present study might represent a key improvement and have a positive impact on endocrine pancreas bioengineering.