Wenguang Zhang

Background Liver fibrosis is driven by activated hepatic stellate cells (HSCs) that overproduce extracellular matrix, particularly collagen. Lificiguat, a soluble guanylate cyclase (sGC) stimulator, exhibits anti-fibrotic potential, but its mechanism in HSC activation remains unclear. This study aims to investigate the anti-fibrotic effect and mechanisms of lificiguat . Methods human HSCs are treated with different concentrations of lificiguat. Cell proliferation was assessed by CCK-8 assay and EdU incorporation assay. Fibrogenic markers of hepatic stellate cell including COL1A1, ACTA2 and TIMP1 are measured with RT-qPCR and Western blot. sGCβ1 (GUCY1B1) or ATG5 knockdown of HSCs are achieved with lentivirus transduction. Bulk RNA sequencing of HSC cells is performed to investigate the differentially expressed genes associated with lificiguat treatment. Serum ALT and AST, hepatic gene expression, and liver histology including Masson and Sirius red staining are analyzed with samples from CCl₄-induced fibrotic mice with or without lificiguat treatment. Results Lificiguat significantly inhibits cell proliferation and COL1A1 expression of HSCs without obvious cytotoxicity. GUCY1B1 knockdown in HSCs doesn’t reverse lificiguat’s effects, which indicates the anti-fibrotic effect of lificiguat doesn’t rely on sGC activity. Lificiguat enhances autophagic flux, but ATG5 knockdown fails to recover COL1A1 expression of HSCs treated with lificiguat. RNA-seq data indicates lificiguat modulates JAK-STAT and IL-17 pathways of HSCs. Lificiguat reduced liver injury markers including serum ALT and AST in CCL₄-challenged mice. In addition, lificiguat reduces mRNA expression of fibrogenic marker gene including Col1a1 and Acta2 and attenuate liver fibrosis in CCl₄ mice models. Conclusion Lificiguat attenuates liver fibrosis by inhibiting HSC proliferation and collagen synthesis through sGC- and ATG5-independent mechanisms, potentially via regulating JAK-STAT and IL-17 pathways.

Purpose Recurrent esophageal variceal bleeding and/or refractory ascites in patients with cavernous transformation of the portal vein (CTPV) is associated with a high fatality rate. Transjugular intrahepatic portosystemic shunt (TIPS) provides a treatment option for preventing esophageal variceal rebleeding and/or refractory ascites. This retrospective study evaluated the safety and efficacy of TIPS for the patients involved. Methods The records of 41 consecutive patients with CTPV who underwent TIPS at our institution from January 2015 to May 2019 were reviewed. Among the 41 patients, 36 patients had variceal rebleeding only, and 5 patients exhibited both variceal rebleeding and refractory ascites. Ten of these patients underwent TIPS via a transjugular pathway alone; a combined transjugular/transhepatic pathway and a combined transjugular/transsplenic pathway were adopted for 21 and 3 patients, respectively; and the remaining 7 patients failed TIPS. Results TIPS succeeded in 34 of 41 (82.9%) patients. Four of 34 patients with CTPV were successfully cured with a thick collateral caval stent shunt operation. After TIPS, the mean portosystemic pressure gradient declined from 24.60 ± 6.15 mmHg to 15.89 ± 4.08 mmHg (P < 0.01). The occurrence rate of variceal rebleeding in the TIPS success group was lower than that in the TIPS failure group (11.8% vs 42.9%, P < 0.05). The occurrence rate of recurrent ascites in the TIPS failure group was greater than that in the TIPS success group (75% vs 15.8%, P < 0.05). TIPS patency was 76.5% (26 of 34 patients). During the follow-up time (median 12.64 months), the rate of hepatic encephalopathy was 5.9%, and the survival rate was 85.3%. Conclusions TIPS is an effective and safe alternative therapy for preventing esophageal variceal rebleeding and/or refractory ascites in patients who exhibit CTPV, and these findings may be beneficial to clinical research.

Malignant central airway obstruction (MCAO) resulting from tumor metastasis and compression severely impairs respiration, posing life-threatening risks. To address this, we employed a synergistic modification strategy, combining cisplatin (CIS) and silver nanoparticles (AgNPs). Polycaprolactone (PCL) served as a drug carrier, enabling the preparation of a functional CIS@AgNPs@PCL fiber membrane-covered airway stent via electrospinning. This approach aimed to enhance the patency rate of MCAO. Characterization via ATR-FTIR, scanning electron microscope-energy-dispersive spectroscopy, and transmission electron microscope confirmed successful immobilization of CIS and AgNPs onto the stent surface. CIS@AgNPs@PCL substantially suppressed non-small cell lung cancer cells (A549), causing DNA damage, ultrastructural disruption, and over 50% apoptosis in 48 h. It also displayed potent antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans biofilms. A mouse subcutaneous tumor recurrence model assessed anti-cancer efficacy. CIS@AgNPs@PCL fiber-covered stents significantly inhibited lung cancer tissue and enhanced anti-cancer effects by up-regulating caspase-3 and Bax, while down-regulating Bcl-2. This study's functional airway stent provides a proof-of-concept for an integrated anti-cancer and antibacterial strategy. It promptly restores the lumen, inhibits biofilm formation, prevents tumor progression, and improves postoperative MCAO patency.

Purpose To explore the feasibility of fenestration in the treatment of shunt dysfunction after transjugular intrahepatic portosystemic shunt (TIPS). Methods Between February 2012 and December 2017, 12 TIPS patients with shunt dysfunction underwent fenestration to resolve recurrent portal hypertension with gastric variceal bleeding or ascites. The demographic data, operative data, postoperative recovery data, hemodynamic data, and complications were analyzed. Results Twelve patients underwent TIPS revision by fenestration, with a technical success rate of 100%. After stent reconstruction, the portal vein diameters decreased gradually with time (before the procedure: at 5 days/1 month/3 months/6 months; after procedure: 1.45 ± 0.11 cm/1.38 ± 0.06 cm/1.36 ± 0.05 cm/1.34 ± 0.05 cm/1.32 ± 0.06 cm, respectively, P = 0.057). Additionally, the blood flow velocity and blood flow rapidly increased in the portal veins and shunts after TIPS revision (P < 0.001). Surprisingly, after 3 months of stent reconstruction, the portal blood flow was 4607.99 ± 1304.10 mL/min which was even lower than the shunt flow at 4651.18 ± 612.74 mL/min. The mean pressure gradient (PSG) prior to TIPS revision was 36.71 ± 3.36 mmHg which decreased to 17.42 ± 3.37 mmHg after the procedure (P < 0.001). Clinical improvement was observed in all patients after the shunt reconstruction. Three patients (25%) had mild intra-abdominal hemorrhage at 1 week after the operation. After a mean 11.0 ± 1.24 months follow-up, ascites and bleeding were well controlled, and no stenosis of the stents was found. Conclusions For patients with failed TIPS revision, fenestration to reconstruct the shunt provides an excellent alternative procedure, which is effective, safe, and has a certain clinical value, for continuing the treatment of portal hypertension.