No abstract

To develop a severe acute pancreatitis (SAP) model transited from mild symptoms, we investigated a “two-hit” strategy with L-arginine in mice. The mice were intraperitoneally injected with ice-cold L-arginine (4 g/kg) twice at an interval of 1 h on the first day and subjected to the repeated operation 72 h afterwards. The results showed the “two-hit” strategy resulted in the destructive damage and extensive necrosis of acinar cells in the pancreas compared with the “one-hit” model. Meanwhile, excessive levels of pro-inflammatory mediators, namely IL-6 and TNF-α, were released in the serum. Remarkably, additional deleterious effects on multiple organs were observed, including high intestinal permeability, kidney injury, and severe acute lung injury. Therefore, we confirmed that the SAP animal model triggered by a “two-hit” strategy with L-arginine was successfully established, providing a solid foundation for a deeper understanding of SAP initiation and therapy research to prevent worsening of the disease.

Heparin has shown benefits in severe acute pancreatitis (SAP) therapy, but the underlying mechanisms were unknown. Extracellular high-mobility group protein-1 (HMGB-1) has been regarded as a central mediator contributing to inflammation exacerbation and disease aggravation. We hypothesized heparin attenuated the disease by targeting HMGB-1-related pathways. In the present study, the possible therapeutic roles of heparin and its non-anticoagulant derivatives, 6-O-desulfulted heparin and N-acylated-heparin, were determined on mouse models induced by “Two-Hit” of L-arginine. The compounds exhibited potent efficiency by substantially decreasing the pancreatic necrosis, macrophage infiltration, and serum inflammatory cytokine (IL-6 and TNF-α) concentration. Moreover, they greatly reduced the rapidly increasing extracellular HMGB-1 levels in the L-arginine injured pancreases. As a result, multiple organ failure and mortality of the mice were inhibited. Furthermore, the drugs were incubated with the RAW264.7 cells activated with damaged pancreatic tissue of SAP mice in vitro. They were found to inhibit HMGB-1 transfer from the nucleus to the plasma, a critical step during HMGB-1 active secretion from macrophages. The results were carefully re-examined with a caerulein and LPS induced mouse model, and similar results were found. The paper demonstrated heparin alleviated SAP independent of the anti-coagulant functions. Therefore, non-anticoagulant heparin derivatives might become promising approaches to treat patients suffering from SAP.

No abstract

Alginate hydrogel has received great attention in diabetic wound healing. However, the limited tunability of the ionic crosslinking method prevents the delicate management of physical properties in response to diverse wound conditions. We addressed this issue by using a microgel particle (fabricated by zinc ions and coordinated through the complex of carboxymethyl chitosan and aldehyde hyaluronic acid) as a novel crosslinker. Then the cation was introduced as a second crosslinker to create a double crosslinked network. The method leads to the precise regulation of the hydrogel characters, including the biodegradation rate and the controlled release rate of the drug. As a result, the optimized hydrogels facilitated the live-cell infiltration in vitro and boosted the tissue regeneration of diabetic wounds in vivo. The results indicated that the addition of the microgel as a new crosslinker created flexibility during the construction of the alginate hydrogel, adapting for diverse applications during diabetic-induced wound therapy.