Research progress of protein induced by vitamin K absence or antagonist II in liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common pathologic type of primary liver cancer. Liver transplantation (LT) is a radical strategy for treating patients with early-stage HCC, which may lead to a better prognosis compared to hepatectomy and ablation. However, survival of patients who develop HCC recurrence after LT is short, and early recurrence is the most common cause of death. Thus, efficient biomarkers are also needed in LT to guide precision therapy to improve patient prognosis and 5-year survival. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an abnormal prothrombin that cannot activate coagulation, and it is significantly increased in patients with HCC, obstructive jaundice, and those taking vitamin K antagonists. Over the past decades, substantial progress has been made in the study of PIVKA-II in diagnosing, surveilling, and treating HCC, but its role in LT still needs to be elaborated. In this review, we focused on the role of PIVKA-II as a biomarker in LT for HCC, especially its relationship with clinicopathologic features, early recurrence, long-term survival, and donor-recipient selection.

Physical Regimes and Mechanisms of Picosecond Laser Fragmentation of Gold Nanoparticles in Water from X-ray Probing and Atomistic Simulations.

Laser fragmentation in liquids has emerged as a promising green chemistry technique for changing the size, shape, structure, and phase composition of colloidal nanoparticles, thus tuning their properties to the needs of practical applications. The advancement of this technique requires a solid understanding of the mechanisms of laser-nanoparticle interactions that lead to the fragmentation. While theoretical studies have made impressive practical and mechanistic predictions, their experimental validation is required. Hence, using the picosecond laser fragmentation of Au nanoparticles in water as a model system, the transient melting and fragmentation processes are investigated with a combination of time-resolved X-ray probing and atomistic simulations. The direct comparison of the diffraction profiles predicted in the simulations and measured in experiments has revealed a sequence of several nonequilibrium processes triggered by the laser irradiation. At low laser fluences, in the regime of nanoparticle melting and resolidification, the results provide evidence of a transient superheating of crystalline nanoparticles above the melting temperature. At fluences about three times the melting threshold, the fragmentation starts with evaporation of Au atoms and their condensation into small satellite nanoparticles. As fluence increases above five times the melting threshold, a transition to a rapid (explosive) phase decomposition of superheated nanoparticles into small liquid droplets and vapor phase atoms is observed. The transition to the phase explosion fragmentation regime is signified by prominent changes in the small-angle X-ray scattering profiles measured in experiments and calculated in simulations. The good match between the experimental and computational diffraction profiles gives credence to the physical picture of the cascade of thermal fragmentation regimes revealed in the simulations and demonstrates the high promise of the joint tightly integrated computational and experimental efforts.

Time-varying gain extended state observer-based adaptive optimal control for disturbed unmanned helicopter.

In this paper, the robust adaptive optimal tracking control problem is addressed for the disturbed unmanned helicopter based on the time-varying gain extended state observer (TVGESO) and adaptive dynamic programming (ADP) methods. Firstly, a novel TVGESO is developed to tackle the unknown disturbance, which can overcome the drawback of initial peaking phenomenon in the traditional linear ESO method. Meanwhile, compared with the nonlinear ESO, the proposed TVGESO possesses easier and rigorous stability analysis process. Subsequently, the optimal tracking control issue for the original unmanned helicopter system is transformed into an optimization stabilization problem. By means of the ADP and neural network techniques, the feedforward controller and optimal feedback controller are skillfully designed. Compared with the conventional backstepping approach, the designed anti-disturbance optimal controller can make the unmanned helicopter accomplish the tracking task with less energy. Finally, simulation comparisons demonstrate the validity of the developed control scheme.

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

Laparoscopic versus Open Inguinal Hernia Repair in Aging Patients: A Propensity Score Matching-Based Retrospective Study.

Objective: Although laparoscopic repair has been widely carried out and promoted due to its minimally invasive advantages, open surgery is still popular compared to elderly patients. This study aims to compare the outcomes of laparoscopic (LIHR) vs open repair of inguinal hernias (OIHR) in elderly patients. Methods: A retrospective analysis of the database was performed to identify elderly patients, from January 2021 through December 2022, who underwent surgery for an inguinal hernia. After a 1:1 propensity score matching (PSM) with a caliper of 0.1 was conducted to balance potential bias, binary logistic regressions were used for categorical and continuous outcomes. Results: After PSM, 78 pairs of elderly patients were enrolled in this study, and there were no significant differences in baseline between LIHR and OIHR groups. Compared to OIHR, univariable and multivariable logistic regression analysis showed that LIHR was independently affected for reducing intraoperative hemorrhage (OR = 0.06, 95% CI: 0.02-0.18, P < 0.001) and shortening postoperative hospitalization time (OR = 0.29, 95% CI: 0.15-0.57, P < 0.001) in elderly patients. Furthermore, LIHR (OR = 0.28, 95% CI: 0.14-0.57, P < 0.001) and age (OR = 0.89, 95% CI: 0.82-0.96, P = 0.002) were independent affecting factors for relieving postoperative pain. Meanwhile, no obvious differences were detected in postoperative complications [LIHR 7.7% (6/78) vs OIHR 14.1% (11/78), P = 0.199]. Conclusion: LIHR was closely associated with reducing intraoperative hemorrhage and shortening postoperative hospitalization time. Whilst LIHR and age were independently affecting factors for relieving postoperative pain.

A Retrospective Study on the Three-Port Technique of Laparoscopic Common Bile Duct Exploration for the Management of Cholelithiasis and Choledocholithiasis.

Background: Laparoscopic cholecystectomy (LC) with laparoscopic common bile duct exploration (LCBDE) is convenient in treating cholelithiasis and choledocholithiasis due to its advantage of accelerated recovery. This retrospective study aimed to summarize the experience of cholelithiasis and choledocholithiasis treatment via three-port approach of LCBDE in Eastern China. Methods: Patients diagnosed with cholelithiasis and choledocholithiasis between July 2019 and October 2021 were included. Patients who received LC+LCBDE+primary suturing of the common bile duct (CBD) via a three-port approach were assigned to the LCBDE-P group, and those who received LC+LCBDE+T-tube drainage of CBD comprised the LCBDE-T group. The measurement data were compared between the two groups. P-values <0.05 indicated statistical significance. Results: A total of 88 patients were divided into two groups: LCBDE-P (n=50) and LCBDE-T (n=38). Multiple logistic regression analysis showed that LCBDE-P is associated with a shorter length of stay (OR=0.115, 95% CI: 0.040-0.329, P<0.001) and lower hospitalization costs (OR=0.120, 95% CI: 0.041-0.357, P<0.001). No significant differences between the two groups were detected in the operation time, intraoperative hemorrhage, clearance rate of CBD stones, postoperative liver function, and postoperative complications (P>0.05). Conclusion: The three-port approach of LCBDE is a safe and feasible strategy for managing cholelithiasis and choledocholithiasis. Compared to LCBDE-T, LCBDE-P reduces the length of hospital stay and medical costs during hospitalization.

A Novel Nomogram for the Preoperative Prediction of Edmondson-Steiner Grade III-IV in Hepatocellular Carcinoma Patients.

Background: Edmondson-Steiner (E-S) grade is a pathological indicator of the degree of hepatocellular carcinoma (HCC) differentiation, and E-S grade III-IV is a poor prognostic factor for HCC patients. Predicting poorly differentiated HCC has essential significance for clinical decision-making. Although some studies have developed predictive models based on magnetic resonance imaging (MRI) and radiomics, radiomic features that require specific software for analysis are impractical for clinical work. This study aims to develop a novel and user-friendly nomogram model to predict E-S grade III-IV. Patients and Methods: Medical data on patients meeting the inclusion criteria were obtained from the Nanjing Drum Tower Hospital HCC database (January 2020 to December 2022). Univariate analysis was used to screen for risk factors associated with E-S grade III-IV. A novel nomogram was established based on the subsequent multivariate logistic regression analysis. The performance of the established model was evaluated through diagnostic ability, calibration, and clinical benefits. Results: Overall, 240 HCC patients were included in this study. Among them, 103 were highly differentiated (E-S grade I-II) HCC and 137 were poorly differentiated (E-S grade III-IV) HCC. A nomogram model that integrated alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb), aspartate aminotransferase to lymphocyte ratio index (ALRI), and macrovascular invasion was established. The novel model had a good diagnostic performance with an area under the curve (AUC) value of 0.763. Meanwhile, the model had a diagnostic accuracy of 72.5%, a sensitivity of 78.1%, and a specificity of 65.1%. The calibration curve showed good calibration of the nomogram model (mean absolute error = 0.043), and the decision curve analysis (DCA) demonstrated that the clinical benefit was provided. Conclusion: Our developed nomogram model could successfully predict E-S grade III-IV in HCC patients, which may be helpful in clinical decision-making.

A decision tree model to predict liver cirrhosis in hepatocellular carcinoma patients: a retrospective study.

Background: The severity of liver cirrhosis in hepatocellular carcinoma (HCC) patients is essential for determining the scope of surgical resection. It also affects the long-term efficacy of systemic anti-tumor therapy and transcatheter arterial chemoembolization (TACE). Non-invasive tools, including aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 (FIB-4), and γ-glutamyl transferase to platelet ratio (GPR), are less accurate in predicting cirrhosis in HCC patients. We aimed to build a novel decision tree model to improve diagnostic accuracy of liver cirrhosis. Patients and Methods: The Mann-Whitney U test, χ2 test, and multivariate logistic regression analysis were used to identify independent cirrhosis predictors. A decision tree model was developed using machine learning algorithms in a training cohort of 141 HCC patients. Internal validation was conducted in 99 HCC patients. The diagnostic accuracy and calibration of the established model were evaluated using receiver operating characteristic (ROC) and calibration curves, respectively. Results: Sex and platelet count were identified as independent cirrhosis predictors. A decision tree model integrating imaging-reported cirrhosis, APRI, FIB-4, and GPR was established. The novel model had an excellent diagnostic performance in the training and validation cohorts, with area under the curve (AUC) values of 0.853 and 0.817, respectively. Calibration curves and the Hosmer-Lemeshow test showed good calibration of the novel model. The decision curve analysis (DCA) indicated that the decision tree model could provide a larger net benefit to predict liver cirrhosis. Conclusion: Our developed decision tree model could successfully predict liver cirrhosis in HCC patients, which may be helpful in clinical decision-making.

Circular RNA in cholangiocarcinoma: A systematic review and bibliometric analysis.

BACKGROUND: Cholangiocarcinoma (CCA) is a common primary liver malignancy with a poor prognosis. Many studies have demonstrated the involvement of circular RNAs (circRNAs) in tumorigenesis and progression. METHODS: Four online databases (PubMed, Web of Science, Embase, and Scopus) were searched on May 04, 2023, for original papers regarding CCA and circRNAs. Bibliometric analysis of included studies was performed on R Studio and GraphPad Prism. RESULTS: Thirty studies were included in the systematic review and bibliometric analysis. The systematic review showed that circRNAs were involved in CCA proliferation, invasion, metastasis, chemotherapy resistance, and other biological processes and were related to the prognosis of patients and many clinicopathological features. Exosomal circRNAs provide a new idea for the early diagnosis of CCA. The bibliometric analysis showed a significant upward trend in the number of studies on CCA and circRNAs. The 30 included papers had 201 authors and were published in 22 English journals. The first paper was published in 2018, and the second paper was the most cited (148 citations). CONCLUSION: This systematic review and bibliometric analysis demonstrates that circRNAs in CCA have not been studied enough. CircRNAs play an important role in the occurrence and progression of CCA. They may become new targets for the diagnosis, treatment, and prognostic monitoring of CCA.

Optimal Control Algorithm for Stochastic Systems with Parameter Drift.

A novel optimal control problem is considered for multiple input multiple output (MIMO) stochastic systems with mixed parameter drift, external disturbance and observation noise. The proposed controller can not only track and identify the drift parameters in finite time but, furthermore, drive the system to move towards the desired trajectory. However, there is a conflict between control and estimation, which makes the analytic solution unattainable in most situations. A dual control algorithm based on weight factor and innovation is, therefore, proposed. First, the innovation is added to the control goal by the appropriate weight and the Kalman filter is introduced to estimate and track the transformed drift parameters. The weight factor is used to adjust the degree of drift parameter estimation in order to achieve a balance between control and estimation. Then, the optimal control is derived by solving the modified optimization problem. In this strategy, the analytic solution of the control law can be obtained. The control law obtained in this paper is optimal because the estimation of drift parameters is integrated into the objective function rather than the suboptimal control law, which includes two parts of control and estimation in other studies. The proposed algorithm can achieve the best compromise between optimization and estatimation. Finally, the effectiveness of the algorithm is verified by numerical experiments in two different cases.

Conversion therapy for massive hepatocellular carcinoma: A case report and literature review.

Key Clinical Message: For potentially resectable HCC, a more aggressive conversion therapy strategy (high-intensity combined with multiple treatment modalities) can be used. Abstract: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. The best treatment for HCC is radical surgical resection, but 70%-80% of patients are ineligible for surgery. Although conversion therapy is an established treatment strategy for various solid tumors, there is no uniform protocol for treating HCC. In this case, we present a 69-year-old male patient diagnosed with massive HCC with Barcelona clinical liver cancer (BCLC) stage B. Because of the insufficient volume of the future liver remnant, we believed radical surgical resection was temporarily impossible. Therefore, the patient received conversion therapy, including four cycles of transcatheter arterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC-Folfox), lenvatinib (8 mg orally once a day), and tislelizumab (an anti-PD-1 antibody, 200 mg intravenously once every 3 weeks). Fortunately, the patient achieved a good treatment response (smaller lesions and improved liver function) and underwent radical surgery finally. There was no clinical evidence of recurrence at 6 months of follow-up. For potentially resectable HCC, this case reveals that a more aggressive conversion therapy strategy (high-intensity combined with multiple treatment modalities) can be used.

Comprehensive treatment for ROS1-overexpressed pulmonary sarcomatoid carcinoma: A case report.

Key Clinical Message: In conclusion author highlights the tumor cell genetic testing or molecular pathological diagnosis plays a key role in the individualized treatment of PSC, which could benefit patients with advanced PSC. Abstract: An uncommon form of non-small-cell lung cancer (NSCLC) with a poor prognosis is pulmonary sarcomatoid carcinoma (PSC). Surgical resection is currently the preferred treatment, but guidelines for adjuvant chemotherapy have not yet been established, especially for the advanced stage. The development of molecular subgroups in the field of tumors may be advantageous to advanced PSC patients with the ongoing progress of genomics and immunology. A 54-year-old man presented to Xishan People's Hospital of Wuxi City with recurrent intermittent dry cough with fever for 1 month. Further examinations suggested the diagnosis of PSC occupying almost the entire right interlobar fissure area combined with malignant pleural effusion (Stage IVa). Pathological examination confirmed the diagnosis of PSC with ROS1 overexpressing via genetic testing. However, after three cycles of chemo-, antiangiogenetic- and immunochemical therapy, the lesion was localized, and pleural effusion disappeared, the patient subsequently received an operation which was performed as R0 resection. Unfortunately, the patient became deteriorated quickly followed by extensive metastatic nodules in the thoracic cavity. Although the patient continued to receive chemo- and immunochemical-therapy, it did not limit the progress of the tumor, leading to widespread metastasis, and eventually died of multiple organ failure. For PSC patients with Stage IVa, chemo-, antiangiogenetic- and immunochemical-therapy performs well in clinical efficacy, and comprehensive panel-based genetic testing may offer PSC patients a somewhat better prognosis. However, blindly implementing surgical treatment may bring harm to the patient and affect long-term survival. It's essential to know the surgical indications precisely by NSCLC guidelines.

The impact of laparoscopic versus open inguinal hernia repair for inguinal hernia treatment: A retrospective cohort study.

Objectives: Although laparoscopic inguinal hernia repair (LIHR) has been widely accepted for treating inguinal hernia, the procedure remains very technical and challenging. The present study aimed to assess the effect of LIHR in relation to operation time, intraoperative hemorrhage and postoperative hospitalization. Methods: A total of 503 patients with inguinal hernia admitted at the Wuxi Rehabilitation Hospital between June 2019 and July 2021 were included in this retrospective cohort study. Binary logistic and linear regressions were used for categorical and continuous outcomes, respectively. The learning curve was drawn by cumulative sum analysis. Results: Multivariate logistic regression analysis identified LIHR as an independent factor associated with prolonging operation time (odd ratio [OR] = 1.750, 95% confidence interval [CI]: 1.215-2.520, p = 0.003) and decreasing intraoperative hemorrhage levels (OR = 0.079, 95 CI: 0.044-0.142, p < 0.001). Multivariate linear regression identified LIHR (Coefficient = -0.702, 95% CI: [-1.050] to [-0.354], p < 0.001) as an independent factor for shortening postoperative hospitalization time. After learning curve, LIHR (OR = 1.409, 95% CI: 0.948 to 2.094, p = 0.090) no longer resulted as a risk factor prolonging operation time. Conclusions: LIHR is an important independent predictive factor for decreasing intraoperative hemorrhage levels and shortening postoperative hospitalization time. Additionally, LIHR does not prolong operation time after the learning curve.

Application of cardiovascular interventions to decrease blood loss during hepatectomy: a systematic review and meta-analysis.

BACKGROUND: Perioperative bleeding and allogeneic blood transfusion are generally thought to affect the outcomes of patients. This meta-analysis aimed to determine the benefits and risks of several cardiovascular interventions in patients undergoing hepatectomy. METHODS: In this systematic review and meta-analysis, randomised controlled trials (RCTs) were searched in the Cochrane Library, Medline, Embase, and Web of Science to February 02, 2023. RCTs focused on cardiovascular interventions aimed at reducing blood loss or blood transfusion requirements during hepatectomy were included. The primary outcomes were perioperative blood loss amount, number of patients requiring allogeneic blood transfusion and overall occurrence of postoperative complications. The secondary outcomes were operating time, perioperative mortality rate, postoperative liver and kidney function and length of hospital stay. RESULTS: Seventeen RCTs were included in the analysis. A total of 841 patients who underwent hepatectomy in 10 trials were included in the comparative analysis between low central venous pressure (CVP) and control groups. The forest plots showed a low operative bleeding volume [(mean difference (MD): -409.75 mL, 95% confidence intervals (CI) -616.56 to -202.94, P < 0.001], reduced blood transfusion rate [risk ratio (RR): 0.47, 95% CI 0.34 to 0.65, P < 0.001], shortened operating time (MD: -13.42 min, 95% CI -22.59 to -4.26, P = 0.004), and fewer postoperative complications (RR: 0.76, 95% CI 0.58 to 0.99, P = 0.04) in the low CVP group than in the control group. Five and two trials compared the following interventions, respectively: 'acute normovolaemic haemodilution (ANH) vs control' and 'autologous blood donation vs control'. ANH and autologous blood donation could not reduce the blood loss amount but greatly decreased the number of patients requiring allogeneic blood transfusion. No benefits were found in the rate of mortality and length of postoperative hospital stay in any of the comparisons. CONCLUSION: Lowering the CVP seems to be effective and safe in adult patients undergoing hepatectomy. ANH and autologous blood donation should be used as a part of blood management for suitable patients in certain circumstances. TRIAL REGISTRATION: PROSPERO, CRD42022314061.

Postoperative complications and short-term prognosis of laparoscopic pancreaticoduodenectomy vs. open pancreaticoduodenectomy for treating pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Although laparoscopic pancreaticoduodenectomy (LPD) has been accepted worldwide for treating pancreatic ductal adenocarcinoma (PDA), it is a very technical and challenging procedure. Also, it is unclear whether LPD is superior to open pancreaticoduodenectomy (OPD). This study summarized the experience and efficacy of LPD for treating PDA in our medical center. METHODS: This retrospective cohort study included patients with PDA admitted at the Affiliated Hospital of Jiangnan University from October 2019 and January 2021. Patients received either LPD or OPD. Clinical outcomes (operation time, duration of anesthesia, intraoperative hemorrhage), postoperative complications, and short-term outcomes were compared. Cox proportional hazard model and Kaplan-Meier method were used to analyze overall survival (OS) and progression-free survival (PFS). RESULTS: Among the PDA patients, 101 patients underwent surgical treatment, 4 patients converted from LPD to OPD, and 7 of them received conservative treatment. Forty-six patients were cured of LPD, and 1 of them died shortly after the operation. Moreover, 44 patients received OPD, and there were 2 postoperative deaths. There were significant differences in the location of the operation time, duration of anesthesia, postoperative hemorrhage, abdominal infections, and postoperative pneumonia between the two groups (all p < 0.05). Multivariate analysis showed that LPD was an independent factor negatively correlated with the incidence of pneumonia (relative risk (RR) = 0.072, 95%CI: 0.016-0.326, p = 0.001) and abdominal infection (RR = 0.182, 95%CI: 0.047-0.709, p = 0.014). Also, there were no differences in OS (hazard ratio (HR) = 1.46, 95%CI: 0.60-3.53, p = 0.40) and PFS (HR = 1.46, 95%CI: 0.64-3.32, p = 0.37) at 12 months between the two groups. CONCLUSIONS: LPD could be efficacy and feasible for managing selected PDA patients. Also, LPD has a better effect in reducing postoperative pneumonia and abdominal infection compared to OPD.

Ultrashort pulse laser ablation in liquids: probing the first nanoseconds of underwater phase explosion.

The ultrafast pump-probe microscopy has shed new light on the complex dynamics of laser-induced explosive phase transformations and highlighted the importance of close integration of experimental, computational, and theoretical efforts.

Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.

Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.

Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion.

Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice.

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Fibrotic Events in the Progression of Cholestatic Liver Disease.

Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.