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.

Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

Ayudas para apoyar a grupos de investigación del sistema Universitario Vasco (IT971-16);

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

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BackgroundThe etiological factor for intrahepatic cholangiocarcinoma (ICC) is not clear. Although it has been widely accepted that intrahepatic biliary tree stone is associated with increased risk of ICC, the role of extrahepatic biliary tree stone in the incidence of ICC is controversial. In the present study we aim to evaluate the association between pre-existing choledocholithiasis and cholecystolithiasis and the risk of ICC.MethodsPubMed, Embase, and Web of Science were searched to identify cohort and case–control studies on the association between choledocholithiasis or cholecystolithiasis and the risk of ICC. Studies that met the inclusion criteria were subjected to a meta-analysis performed with Stata statistical software. Either a fixed or random effect model was used, depending on the heterogeneity within the studies. Egger’s test was performed to assess publication bias.ResultsSeven case–control studies met our inclusion criteria. Of the 123,771 participants, 4763 (3.85 %) were patients with ICC, and 119,008 were tumor-free controls. The presence of pre-existing bile duct stones (choledocholithiasis alone or choledocholithiasis accompanied by hepatolithiasis) was associated with the risk of ICC (odds ratio [OR] 17.64, 95 % confidence interval [CI] 11.14–27.95). Even the presence of choledocholithiasis alone (in the absence of hepatolithiasis) was associated with a high risk of ICC (OR 11.79, 95 % CI 4.17–33.35). Cholecystolithiasis may possibly contributed to the incidence of ICC (OR 2.00, 95 % CI 1.16–3.42), with large heterogeneity within studies (I2 = 78.5 %).ConclusionsBile duct stones including choledocholithiasis are important risk factors for ICC. Careful surveillance of patients with extrahepatic biliary tree stone should be considered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1870-0) contains supplementary material, which is available to authorized users.

Pulsed laser ablation in liquids (PLAL) is a promising technique for the generation of colloidal alloy nanoparticles that are of high demand in a broad range of fields, including catalysis, additive manufacturing, and biomedicine. Many of the applications have stringent requirements on the nanoparticle composition and size distributions, which can only be met through innovations in the PLAL technique guided by a clear understanding of the nanoparticle formation mechanisms. In this work, we undertake a combined computational and experimental study of the nanoparticle formation mechanisms in ultrashort PLAL of Ag/Cu and Cu/Ag bilayer thin films. Experimental probing of the composition of individual nanoparticles and predictions from large-scale atomistic simulations provide consistent evidence of limited mixing between the two components from bilayer films by PLAL. The simulated and experimental distributions of nanoparticle compositions exhibit an enhanced abundance of Ag-rich and Cu-rich nanoparticles, as well as a strongly depressed population of well-mixed alloy nanoparticles. The surprising observation that the nanoscale phase separation of the two components in the bilayer films manifests itself in the sharp departure from the complete quantitative mixing in the colloidal nanoparticles is explained by the complex dynamic interaction between the ablation plume and liquid environment revealed in the simulations of the initial stage of the ablation process. The simulations predict that rapid deceleration of the ablation plume by the liquid environment results in the formation of a transient hot and dense metal region at the front of the plume, which hampers the mixing of the two components and, at the same time, contributes to the stratification of the plume in the emerging cavitation bubble. As a result, nanoparticles of different sizes and compositions are produced in different parts of the emerging cavitation bubble during the first nanoseconds of the ablation process. Notably, the diameters of the largest nanoparticles generated in the simulations of the initial stage of the ablation process are more than twice larger than the thickness of the original bilayer films. This observation provides a plausible scenario for the formation of large nanoparticles observed in the experiments. The conclusion on limited elemental mixing in the nanoparticles is validated in simulations of bilayers with different spatial order of Cu and Ag layers, even though the two systems exhibit some notable quantitative differences mainly related to the different strength of electron−phonon coupling in Cu and Ag. Overall, the results of this study provide new insights into the formation mechanism of bimetallic nanoparticles in ultrashort PLAL from thin bilayer targets and suggest that the formation of alloy nanoparticles from immiscible elements may be hampered for targets featuring distinctive elemental segregation.

Targeted inhibition of the c-Jun N-terminal kinases ( JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO) hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO Δhepa /JNK1 Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO Δhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO Δhepa (NEMO Δhepa /JNK Δhepa ) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO Δhepa /JNK1 Δhepa mice recapitulated the phenotype of NEMO Δhepa /JNK Δhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO Δhepa mice. We found that NEMO Δhepa /JNK Δhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf )-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMO Δhepa /JNK Δhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis. (Hepatology Communications 2020;4:834-851). Bile duct hyperplasia and aberrant cholangiocyte growth can result in hepatic cystogenesis, differentially diagnosed on the basis of cholangioma, cholangiofibrosis, intrahepatic cholangiocarcinoma (CCA), and oval cell hyperplasia. (1,2) CCA, a malignancy that arises in the setting of chronic inflammation of biliary epithelium cells, has an increasing incidence and is the second most common primary Abbreviations: α-SMA, alpha smooth muscle actin; Δhepa, hepatocy...