Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg⁻¹·day⁻¹) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl₄-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment. Lactic acid (LA) has been identified as an influential factor in promoting immune escape and tumor progression. However, the mechanisms through which LA modulates TAMs in colorectal cancer (CRC) remain poorly understood. We used qRT-PCR to quantify the expression of LA-related genes (LDHA and LAMP2) in CRC tumor tissues and adjacent nontumor tissues (n = 64). The biological effects and mechanisms of LA on macrophages and tumors were evaluated via qRT-PCR, Western blot, RNA-seq, wound healing assay, colony formation assay in vitro, and allograft mouse tumor models in vivo. We found the expression of LDHA and LAMP2 was highly elevated in the tumor regions and positively associated with a poor clinical stage of CRC. A high concentration of LA was generated under hypoxia; it could promote tumor progression and metastasis with the involvement of macrophages. The inhibition of LA release impaired this protumor phenomenon. Mechanically, LA induced M2 macrophages through the AKT/ERK signaling pathway; subsequently, M2 macrophages secreted CCL8 and facilitated the proliferation and metastasis of CRC cells by activating the CCL8/CCR5/mTORC1 axis. This effect was inhibited by the antagonist or knockdown of CCR5. In conclusion, lactate-induced CCL8 in TAMs accelerated CRC proliferation and metastasis through the CCL8/CCR5/mTORC1 axis.

Laparoscopic cholecystectomy and percutaneous transhepatic gallbladder drainage (PTGBD) are common treatments for patients with acute cholecystitis. However, the safety and efficacy of emergency laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC) after PTGBD in patients with acute cholecystitis remain unclear. The PubMed, EMBASE, and Cochrane Library databases were searched through October 2019. The quality of the included nonrandomized studies was assessed using the Methodological Index for Nonrandomized Studies (MINORS). The meta-analysis was performed using STATA version 14.2. A random-effects model was used to calculate the outcomes. A total of fifteen studies involving 1780 patients with acute cholecystitis were included in the meta-analysis. DLC after PTGBD was associated with a shorter operative time (SMD − 0.51; 95% CI − 0.89 to − 0.13;P = 0.008), a lower conversion rate (RR 0.43; 95% CI 0.26 to 0.69;P = 0.001), less intraoperative blood loss (SMD − 0.59; 95% CI − 0.96 to − 0.22;P = 0.002) and longer time of total hospital stay compared to ELC (SMD 0.91; 95% CI 0.57–1.24;P < 0.001). There was no difference in the postoperative complications (RR 0.68; 95% CI 0.48–0.97;P = 0.035), biliary leakage (RR 0.65; 95% CI 0.34–1.22;P = 0.175) or mortality (RR 1.04; 95% CI 0.39–2.80;P = 0.933). Compared to ELC, DLC after PTGBD had the advantages of a shorter operative time, a lower conversion rate and less intraoperative blood loss.