Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport Guanosine diphosphate-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 ( Slc35c1 cKO ) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T cell, neutrophil, and F4/80 macrophage infiltration but did not affect the levels of serum and liver BA in mouse models of cholestasis. Liquid chromatography with tandem mass spectrometry analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5- ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Protective Effect of Alprostadil on Acute Pancreatitis in Rats via Inhibiting Janus Kinase 2 (JAK2)/STAT3 Signal Transduction Pathway.

BACKGROUND Alprostadil can inhibit inflammation and reduce inflammation-related injury in many inflammatory diseases. However, the anti-inflammatory effect of alprostadil in decreasing acute pancreatitis (AP) injury remains unknow. This study aimed to investigate the possible protective effects and mechanism of alprostadil against AP in rats. MATERIAL AND METHODS Forty healthy Sprague­Dawley rats were randomly divided into a control group, an AP group, an AP-alprostadil group, an AP-AG490 group, and an AP-(alprostadil+AG490) group. An animal model of acute pancreatitis was established. The pathological changes of the pancreases in each group were observed. We assessed levels of malondialdehyde (MDA), superoxide dismutase (SOD), and myeloperoxidase (MPO), as well as serum IL-1ß, IL-6, IL-10, and TNF-alpha. TUNEL assay was used to detect apoptosis of pancreatic cells. The proteins p-Jak2 and p-Stat3 were investigated by Western blot. RESULTS Compared with the control group, pancreatic pathological score, pancreatic apoptosis, MDA, MPO, serum IL-1ß, IL-6, and TNF-alpha levels were significantly higher in the AP group, and SOD levels were significantly decreased. Compared with the AP group, after treatment with alprostadil, AG490, and alprostadil+AG490, respectively, the pancreatic pathological score, apoptosis, MDA, MPO, serum IL-1ß, IL-6, and TNF-alpha were significantly decreased in AP rats, while SOD levels were significantly increased. The protein levels of p-JAK2 and p-STAT3 were significantly upregulated in the AP group compared with the control group, and the protein levels of p-JAK2 and p-STAT3 after treatment with alprostadil, AG490, and alprostadil+AG490 were significantly decreased, and the effect of alprostadil+AG490 was the strongest. CONCLUSIONS Alprostadil can reduce pancreatic tissue damage, delay pancreatic cell apoptosis, and reduce inflammation and anti-oxidative stress by inhibiting the JAK2/STAT3 signal pathway, thus protecting the pancreas.

Comparative Study of Dezocine and Ketorolac Tromethamine in Patient-Controlled Intravenous Analgesia of Laparoscopic Cholecystectomy.

Purpose: This study aimed to observe the application value of dezocine and ketorolac tromethamine in patient-controlled intravenous analgesia (PCIA) of patients undergoing laparoscopic cholecystectomy (LC). Methods: A total of 154 patients who underwent LC surgery in our hospital and received PCIA after surgery from September 2020 to September 2021 were selected, they were divided into group A (n = 77) and group B (n = 77). Group A was given dezocine and group B was given ketorolac tromethamine. The analgesia, sedation, comfort, and adverse reactions of the two groups were closely observed at 4, 8, 12, and 24 h after surgery. Results: At 4, 8, 12, and 24 h after surgery, the visual analog scale scores in group B were lower than those in group A (P < 0.05). At 4, 8, 12, and 24 h after surgery, the Ramsay scores in group B were higher than those in group A (P < 0.05). At 4, 8, 12, and 24 h after surgery, there was no significant difference in Bruggrmann comfort scale scores between the two groups (P > 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion: Both dezocine and ketorolac tromethamine have high clinical application value in patients who underwent LC surgery and received PCIA, with higher patient comfort and fewer adverse reactions. But compared with dezocine, ketorolac tromethamine can achieve better sedative and analgesic effects, which is worthy of clinical promotion.