MitoQ protects against carbon tetrachloride-induced hepatocyte ferroptosis and acute liver injury by suppressing mtROS-mediated ACSL4 upregulation.

Ferroptosis has been shown to be involved in carbon tetrachloride (CCl4)-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl4-induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl4-induced mice. In vitro, CCl4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl4-evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl4-induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl4-exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl4-induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl4-exposed human hepatocytes. Moreover, CCl4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl4-evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl4 exposure. Finally, MitoQ pretreatment alleviated CCl4-induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl4-induced ALI via the mtROS-ACSL4 pathway.

Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner.

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.

Alterations of actin cytoskeleton and arterial protein level in patients with obstructive jaundice.

Vascular hypo-responsiveness to vasopressors in patients with obstructive jaundice (OJ) is a common anesthetic event, which leads to perioperative complications and increased mortality. The cause of this clinical issue remains unclear. In this study, we estimated the actin cytoskeleton and arterial protein level in the artery of OJ patients by proteomic analysis. Ten patients with OJ due to bile duct diseases or pancreatic head carcinoma were enrolled, while another ten non-jaundice patients with chronic cholecystitis or liver hemangioma as the control group. Vascular reactivity to noradrenaline was measured before anesthesia on the day of surgery. Artery samples in adjacent tissues of removed tumor were collected and evaluated by 2-dimensional electrophoresis. Proteins with differential expression were detected by MALDI-TOF mass spectrometry with immunoblot confirmation. The results confirmed the phenomenon of vascular hypo-reactivity in OJ patients as suppressed aortic response to noradrenaline were existed in these patients. We also found that actin cytoskeleton and several actin-binding proteins were up- or down-regulated in the artery of OJ patients. These proteins changed in OJ patents might be the basic mechanism of vascular hypo-reactivity, further studies to uncover the role of these proteins in OJ is critical for clinical treatment of these patients.

Baseline neutrophil-lymphocyte ratio is associated with survival for infant living donor liver transplantation for biliary atresia.

Living donor liver transplantation (LDLT) in infants for congenital biliary atresia (BA) poses various challenges nowadays. We aim to investigate independent preoperative risk factors for LDLT in infants. We retrospectively analyzed medical records of infant patients who underwent LDLT surgery for BA from 1 July 2014 to 31 December 2016. Cox regression was used to explore risk factors. The Kaplan-Meier method was used to calculate the recipient and graft survival, and subgroup analysis was then applied according to the risk factors. Independent t test or Mann-Whitney U test was applied for comparison of certain factors between survival patients and death. A total of 345 infant LDLT for BA were included in the analysis. In the multivariate Cox-regression model, 3 factors were determined as independent risk factors for recipient and graft survival, there were neutrophil-lymphocyte ratio (NLR), pediatric end-stage liver disease (PELD), and recipient age. The HR (95% CI) of baseline NLR for recipient and graft survival were 1.25 (1.12-1.38) and 1.25 (1.13-1.39), with all P < .0001. Kaplan-Meier curves for NLR using different cut-offs (1.5; 1, 2) suggested that higher baseline NLR was significantly associated with recipient and graft survival. The subgroup analysis indicated that for infants with elevated NLR, the recipient survival was significantly lower when their age >6 months or PELD >20. Our results indicate that infants with higher baseline NLR value may have lower survival rate 3 years after transplantation. Further investigations about broaden the application of pre- and post-transplant NLR to guide nutrition intervention and immunosuppression therapy are necessary.

Colonic vitamin D receptor expression is inversely associated with disease activity and jumonji domain-containing 3 in active ulcerative colitis.

BACKGROUND: The expression of jumonji domain-containing 3 (Jmjd3) and trimethylated H3 lysine 27 (H3K27me3) in active ulcerative colitis (UC) and the correlation between vitamin D receptor (VDR) and the Jmjd3 pathway are unknown. AIM: To study the relationship between VDR, Jmjd3 and H3K27me3 in patients with active UC. METHODS: One hundred patients with active UC and 56 healthy controls were enrolled in this study. The patients with active UC were divided into groups according to mild (n = 29), moderate (n = 32) and severe (n = 29) disease activity based on the modified Mayo score. Vitamin D levels were measured by radioimmunoassay. Colonic mucosal tissues from UC patients and controls were collected by colonoscopy. The expression of VDR, Jmjd3 and H3K27me3 in the intestinal mucosa was determined by immunohistochemistry staining. RESULTS: Patients with active UC had lower levels of serum vitamin D (13.7 ± 2.8 ng/mL, P < 0.001) than the controls (16.2 ± 2.5 ng/mL). In the UC cohort, serum vitamin D level was negatively correlated with disease activity (r = -0.323, P = 0.001). VDR expression in the mucosa of UC patients was reduced compared to that in normal tissues (P < 0.001) and negatively correlated with disease activity (r = -0.868, P < 0.001). Similar results for VDR expression were noted in the most serious lesion (defined as UC diseased) and 20 cm proximal to the anus (defined as UC normal) (P < 0.05). Simultaneously, Jmjd3 expression significantly increased in UC patients (P < 0.001), but no difference was found between the different sites in UC patients. H3K27me3 expression in UC patients was significantly down-regulated when compared with normal tissues (P < 0.001), but up-regulated in the mild disease activity group in comparison with the moderate disease activity group of UC patients (P < 0.05). Jmjd3 Level was negatively correlated with the level of VDR (r = -0.342, P = 0.002) and H3K27me3 (r = -0.341, P = 0.002), while VDR level was positively correlated with H3K27me3 (r = 0.473, P < 0.001). CONCLUSION: Serum vitamin D and VDR were inversely correlated with disease activity in active UC. Jmjd3 expression increased in the colonic mucosa of active UC patients and was negatively associated with VDR and H3K27me3 level.

Distant survival for patients undergoing surgery using volatile versus IV anesthesia for hepatocellular carcinoma with portal vein tumor thrombus: a retrospective study.

BACKGROUND: Whether anesthesia type is associated with the surgical outcome of Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) remains to be determined. This study aims to investigate the impact of volatile inhalational anesthesia (INHA) versus total IV anesthesia (TIVA) on the survival outcomes in HCC patients with PVTT. METHODS: A cohort of in-patients whom were diagnosed of HCC with PVTT in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, from January 1, 2008 to December 24, 2012 were identified. Surgical patients receiving the INHA and TIVA were screened out. The overall survival (OS), recurrence-free survival (RFS) and several postoperative adverse events were compared according to anesthesia types. RESULTS: A total of 1513 patients were included in this study. After exclusions are applied, 263 patients remain in the INHA group and 208 in the TIVA group. Patients receiving INHA have a lower 5-year overall survival rate than that of patients receiving TIVA [12.6% (95% CI, 9.0 to 17.3) vs. 17.7% (95% CI, 11.3 to 20.8), P = 0.024]. Results of multivariable Cox-regression analysis also identify that INHA anesthesia is significantly associated with mortality and cancer recurrence after surgery compare to TIVA, with HR (95%CI) of 1.303 (1.065, 1.595) and 1.265 (1.040, 1.539), respectively. Subgroup analysis suggested that in more severe cancer patients, the worse outcome related to INHA might be more significant. CONCLUSION: This retrospective analysis identifies that TIVA is associated with better outcomes compared with INHA. Future prospective studies clinical and translational studies are required to verify this difference and investigate underlying pathophysiology.

Involvement of the p38 MAPK-pHsp27 pathway in vascular hyporeactivity induced by obstructive jaundice in rats.

Patients with obstructive jaundice are prone to develop cardiovascular complications during surgery. However, the underlying mechanisms remain largely unknown. The present study was aimed to investigate the role of p38 MAPK-pHsp27 pathway in vascular hyporesponsiveness induced by obstructive jaundice. Firstly, an experimental rat obstructive jaundice model was established by bile duct ligation (BDL). We found that the thoracic aorta rings isolated from BDL rats showed decreased response to norepinephrine and acetylcholine, while continuous intraperitoneal injection with SB203580, a selective P38 MAPK inhibitor, could significantly prevented BDL-induced hyporeactivity. Also, the immunohistochemistry and Western blot assays revealed that the up-regulation of pHsp27 and F-actin in thoracic aorta rings from BDL rats and bilirubin-treated vascular smooth muscle cells (VSMCs) were also inhibited by SB203580. Moreover, we identified that bilirubin could induced decreased cell proliferation of VSMCs by using CCK8 assay and which was also prevented by SB203580. All these data demonstrated that p38 MAPK-pHsp27 mediates vascular hyporesponsiveness in rats with obstructive jaundice by modulating the expression level of pHsp27 and F-actin, and that inhibition of p38 MAPK signaling could remodel the vascular activity.

Association between Anaesthetic Technique and Oncological Outcomes after Colorectal Carcinoma Liver Metastasis Resection.

Background: Recently published studies suggest that the anaesthetic technique used during oncologic surgery can improve patient outcomes. Therefore, the authors evaluated the survival of patients with resected colorectal carcinoma liver metastases (CRCLMs) who received either EGA (general anaesthesia [GA] combined with epidural anaesthesia [EA]) or GA alone. Methods: We conducted an ambispective cohort study including 225 post-surgical CRCLM patients between May 2007 and July 2012 and performed a follow-up investigation of survival in July 2017. Results: The basic characteristics in the two groups were largely similar. The median (quartiles) recurrence interval for all patients was 10 (2.5, 23) months, and the median (quartiles) survival for CRCLM patients post-surgically was 37 (30.5, 51.5) months. Perioperative EA was associated with survival (P =0.039, log-rank test), with an estimated hazard ratio of 0.737 (95% CI 0.551-0.985) in the univariate analysis. Kaplan-Meier estimates of survival for GA and EGA suggested that GA might provide better outcomes than EGA [P=0.028, hazard ratio of 0.7328 (95% CI 0.5433-0.9884)]. Significant differences in anaesthesia techniques were found (P=0.048), with an adjusted estimated hazard ratio of 0.741 (95% CI 0.550-0.998) in the multivariate analysis. Subgroup analyses of patients in different age groups (< 40, ≥ 40 but <60, and ≥ 60 years old) suggested that no significant differences existed among all three subgroups. Conclusions: Compared with EGA, GA may provide a better survival outcome for CRCLM patients. The benefits of anaesthetic techniques in oncological surgery are most likely related to certain cancer types.